Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cord blood research, banking, and transplantation: achievements, challenges, and perspectives


The first hematopoietic transplant in which umbilical cord blood (UCB) was used as the source of hematopoietic cells was performed in October 1988. Since then, significant achievements have been reported in terms of our understanding of the biology of UCB-derived hematopoietic stem (HSCs) and progenitor (HPCs) cells. Over 40,000 UCB transplants (UCBTs) have been performed, in both children and adults, for the treatment of many different diseases, including hematologic, metabolic, immunologic, neoplastic, and neurologic disorders. In addition, cord blood banking has been developed to the point that around 800,000 units are being stored in public banks and more than 4 million units in private banks worldwide. During these 30 years, research in the UCB field has transformed the hematopoietic transplantation arena. Today, scientific and clinical teams are still working on different ways to improve and expand the use of UCB cells. A major effort has been focused on enhancing engraftment to potentially reduce risk of infection and cost. To that end, we have to understand in detail the molecular mechanisms controlling stem cell self-renewal that may lead to the development of ex vivo systems for HSCs expansion, characterize the mechanisms regulating the homing of HSCs and HPCs, and determine the relative place of UCBTs, as compared to other sources. These challenges will be met by encouraging innovative research on the basic biology of HSCs and HPCs, developing novel clinical trials, and improving UCB banking both in the public and private arenas.

The first 30 years

On October 6, 1988, the first hematopoietic transplant in which human umbilical cord blood (UCB) was used as the source of hematopoietic cells was performed at Hopital Saint-Louis, in Paris, France [1]. The patient was a 5-year old boy with Fanconi anemia, a hereditary bone marrow failure syndrome [2], who received cells from his human leukocyte antigens (HLA)-identical sister. The transplant was a success, and today that UCB transplant recipient is alive and well, with complete cure of the hematological manifestations of the disease. Cord blood transplantation was motivated and scientifically supported by pivotal laboratory studies at the Indiana University School of Medicine, together with collaborators in New York and North Carolina, where the initial characterization of UCB-derived hematopoietic stem (HSCs) and progenitor (HPCs) cells was performed that suggested that a single-UCB unit may contain sufficient numbers of such immature cells for their use in clinical settings [3]. Both reports appeared in the specialized international literature in 1989, and at that time, very few, if any, would likely have thought that UCB was going to have such a significant impact both in stem cell research and in hematopoietic transplantation. In fact, in those years, editorial articles in some of the most prestigious journals indicated that cord blood transplantation would not last due to severe problems such as maternal T-cell contamination, which would lead to lethal graft-versus-host-disease (GVHD), and inadequate HSC dose, resulting in excess graft failure and delayed lympho-hematopoietic recovery, limiting its use to very young children. Surrounded by uncertainty and controversy a new medical and scientific field was born. During the following years significant advances were reported in the biologic, banking, and transplantation arenas. The purpose of this review article is to highlight recent major advances in the UCB field, discuss the status of UCB transplants (UCBTs), and present our perspective on the future of this HSC source.

UCB biology

Studies by several laboratories aimed at understanding the basic biology of cord blood cells demonstrated that UCB is a rich source of HSCs and HPCs. Indeed, the relative frequencies of both severe combined immunodeficiency (SCID)-repopulating cells (self-renewing cells capable of long-term repopulation of the hematopoietic system in immunodeficient mice; actual HSCs by our current standard definitions) and colony-forming cells (progenitors capable of giving rise to hematopoietic colonies of different cell lineages in semisolid medium) are significantly higher in UCB than in adult bone marrow or mobilized peripheral blood [4,5,6]. The levels of early progenitor cells—i.e., those giving rise to mixed myelo-erythroid colonies and those producing large erythroid colonies—are particularly increased in UCB samples. Moreover, the in vivo hematopoietic reconstitution capacity of UCB-derived HSCs in immune-deficient sublethally irradiated mice is superior to that of adult marrow cells [7, 8], and cord blood HSCs and HPCs possess higher in vitro proliferation and expansion potentials than their adult counterparts (Fig. 1) [9].

Fig. 1

Differences between CD34+ cells from UCB and adult sources (bone marrow/mobilized peripheral blood). a Expression of the CD34 antigen in hematopoietic cells from UCB and adult sources. Results represent the levels of expression of the CD34 antigen per cell and correspond to mean ± S.D. (n = 14). b Comparison of the mean telomere length in UCB and adult (mobilized peripheral blood) cells. Data represent mean telomere length, as determined by single-telomere length analysis (STELA) and correspond to mean ± S.D. of six UCB samples and three MPB samples studied. c Proliferation kinetics of CD34+ Lin cells from UCB and adult sources in cytokine-supplemented, serum-free cultures. Cells were cultured in the presence of a combination of early- and late-acting recombinant cytokines, and the generation of total nucleated cells was determined throughout culture. Results represent mean ± S.D. (n = 14–21), and correspond to the fold-increase observed at different time points, as compared to day 0, where cell number = 1. Data presented are based on data from ref. [11]

The reasons for these latter observations are still not fully understood; however, several mechanisms have been implicated [10, 11]. UCB cells express higher levels of the CD34 antigen than adult cells (Fig. 1). Telomeres—which seem to act as mitotic clocks—are, in average, 4 kb longer in UCB HSCs than in adult HSCs (Fig. 1). UCB cells exit the G0/G1 phase of the cell cycle more rapidly than their adult counterparts do, and thus, they are capable of performing more cell divisions than the latter when cultured under the same conditions. Certain transcription factor pathways, such as NF-kB, are overrepresented in UCB cells, as compared to adult cells, and this seems to have a significant impact on the physiology of neonatal cells (higher self-renewal capacity). Gene-expression profiles suggest that UCB cells show features of an activated state relative to adult cells. Finally, UCB cells seem to display an increased autocrine production of certain cytokines, such as granulocyte-macrophage colony-stimulating factor and IL-3.

Considering their elevated in vitro growth potential, HSCs and HPCs from UCB can be significantly expanded using a wide variety of experimental approaches. These, include liquid cultures supplemented with mixtures of recombinant stimulatory cytokines, acting at early, intermediate and late levels of hematopoiesis, together with feeder stromal cells, metal chelators, Notch ligands, epigenetic modifiers, or small molecules that favor self-renewal [12,13,14,15]. Although significant variability has been reported, depending on the experimental system used, HSCs and HPCs numbers have been increased many fold [13]. As we shall see below, ex vivo expansion of stem and progenitor cells has become of significant relevance in clinical settings.

It is noteworthy that besides being a rich source of HSCs and HPCs, UCB is also a source of non-HSCs with broad proliferation and differentiation capacities. These, include mesenchymal stromal cells (MSCs; capable of producing cells of the osteogenic, adipogenic, and chondrogenic lineages) and unrestricted somatic stem cells (USSCs; a primitive cell type that expresses some features of pluripotent embryonic stem cells). UCB MSCs share immunophenotypic and functional properties with those derived from adult marrow [16], although some differences have been observed between both types of MSCs in terms of differentiation capacities and derivation efficiency [17, 18]. Regarding USSCs, some in vitro studies have shown that those obtained from UCB can give rise to osteoblasts, chondroblasts, and adipocytes, as well as hematopoietic and neural cells [19]. In vivo animal studies, on the other hand, have demonstrated that such cells can produce mesodermal and endodermal cell lineages [19]. It is important to point out, however, that further characterization of USSCs, in terms of their identity and function, is still required.

UCB banking

Since the first studies [3], it was clear that UCB cells could be stored at −196 °C and then thawed for their use in the clinic. In fact, the first five HLA-matched sibling UCBTs performed used cord blood cells that had been stored in a proof-of-principle cord blood bank in a laboratory setting [1, 3, 20, 21]. If properly cryopreserved, cord blood units can be stored for more than 20 years without compromising their biologic properties [22]. The fact that UCB units can be stored prompted several public organizations and institutions, as well as private companies, to create UCB banks. Thus, both public and private (family) UCB banks have been established. The first public cord blood bank was established in New York in 1993; today, around 800,000 UCB units are being stored in public UCB banks from 45 countries, and it is estimated that over 4 million units are being cryopreserved in family banks from almost 100 countries [23]. Such numbers indicate significant clinical achievements supported by intensive basic research.

UCB banking has resulted in reduced searching times for unrelated donors, as compared to adult sources. Indeed, whereas the median search time for unrelated marrow or mobilized peripheral blood donors through the National Marrow Donor Program of the USA is 3–4 months, the median search time for unrelated UCB can be as fast as 12 days [24]. In some cases, such a difference may be critical for treatment outcome. The numbers of units that need to be kept in a bank to satisfy the public demand differ depending on the characteristics of the population; thus, the release rate among banks shows great variability. Worldwide, release rates at public banks are usually low. According to recent registries, there are over 800,000 units stored in public banks around the world and the number of units released is about 4100 per year [23]. Interestingly, some banks, such as the ones in Besancon, Mexico City (IMSS), and Tokyo report high release rates (10.0–16.0% of their inventory). Release rates for private banks are even lower (there are over 4 million units stored worldwide and 130 units, in average, are released annually) [23]. Single institutions and multinational organizations, as well as government regulatory agencies, such as the National Bone Marrow Donor Program, NETCORD, and FACT, have been actively involved in establishing regulatory guidelines for optimizing UCB collection, processing and banking [25, 26]. It is important to point out that such organizations have also promoted the creation of registries, such as Eurocord, for the validation and evaluation of the units that have been released for transplantation and the transplant outcomes.

UCB transplantation

The first UCBTs performed in Paris and Cincinnati were in pediatric patients with hereditary bone marrow failure (Fanconi anemia). The first transplant in a patient with leukemia (a child with juvenile myelomonocytic leukemia) took place in Baltimore in 1990 [20], and 5 years later, the first adult leukemia patient was transplanted [27]. To date, it is estimated that over 40,000 UCBTs have been performed worldwide [28]. In the pediatric arena, the results reported for related UCBTs for the treatment of patients with leukemia are as good as those using bone marrow from sibling donors. In the HLA-matched setting, UCBTs have been used successfully with transplant-related mortality and 3-year overall survival rates statistically similar to those found in bone marrow transplants [29]. For bone marrow failure and hemoglobinopathies, results of UCBTs seem to be comparable to those of marrow transplants.

In the unrelated setting, UCBTs are comparable to superior as compared to marrow transplants. For malignant diseases, they have shown overall survival at 2 years of around 47%; neutrophil and platelet engraftment was observed in around 80% and 65% of the patients, respectively, and there was low incidence of GVHD [30]. Results for non-malignant diseases (immunodeficiencies and metabolic syndrome) have also been good, with neutrophil and platelet engraftments in around 87% and 73% of patients, respectively. In patients with bone marrow failure syndromes, however, the overall survival rates are around 49% after 3 years [31]. Overall, the experience generated to date suggests that for hematopoietic transplants in children, a 6/6 matched UCB unit should be considered as the first line source of HSCs and HPCs, if the cell dose is adequate. However, since the probability of finding such a donor unit is low (around 10%), alternative options would be an 8/8 matched unrelated bone marrow, 5/6 mismatched unrelated UCB, or 4/6 mismatched unrelated UCB [32].

Transplantation of UCB cells in adult patients has shown that UCB could be used as an alternative source of HSCs and HPCs when an HLA-matched unrelated adult donor is lacking and when transplant is urgently needed. Most studies reported to date have shown comparable survival rates and lower grade 2–4 GVHD, as compared to marrow or peripheral blood transplants [32,33,34]. However, there is also extensive evidence for delayed engraftment and, in some cases, lower survival rates, as well as a higher transplant-related mortality, as compared to marrow or mobilized peripheral blood transplants [32,33,34]. Such outcomes are in part related to the reduced absolute numbers of cells in a cord blood unit. That is to say, each individual UCB unit has a fixed cell number, which is usually <30% of the cell number that can be obtained from a marrow or mobilized peripheral blood collection. Thus, adult patients receive a low cell dose per kg of body weight, which results in engraftment times of >20 days for neutrophils, and >40 days for platelets. Hence, morbidity and mortality in adult patients are usually higher after UCBTs. It is noteworthy, however, that UCBTs have important advantages over adult sources, such as a faster availability and less restrictions in HLA matching, as well as reduced GVHD incidence.

The experience generated during the last two decades for adult patients indicates that, as compared to matched adult marrow or mobilized peripheral blood transplants, mismatched UCBTs result in delayed engraftment, decreased incidence of GVHD, and similar relapse rates. Disease-free survival and transplant related mortality are comparable to those seen in adult marrow transplants [35]. To date, 8/8 HLA-matched bone marrow still is the “gold standard” for alternative donor hematopoietic transplants. However, UCB is a reasonable option, especially in those patients that do not have such a donor available and those in whom the time to transplant is critical, such that waiting for an unrelated marrow would not be a realistic option for the patient.

Current challenges

Three decades after the first UCBT, the cord blood field has grown in a significant manner and its positive impact in medicine has been evident from many different points of view. In biological terms, HSCs and HPCs from UCB have been shown to be qualitatively superior as compared to their adult counterparts (i.e., higher frequency, as well as increased self-renewal, proliferation, and expansion capacities) and they have become invaluable tools for stem cell research. In practical terms, UCB cells can be easily obtained without compromising the mother or the newborn, and such cells can be long-term stored for clinical purposes. Today, UCB banking has expanded to the point that the number of units in public and private banks worldwide is approaching the 1 and 5 million figures, respectively. The number of UCBTs performed to date is over 40,000, and over 80 disorders are currently being treated, including hematologic malignancies—such as leukemia—hereditary and acquired marrow failure syndromes, hemoglobinopathies, and immunodeficiencies, as well as a wide variety of nonhematologic disorders [23]. It is noteworthy that UCB cells have also been used in numerous regenerative medicine clinical trials [23].

While UCB is immediately available and associated with less GVHD despite the high degree of HLA mismatch, limiting numbers of HSCs and HPCs in UCB units have resulted in delayed neutrophil and platelet recovery, and suboptimal engraftment, particularly in adult patients. This, in turn, has resulted in longer initial hospitalization and increased resource utilization, as well as increased graft costs. Some institutions (e.g., University of Minnesota, Memorial Sloan-Kettering Cancer Center, and Fred Hutchinson Cancer Center) have found no significant differences in results between UCBTs and bone marrow/mobilized peripheral blood transplants for adult patients. However, in the majority of the studies reported to date marrow/peripheral blood transplants showed faster hematologic and immunologic recoveries and better engraftment, as compared to UCBTs. Accordingly, a major focus in the UCB transplantation field has been to enhance engraftment, so the risk of infection and the cost of the procedure can be potentially reduced. This is an issue in which different areas of research, including biomedical and clinical approaches, converge.

In adult patients, neutrophil engraftment after marrow or mobilized peripheral blood transplants can be reached in 13–18 days; in contrast, neutrophil engraftment after UCBTs is reached after >20 days [32]. A relatively low-total nucleated cell content, including HSCs and HPCs, in a UCB unit has been recognized as the principal reason for delayed hematopoietic recovery and poorer engraftment. A cell dose of 2.5–3.0 × 107 total nucleated cells per kg of the patient’s body weight has been widely established as the minimum cell number necessary for UCB engraftment. Although this is a cell dose usually achievable with a single-UCB unit if the patient is a young child, a single unit is often not enough for adults over 60 kg of weight. Thus, one of the major challenges with UCB is to find ways to increase the number of HSCs and HPCs or alternatively, enhance the proportion of HSCs that successfully home to the marrow microenvironment without altering the absolute number of cells infused [36,37,38].

Increasing HSCs and HPCs numbers

Different approaches have been adopted as strategies to increase the absolute number of UCB cells transplanted. These include the coinfusion of two different unmanipulated UCB units in a single patient; the coinfusion of UCB cells together with T cell-depleted haploidentical peripheral blood; and the coinfusion of UCB cells together with HSCs and HPCs from a different UCB unit that has been previously ex vivo expanded.

Double-unit transplants

The concept of double-unit transplantation was initially proposed as a strategy to evaluate the safety and efficacy of ex vivo expansion culture. Specifically, the concept was to expand one unit with a second unexpanded unit infused as a safety measure should the cultured cells have reduced engraftment potential. Because the units were from two genetically distinct donors, the contribution of the expanded unit to hematopoietic recovery could be monitored long-term. However, prior to evaluating the expanded cells, the safety of the approach was evaluated with two partially HLA matched unmanipulated units that ultimately led to its widespread use particularly in adults for whom an adequately dosed single unit could not be identified [39]. Since that time, the safety of this procedure has been clearly established, in spite of the initial concern that the two units might react against each other. The overall outcomes have been comparable to those seen after a matched-related or a match-unrelated donor marrow transplant [40, 41]. In some settings, the benefits of such double-unit transplants seem to be not only clinical, but economical in the context of quality-adjusted life years. A recent study performed in France demonstrated that double cord blood transplants were more cost-effective than single-cord transplants, as they were associated with better outcomes when adjusted for life years [42].

Interestingly, in approximately 90% of patients, one unit predominates often due to the active rejection of one unit by the other but also by a competitive repopulation advantage potentially due to greater numbers of viable CD34+ cells in one unit. Different studies have suggested that early CD3+ cell engraftment, a high post-thaw CD34+ cell content, and the chimerism in CD4+, CD8+, and NK cell subsets can predict the winning unit [43]. At this time, it is important to point out that no single absolute predictor exists; however, what seems to be clear is that the winning UCB unit establishes itself early in the transplant process. Anecdotally, engraftment of both units is associated with faster recovery and poorer survival most often due to an increased risk of relapse in patients transplanted with hematological malignancy.

UCB plus haploidentical donor transplants

A second approach has been undertaken in patients that are candidates for UCB transplantation but the UCB unit to be infused has a low cellularity. This approach consists of infusing the UCB unit together with mobilized peripheral blood-derived CD34+ cells from a (haploidentical) third party donor. This type of transplant has been conducted using both mieloablative and reduced-intensity conditioning regimens. The results reported so far have shown early hematopoietic recovery, low incidence of GVHD, and durable remissions [44,45,46]. Low frequency of delayed opportunistic infections, reduced transfusion requirements, shortened length of stay, and good long-term outcomes were also observed [46]. Interestingly, in the majority of patients, there was an early haploidentical engraftment that was replaced by durable UCB engrafment. In patients subjected to mieloablative conditioning, the median times to neutrophil and platelet recovery were 10 and 33 days, respectively. In patients subjected to reduced intensity, the median times to neutrophil and platelet recovery were 11 and 19 days, respectively. More recently, UCB-Haplo transplants have been performed using double-UCB unit transplants [47, 48].

UCB-Haplo transplants represent a good alternative for a significant proportion of patients and results have been encouraging. It is noteworthy, however, that availability of suitable haplo donors may be compromised in some patients, particularly in African ancestry patients. Indeed, in a recent study in which 89 patients were included, it was found that around 7% of patients in need of a hematopoietic transplant do not have a suitable haplo donor [48]. Thus, haplo availablity cannot be assumed in all adults without 8/8 HLA-matched unrelated donors. The need to workup multiple donors per patient can increase the cost of the whole procedure.

Ex vivo cell expansion

From the pioneering work of several investigators, it was clear that the in vitro growth of HSCs and HPCs depends on the presence of early-, intermediate-, and late-acting hematopoietic cytokines [49]. Accordingly, initial efforts to expand primitive hematopoietic cells from UCB were based on the use of different combinations of recombinant hematopoietic cytokines, and were focused on the expansion of HPCs, assessing increments in CFCs and CD34+ cell numbers [50,51,52,53,54]. Since early-acting cytokines favor self-renewal, different combinations of growth factors, including stem cell factor, FLT3-ligand, and thrombopoietin, were extensively tested. Those studies demonstrated significant increments in the numbers of HPCs; however, real increments in the numbers of actual HSCs were controversial [55, 56].

In keeping with the fact that the in vivo development of HSCs and HPCs takes place in close association with microenvironment cells and their products [57,58,59], ex vivo systems were established in which stromal cells were used as feeder layers, to allow for the expansion of primitive hematopoietic cells, including HSCs. To this purpose, different types of stromal cells have been assessed, including primary whole bone marrow stroma, endothelial cells, stroma cell lines, and MSCs, the latter from different tissues [60,61,62,63]. These studies have demonstrated that stromal cells, particularly MSCs, are capable of promoting the ex vivo expansion of primitive cells in a process that may involve both cell-to-cell-contact and cytokine secretion.

More recently, a diverse range of different molecules have also been tested in combination with recombinant cytokines and have demonstrated significant positive effects on the ex vivo expansion of immature UCB cells (HSCs and different types of HPCs). One of the first such molecules was tetraethylenepentamine (TEPA), a copper chelator [64]. Delta-like ligand-1 (DL1), a ligand for Notch, has also been studied for several years in different ex vivo systems and presented to the hematopoietic cells either as a single molecule or expressed on the surface of stromal cells [65, 66]. Other small molecules include nicotinamide, a form of vitamin B3 [67]; StemRegenin-1 (SR1), a purine derivative that acts via engagement of the aryl hydrocarbon receptor [68]; UM171, a pyrimidoindole derivative [69]; OAC1, a small compound that activates the pluripotent transcription factor Oct4 [70]; a PPAR-γ antagonist that enhances glycolysis [71]; and HDAC inhibitors, such as valproic acid [72].

Some of these expansion approaches have already been taken to the clinic. Indeed, the first clinical trials with ex vivo expanded cells were initiated over 15 years ago. In such studies, UCB cells expanded with recombinant cytokines (SCF, FL, TPO, and erythropoietin) were infused into patients, and although no positive effects were observed in terms of myeloid, erythroid, or platelet engraftment, those studies concluded that the procedure was feasible and safe [73, 74]. Further trials involving cells expanded with TEPA, MSCs, DL1, nicotinamide, or SR1 have also been reported [65, 75,76,77,78]. Among them, those in which cells were expanded with MSCs, DL1, nicotinamide, or SR1 have shown encouraging results, since in all of them there was a significant expansion of CD34+ cells (CD133+ cells for the study using nicotinamide), and significant reductions in the times to engraftment were observed compared to historical controls.

A few remarks regarding the above studies should be considered. In most of the studies reported to date, the expanded cells have been infused into patients together with unmanipulated cells. Some investigators fear that the expansion protocols may induce increments in HPC numbers at the expense of HSC levels or that the ex vivo expansion conditions used induce some changes in the biology of the expanded cells, so that they are unable to persist long-term post-transplant. Regarding this last point, it is noteworthy that a recent study showed that the cells being generated in vitro differ significantly—in terms of gene transcription patterns and in vitro growth capacities—from the cells obtained directly from fresh UCB units [79]. Thus, we still need to understand in greater detail the dynamics and mechanisms involved in this process.

It is also important to point out that some studies have recently been performed in which UCB cells expanded with nicotinamide, UM171 or SR1 were used as stand-alone grafts. Just recently, Horwitz and colleagues reported on the first of such trials. The study consisted on assessing the safety and efficacy of a UCB graft that was previously ex vivo expanded in the presence of nicotinamide. The authors observed a reduction in the median time to neutrophil and platelet recoveries of 9.5 and 12 days, respectively. The study established the feasibility, safety, and efficacy of an ex vivo nicotinamide-expanded UCB unit as a stand-alone graft [80]. In the case of UCB cells expanded in the presence of UM171 or SR1 and transplanted into hematologic patients as stand-alone grafts, we need to wait for the first reports in order to determine their safety and efficacy.

Finally, ex vivo expansion of UCB cells should be considered not only for increasing the numbers of HSCs and HPCs, but also for expanding particular mature cell subsets, such as the ones of the immune system (e.g., CD4+, CD8+, and NK cells). This could have important implications, since it has been suggested that some of these populations might be involved in the engrafting process and immune reconstitution after single- or double-unit transplants [37]. Thus, they may be used to make UCB engraftment a more efficient process.

Approaches to enhancing homing

When transplanted into patients, hematopoietic cells are infused via intra venous (i.v.) injection. Thus, circulating immature cells (including HSCs and HPCs) need to migrate and home to the bone marrow (which involves transendothelial migration) and establish themselves in a microenvironment or niche [57, 58]. Then, they will proliferate and expand and finally, they will differentiate and give rise to mature cells. It has been observed that not all transplanted cells reach the marrow microenvironment; in fact, a significant proportion of such cells never get to the marrow [81]. Thus, increasing the homing capacity of stem and progenitor cells is another way to improve UCBTs [82]. To this end, different approaches have been followed.

Intra-femoral injection

By injecting hematopoietic cells directly into the medullary cavity there would be no need for cell homing to the marrow; however, the cells will still need to migrate within the marrow cavity to find their niche. Studies in animal models have shown that although there is an early advantage for marrow injected cells over those i.v. infused, there is no clear long-term benefit after intra-bone injection [83]. When UCB cells have been injected directly into the patient’s marrow the procedure is well tolerated; however, median engraftment times remain >20 days [84, 85]. Nevertheless, some clinical benefits have been observed in some patients, such as reduction in GVHD rates, an early platelet recovery and a low-relapse rate [84, 85]. Thus, this approach may be a good alternative for particular patients.

Manipulation of the SDF-1-CXCR4 axis by inhibiting DPP4

One key element in the homing process is the interaction between stroma cell derived factor-1 (SDF-1, also known as CXCL12) and its ligand, CXCR4. SDF-1 is a potent chemoattractant produced and secreted by a variety of stromal cells, whereas CXCR4 is expressed by different cell types, including HSCs and HPCs. Interestingly, SDF-1 can be truncated by an enzyme known as dipeptidylpeptidase 4 (DPP4); the resulting molecule lacks chemotactic activity and can block the chemotactic activity of full-length SDF-1 [86]. Inhibition of DPP4 or deletion of the dpp gene in mice augments chemotaxis of HPCs, and enhances the homing and engrafting ability of marrow HSCs [87]. Based on this information, clinical trials have been performed in which sitagliptin, an FDA-approved DPP4 inhibitor was orally administered in patients with leukemia receiving a single UCB unit [88,89,90]. The results of these trials indicate that this safe and relative simple and inexpensive procedure can induce neutrophil engraftments in patients at <20 days [82]. Future studies will be needed to determine the effect of sitagliptin on the engraftment of platelets and immune cells. If results are positive, sitagliptin may become a very simple way to enhance UCB engraftment.


Fucosylation (addition of fucose sugar units to a particular molecule) has been described as a key mechanism within the homing and engraftment process [82]. Since there seems to be reduced levels of fucosylation of P-, and E-selectin ligands on UCB cells, it was postulated that increasing the fucosylation levels on the surface of cord blood cells, including HSCs and HPCs, would improve the engraftment capacity of such cells during transplantation [91]. When this hypothesis was tested in clinical trials, it was observed that the median time to neutrophil engraftment was 17 days compared to historical control values of 26 days; platelet engraftment was reached at a median of 35 days compared to historical controls of 45 days [92].

Prostaglandin E2

Prostaglandin E2 (PGE2) has long been recognized as a modulator of hematopoiesis [93, 94], and it has also been shown to enhance homing and engraftment of HSCs and HPCs in a mouse model [95]. Based on such observations, a clinical trial was conducted in which patients undergoing a nonmyeloablative preparative regimen received a PGE2-primed UCB unit along with an unmanipulated UCB unit (double-unit transplant). The median time to neutrophil engraftment was 17.5 days versus 21 days for historical controls [96].

Other approaches

Based on the observation that priming CD34+ hematopoietic cells with complement fragment 3a improves homing and engraftment in preclinical models, UCB cells were primed with such a molecule and infused into patients with hematological malignancies, together with an unmanipulated UCB unit in a double UCB transplantation setting after nonmyeloablative conditioning. Although no major adverse effects were observed, and mortality and survival were not affected, C3a priming did not skew chimerism toward the treated unit [97].

Besides the approaches presented above, it has been reported that treating UCB cells with short-term hyperthermia prior to transplantation could improve cell engraftment in an animal model [98]. Evidently, this will have to be tested in clinical settings as a single procedure or in combination with other approaches. It has also been shown that specific HDAC5 inhibition upregulates CXCR4 surface expression in human HSCs and HPCs. This results in enhanced SDF-1/CXCR4-mediated chemotaxis and increased homing, with elevated SCID-repopulating cell frequency and enhanced long-term engraftment in NSG mice [99]. This study demonstrates a negative epigenetic regulation of HSC homing and engraftment by HDAC5. Similarly, glucocorticoid hormone signaling has been identified as an activator of CXCR4 expression in human UCB-derived HSCs and HPCs. Thus, short-term glucocorticoid pretreatment of human UCB cells increased SDF-1/CXCR4-mediated chemotaxis, homing and long-term engraftment in primary and secondary NSG mice [100].

The economic challenge

Beyond the biological, practical, and clinical advantages of UCB as compared to adult marrow or mobilized peripheral blood as a source of hematopoietic cells for transplantation, many specialists in the field have recognized major economic concerns related to UCB banking and transplantation. How to make UCB transplantation a more affordable therapeutic option? This question is of particular relevance, since UCB is being used less frequently in the adult setting (from 2010 to 2018 the number of UCBTs has fallen 34%; Fig. 2) due, at least in part, to high acquisition costs and greater healthcare resource utilization in the early transplant period [36, 101].

Fig. 2

Approximate trends of the relative frequencies of hematopoietic cell transplants (between the years 1980 and 2016) according to the source of hematopoietic cells. UCB, umbilical cord blood; BM, adult bone marrow; mPB, adult mobilized peripheral blood. Data presented are based on data from refs. [23] and [36]

A survey performed by the World Marrow Donor Association in 2013 indicated that only 16 of 139 public cord blood banks operating worldwide at that time were financially sustainable [WMDA Annual Report Cord Blood Bank/Registries 2013]. While decreasing sales (i.e., utilization) play the most significant role in the lack of financial sustainability in nearly 90% of UCB banks, increasing costs related to unit licensure and poor collection efficiency (i.e., discard rates for units not meeting the higher nucleated cell count requirements) are also important factors. It is estimated that during the last decade, an average of 3500 UCB units per year had been released [23]. This represents around 0.5% of the number of units in the global inventory [23]. The current cost of a UCB unit in developed countries is USD $30,000–$60,000 [102, 103]. Expectedly, the use of two UCB units for recipients without an adequate single-unit transplant increases the cost dramatically. For these reasons, the UCB banking industry relies on subsidies from governmental agencies, philanthropy and revenues from autologous banking services. In developing countries, the processing and banking expenses also represent a significant cost for the medical institutions involved.

Besides the acquisition costs, the UCB transplant is considered to be more expensive than an adult marrow or a mobilized peripheral blood transplant based on single center reports. While additional cost analyses are needed, cost containment is a critical issue for the future success of UCB transplant [104]. In this regard, improving collection performance (by training obstetricians and mid-wives) and optimizing donor selection, based on maternal and infant characteristics that influence UCB unit quality, will help to the financial viability of UCB banks. It is also expected that the different laboratory strategies to enhance UCB engraftment will help in reducing the costs of UCBTs. Another key issue that may help to increase the demand for UCB units will be the use of cord blood cells for a broader setting of disorders, including brain, metabolic, spinal cord, muscular, and immune disorders. This, in fact, is already happening, both in the public and in private sectors, at an increasing pace. Such a wider utilization of UCB cells in regenerative medicine protocols will most likely help to reduce the processing and banking costs [23].


During the past 3 decades, UCBTs have filled a void in the transplantation arena, making HSCs/HPCs available more rapidly and to a greater proportion of patients, particularly to those from ethnic and racial minorities for whom an HLA matched donor could not be identified. Although some transplant hematologists feel that UCB already served its clinical purpose in the 1990s and early 2000s, and that it will now be replaced by haploidentical transplants, many others feel that UCB still has a long way to go in the clinical arena, and it is just entering a new phase.

Major efforts have focused on the development of strategies to speed hematopoietic engraftment in order to reduce hospital days, transfusion use, and the risks of infection. Together, this could lead to reduced costs of the transplant procedure. To this end, we need to keep performing rigorous and high quality basic and clinical research. Indeed, we still do not know all the details on how to enhance self-renewal of HSCs in culture without inducing their differentiation. We are still searching for the ideal culture system and ex vivo conditions for the clinical-scale expansion of HSCs. Whether expansion culture alters homing potential is also under investigation. We need to understand the biology behind the interaction between two cord blood units coinfused into a single patient in order to predict the winning unit after a double-unit UCBT.

During the last decade the infusion of ex vivo-expanded UCB hematopoietic cells appears to have a beneficial impact on engraftment, Today, however, its therapeutic use is still rather limited and only a few groups are currently using ex vivo-expanded cells in clinical settings. Three main reasons for this can be stated: first, the fact that, as mentioned above, we still need to understand in greater detail the mechanisms by which HSCs self-renew, so we can learn how to manipulate this process and how to enhance it in culture. Second, ex vivo expansion is still an area in progress, so, we need to develop reliable and consistent ex vivo systems. Third, clinically-oriented ex vivo expansion may be an expensive procedure that has to be performed under particular—GMP—conditions. Therefore, It is expected that in the near future new approaches will be developed to make ex vivo expansion a more reliable, consistent and affordable practice.

It is noteworthy, however, that larger phase II and more definitive phase III studies with expanded cells are currently in progress. In some cases, the cells are infused in conjunction with an unmanipulated unit, but in others, the expanded product is sufficient as a stand-alone graft. The use of expanded UCB hematopoietic cells is still an emerging field. It is possible that a combination approach may achieve even faster times to recovery more consistently.

Today, various laboratories are evaluating new expansion-promoting small molecules [105], and novel culture conditions (e.g., 3D structures combining marrow or liver stromal cells and extracellular matrix proteins [106]). For example, an automated closed-system process using a controlled fed-batch media dilution approach has been developed [107]. In this system, there is continuous removal of Lin+ cells, so that the accumulation of certain metabolites and negative regulators is prevented, whereas primitive Lineage-negative cells are reselected and cultured throughout several days. The authors have reported significant increments in the numbers of total nucleated cells (179-fold), CFC (64-fold), CD34+ cells (80-fold), and long-term culture–initiating cells (29-fold). Importantly, SCID-repopulating cells were also significantly expanded (11-fold), and they were capable of multilineage engraftment when transplanted into secondary murine recipients. Although these results suggest that such a bioprocess may have medical relevance in the near future, this experimental system has yet to be tested in clinical settings.

In addition to its marrow restorative capacity, interesting new uses for UCB cells have been described. For example, cells of the monocytic lineage have been used in the treatment of specific inherited metabolic disorders and other neurologic disorders, including cerebral palsy, autism and demyelinating brain disorders [108,109,110,111,112,113,114]. Using animal model systems and clinical studies it has been suggested that a UCB-derived macrophage-like cell population expressing CD45, CD11b, CD14, CD16, CD206, Iba1, HLA-DR, and iNOS may play a key role in local repair and enzyme and other protein replacement in those with metabolic diseases. Indeed, such cells may induce clinically relevant changes in the function of neural cells and may provide lifelong enzyme replacement that prevents neurological deterioration and significantly extends the lives of affected children. Of interest, improvements in patients with autism have been associated with increased structural connectivity in brain networks that support social, communication, and language abilities [115].

Most of the clinical studies described above have been performed in pediatric patients; however, UCB cells have also been recently used for the treatment of adult patients. A phase I open-label trial to assess the safety and feasibility of a single I.V. infusion of unrelated allogeneic UCB cells into adult patients with ischemic stroke has just been reported. The results of the study were encouraging and support the conduct of a phase II study [116]. Although the actual cellular and molecular mechanisms behind the effects reported in the studies above are still not fully understood, these findings may have a significant clinical impact. Whether or not these new uses for UCB cells will prove to be clinically useful remains to be determined.

UCB is also a rich source of non-HSCs and HPCs, particularly MSCs and endothelial progenitors [16,17,18,19,20]. Some of these—i.e., MSCs—have already been used in clinical trials for disorders such as rheumatoid arthritis [117], cerebral palsy [118], burned patients [119], bronchopulmonary dysplasia [120], and atopic dermatitis [121]. While not yet proven to be an effective approach, there is much interest in evaluating UCB-derived MSCs for the treatment of a wide variety of hematologic and non-hematologic diseases. As a result, these studies continue to reinforce interest in UCB banking. Although it is beyond the scope of the present article, it is important to mention that placenta and umbilical cord tissue are important sources of MSCs, and that such cells have already been assessed in preclinical studies with encouraging results reported by different groups [122,123,124].

Functional neural cells have been derived in vitro from either CD34+ cells or from CD133+ cells from cord blood [125, 126]. Such a plasticity can be induced by either manipulation of the culture conditions or by enforcing the ectopic expression of particular transcription factors, such as Sox2. Differentiation plasticity of HSCs towards non-hematologic tissues is still a very controversial and still not proven issue, and a wide proportion of the hematopoietic community is skeptical about it, based on current evidence. However, it might be worth it to explore it, since production of non-hematopoietic cells from UCB-derived HSCs/HPCs may have important implications in regenerative medicine. Lastly, UCB hematopoietic cells have also been used to generate induced pluripotent stem cells [22, 127, 128], a finding that is relevant in basic stem cell biology and that may eventually have potential implications in cellular therapy.

Concluding remarks

The UCB field has come a long way after 30 years of biomedical and clinical research supported by public and private cord blood banking. Research on the biology of HSCs and HPCs has become invaluable for our understanding of the cellular and molecular mechanisms involved in hematopoiesis and for the development of new strategies in regenerative medicine. Over 40,000 UCBTs have been performed, both in children and in adults, for the treatment of around 80 different medical disorders. Cord blood banking has been developed to the point that around 800,000 units are being stored in public banks and over 4 million units in private banks worldwide.

Currently, ex vivo systems are being developed for the clinical-scale expansion of hematopoietic and mesenchymal stem cells. Novel approaches for speeding hematopoietic recovery are in phase II and III clinical trials with exciting results. New uses for UCB cells are being explored. UCB-derived immune cells—e.g., regulatory T cells and thymic progenitors—are being analyzed to improve transplant results. Finally, we really need randomized trials to determine the relative place of unrelated UCBTs, as compared to haploidentical transplants, and unrelated bone marrow/mobilized peripheral blood transplants. The more choices physicians have to offer their patients, the better.

The challenges presented and discussed herein, as well as others will be elucidated by greater research efforts on the basic biology of HSCs and HPCs, by developing innovative clinical trials for hematologic and non-hematologic disorders, by expanding the use of cord blood cells, and by improving UCB banking both in the public and private arenas. Unanswered questions and unsolved problems regarding the biology and clinical application of UCB cells remain.


  1. 1.

    Gluckman E, Broxmeyer HE, Auerbach AD, Friedman HS, Douglas GW, Devergie A, et al. Hematopoietic reconstitution of a patient with Fanconi anemia by means of umbilical cord blood from an HLA-identical sibling. N Engl J Med. 1989;321:1174–8.

    CAS  Google Scholar 

  2. 2.

    Smith AR, Wagner JE. Current clinical management of Fanconi anemia. Expert Rev Hematol. 2012;5:513–22.

    CAS  Google Scholar 

  3. 3.

    Broxmeyer HE, Douglas GW, Hangoc G, Cooper S, Bard J, English D, et al. Human umbilical cord blood as a potential source of transplantable hematopoietic stem/progenitor cells. Proc Natl Acad Sci USA. 1989;86:3828–32.

    CAS  PubMed  Google Scholar 

  4. 4.

    Broxmeyer HE, Hangoc G, Cooper S, Ribeiro RS, Graves V, Yoder M, et al. Growth characteristics and expansion of human umbilical cord blood and estimation of its potential for transplantation in adults. Proc Natl Acad Sci USA. 1992;89:4109–13.

    CAS  Google Scholar 

  5. 5.

    Wang JCY, Doedens JCY, Dick JE. Primitive human hematopoietic cells are enriched in cord blood compared with adult bone marrow or mobilized peripheral blood as measured by the quantitative in vivo SCID-repopulating cell assay. Blood. 1997;89:3919–24.

    CAS  Google Scholar 

  6. 6.

    Mayani H, Lansdorp PM. Biology of human umbilical cord blood-derived hematopoietic stem/progenitor cells. Stem Cells. 1998;16:153–65.

    CAS  Google Scholar 

  7. 7.

    Vormoor J, Lapidot T, Pflumio F, Risdon G, Patterson B, Broxmeyer HE, et al. Immature human cord blood progenitors engraft and proliferate to high levels in severe combined immunodeficient mice. Blood. 1994;83:2489–97.

    CAS  Google Scholar 

  8. 8.

    Bock TA, Orlic D, Dunbar CE, Broxmeyer HE, Bodine DM. Improved engraftment of human hematopoietic cells in severe combined immunodeficient (SCID) mice carrying human cytokine transgenes. J Exp Med. 1995;182:2037–43.

    CAS  Google Scholar 

  9. 9.

    Lansdorp PM, Dragowska W, Mayani H. Ontogeny-related changes in proliferative potential of human hematopoietic cells. J Exp Med. 1993;178:787–91.

    CAS  Google Scholar 

  10. 10.

    Broxmeyer HE. Proliferative, self-renewal, and survival characteristics of cord blood hematopoietic stem and progenitor cells. In: Cord Blood: Biology, Immunology, Banking and Clinical Transplantation. AABB Press; 2004. p. 1–21.

  11. 11.

    Mayani H. Biological differences between neonatal and adult human hematopoietic stem/progenitor cells. Stem Cells Dev. 2010;19:285–98.

    Google Scholar 

  12. 12.

    Broxmeyer HE. Inhibiting HDAC for human hematopoietic stem cell expansión. J Clin Invest. 2014;124:2365–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Flores-Guzmán P, Fernández-Sánchez V, Mayani H. Concise review: ex vivo expansion of cord blood-derived hematopoietic stem and progenitor cells: basic principles, experimental approaches, and impact in regenerative medicine. Stem Cells Transl Med. 2013;2:830–8.

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Pineault N, Abu-Khader A. Advances in umbilical cord blood stem cell expansion and clinical translation. Exp Hematol. 2015;43:498–513.

    Google Scholar 

  15. 15.

    Mehta RS, Rezvani K, Olson A, Oran B, Hosing C, Shah N, et al. Novel techniques for ex vivo expansion of cord blood: clinical trials. Front Med. 2015; 2: 89.

  16. 16.

    Erices A, Conget P, Minguell JJ. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol. 2000;109:235–42.

    CAS  Google Scholar 

  17. 17.

    Rebelatto CK, Aguiar AM, Moretao MP. Dissimilar differentiation of mesenchymal stem cells from bone marrow, umbilical cord blood, and adipose tissue. Exp Biol Med. 2008;233:901–13.

    CAS  Google Scholar 

  18. 18.

    Montesinos JJ, Flores-Figueroa E, Castillo-Medina S, Flores-Guzman P, Hernandez-Estevez E, Fajardo-Orduña G, et al. Human mesenchymal stromal cells from adult and neonatal sources: comparative analysis of their morphology, immunophenotype, differentiation patterns, and neural protein expression. Cytotherapy. 2009;11:163–76.

    CAS  Google Scholar 

  19. 19.

    Kogler G, Sensken S, Airey JA, Trapp T, Müschen M, Feldhahn N, et al. A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J Exp Med. 2004;200:123–35.

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Wagner JE, Broxmeyer HE, Byrd RL, Zehnbauer B, Schmeckpeper B, Shah N, et al. Transplantation of umbilical cord blood after myeloablative therapy: analysis of engraftment. Blood. 1992;79:1874–81.

    CAS  Google Scholar 

  21. 21.

    Wagner JE, Kernan NA, Steinbuch M, Broxmeyer HE, Gluckman E. Allogeneic sibling umbilical cord blood transplantation in children with malignant and non-malignant disease. Lancet. 1995;346:214–9.

    CAS  Google Scholar 

  22. 22.

    Broxmeyer HE, Lee MR, Hangoc G, Cooper S, Prasain N, Kim YJ, et al. Hematopoietic stem/progenitor cells, generation of induced pluripotent stem cells, and isolation of endothelial progenitors from 21- to 23.5-year cryopreserved cord blood. Blood. 2011;117:4773–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Dessels C, Alessandrini M, Pepper MS. Factors influencing the umbilical cord blood stem cell industry. Evol Treat Landsc Stem Cells Transl Med. 2018;7:643–50.

    Google Scholar 

  24. 24.

    National Marrow Donor Program. Unrelated donor search process, step by step. Minneapolis, MN: National Marrow Donor Program; 2009.

    Google Scholar 

  25. 25.

    Wernet PW. The international NETCORD foundation. In: Broxmeyer HE, (ed.) Cord Blood: Biology, Immunology, Banking and clinical transplantation. Bethesda, MD: AABB Press; 2004. p. 429–35.

  26. 26.

    Navarrete C, Contreras M. Cord blood banking: a historical perspective. Brit J Haematol. 2009;147:236–45.

    Google Scholar 

  27. 27.

    Laughlin MJ, Barker J, Bambach B, Koc ON, Rizzieri DA, Wagner JE, et al. Hematopoietic engraftment and survival in adult recipients of umbilical cord blood from unrelated donors. N Engl J Med. 2001;344:1815–22.

    CAS  Google Scholar 

  28. 28.

    Ballen K, Gluckman E, Broxmeyer HE. Umbilical cord blood transplantation: the first 25 years and beyond. Blood. 2013;122:491–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Rocha V, Kabbara N, Ionescu I, Ruggeri A, Purtill D, Gluckman E. Pediatric related and unrelated cord blood transplantation for malignant diseases. Bone Marrow Transpl. 2009;44:653–9.

    CAS  Google Scholar 

  30. 30.

    Eapen M, Rubinstein P, Zhang MJ, Stevens C, Kurtzberg J, Scaradavou A, et al. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukemia: a comparison study. Lancet. 2007;369:1947–54.

    Google Scholar 

  31. 31.

    Prasad VK, Kurtzberg J. Umbilical cord blood transplantation for nonmalignant diseases. Bone Marrow Transpl. 2009;44:643–51.

    CAS  Google Scholar 

  32. 32.

    Smith AR, Wagner JE. Alternative haematopoietic stem cell sources for transplantation: place of umbilical cord blood. Br J Haematol. 2009;147:246–61.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Ooi J. Cord blood transplantation in adults. Bone Marrow Transpl. 2009;44:661–6.

    CAS  Google Scholar 

  34. 34.

    Eapen M, Rocha V, Sanz G, Scaradavou A, Zhang MJ, Arcese W, et al. Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukemia: a retrospective analysis. Lancet Oncol. 2010;11:653–60.

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Rocha V, Labopin M, Sanz G, Arcese W, Schwerdtfeger R, Bosi A, et al. Transplants of umbilical cord blood or bone marrow from unrelated donors in adults with acute leukemia. New Engl J Med. 2004;351:2276–85.

    CAS  Google Scholar 

  36. 36.

    Munoz J, Shah N, Rezvani K, Hosing C, Bollard CM, Oran B, et al. Concise review: umbilical cord blood transplantation: past, present and future. Stem Cells Transl Med. 2014;3:1435–43.

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Lund TC, Boitano AE, Delaney CS, Shpall EJ, Wagner JE. Advances in umbilical cord blood manipulation—from niche to bedside. Nat Rev Clin Oncol. 2015;12:163–74.

    Google Scholar 

  38. 38.

    Mehta RS, Dave H, Bollard CM, Shpall EJ. Engineering cord blood to improve engraftment after cord blood transplant. Stem Cell Invest. 2017;4:41.

    Google Scholar 

  39. 39.

    Barker JN, Weisdorf DJ, Wagner JE. Creation of a double chimera after the transplantation of umbilical cord blood from two partially matched unrelated donors. N Engl J Med. 2001;344:1870–1.

    CAS  Google Scholar 

  40. 40.

    Sideri A, Neokleous N, Brunet de la Grange P, Guerton B, Le Bousse Kerdilles MC, Uzan G, et al. An overview of the progress on umbilical cord blood transplantation. Haematologica. 2011;96:1213–20.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Scaradavou A, Brunstein CG, Eapen M, Le-Rademacher J, Barker JN, Chao N, et al. Double unit grafts successfully extend the application of umbilical cord blood transplantation in adults with acute leukemia. Blood. 2013;121:752–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Labopin M, Ruggeri A, Gorin NC, Gluckman E, Blaise D, Mannone L, et al. Cost-effectiveness and clinical outcomes of double versus single cord blood transplantation in adults with acute leukemia in France. Haematologica. 2014;99:535–40.

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Ramirez P, Wagner JE, DeFor TE, Blazar BR, Verneris MR, Miller JS, et al. Factors predicting single-unit predominance after double cord blood transplantation. Bone Marrow Transpl. 2012;47:799–803.

    CAS  Google Scholar 

  44. 44.

    Magro E, Regidor C, Cabrera R, Sanjuan I, Fores R, Garcia-Marco JA, et al. Early hematopoietic recovery after single unit unrelated cord blood transplantation in adults supported by co-infusion of mobilized stem cells from a third party donor. Haematologica. 2006;91:640–8.

    Google Scholar 

  45. 45.

    Bautista G, Cabrera JR, Regidor C, Fores R, Garcia-Marco JA, Ojeda E, et al. Cord blood transplants supported by co-infusion of mobilized by hematopoietic stem cells from a third party donor. Bone Marrow Transpl. 2009;43:365–73.

    CAS  Google Scholar 

  46. 46.

    Liu H, Rich ES, Godley L, Odenike O, Joseph L, Marino S, et al. Reduced-intensity conditioning with combined haploidentical and cord blood transplantation results in rapid engraftment, low GVHD, and durable remissions. Blood. 2011;118:6438–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Sanchez ME, Ponce DM, Lauer E. Double-unit cord blood (CB) transplantation (DCBT) combined with haplo-identical peripheral blood CD34+ cells (HaploCD34) is associated with enhanced neutrophil recovery, universal haplo rejection, and frequent pre-engraftment syndrome. Biol Blood Marrow Transpl. 2015;21:S43–S44.

    Google Scholar 

  48. 48.

    Kosuri S, Wolff T, Devlin SM, Byam C, Mazis CM, Naputo K, et al. Prospective evaluation of unrelated donor cord blood and haploidentical donor access reveals graft availability varies by patient ancestry: practical implications for donor selection. Biol Blood Marrow Transpl. 2017;23:965–70.

    Google Scholar 

  49. 49.

    Metcalf D. Hematopoietic cytokines. Blood. 2008;111:481–5.

    Google Scholar 

  50. 50.

    Mayani H, Dragowska W, Lansdorp PM. Cytokine-induced selective expansion and maturation of erythroid versus myeloid progenitors from purified cord blood precursor cells. Blood. 1993;81:3252–8.

    CAS  Google Scholar 

  51. 51.

    Cardoso A, Li M_L, Batard P. Release from quiescence of CD34+ CD38- human umbilical cord blood cells reveals their potentiality to engraft adults. Proc Natl Acad Sci USA. 1993;90:8707–11.

    CAS  Google Scholar 

  52. 52.

    Cicuttini FM, Welch KL, Boyd AW. The effect of cytokines on CD34+ Rh-123high and low progenitor cells from human umbilical cord blood. Exp Hematol. 1994;22:1244–51.

    CAS  Google Scholar 

  53. 53.

    Mayani H, Lansdorp PM. Thy-1 expression is linked to functional properties of primitive hematopoietic progenitor cells from human umbilical cord blood. Blood. 1994;83:2410–7.

    CAS  PubMed  Google Scholar 

  54. 54.

    Mayani H, Lansdorp PM. Proliferation of individual hematopoietic progenitors purified from umbilical cord blood. Exp Hematol. 1995;23:1453–62.

    CAS  Google Scholar 

  55. 55.

    de Wynter EA, Nadali G, Coutinho L, Testa NG. Extensive amplification of single cells from CD34+ subpopulations in umbilical cord blood and identification of long-term culture-initiating cells present in two subsets. Stem Cells. 1996;14:566–76.

    Google Scholar 

  56. 56.

    Piacibello W, Sanavio F, Garetto L, Aglieta M. Extensive amplification and self-renewal of human primitive hematopoietic stem cells from cord blood. Blood. 1997;89:2644–53.

    CAS  Google Scholar 

  57. 57.

    Scadden DT. The stem cell niche as an entity of action. Nature. 2006;441:1075–9.

    CAS  Google Scholar 

  58. 58.

    Morrison SJ, Spradling AC. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell. 2008;132:598–611.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Nagasawa T, Omatsu Y, Sugiyama T. Control of hematopoietic stem cells by the bone marrow stromal niche: the role of reticular cells. Trends Immunol. 2011;32:315–20.

    CAS  Google Scholar 

  60. 60.

    Rosler E, Brandt J, Chute J, Hoffman R. Cocultivation of umbilical cord blood cells with endothelial cells leads to extensive amplification of competent CD34+ CD38- cells. Exp Hematol. 2000;28:841–52.

    CAS  Google Scholar 

  61. 61.

    Robinson SN, Ng J, Niu T, Yang H, McMannis JD, Karandish S, et al. Superior ex vivo cord blood expansion following co-culture with bone marrow-derived mesenchymal stem cells. Bone Marrow Transpl. 2006;37:359–66.

    CAS  Google Scholar 

  62. 62.

    Fei XM, Wu YJ, Chang Z, Miao KR, Tang YH, Zhou XY, et al. Co-culture of cord blood CD34+ cells with human BM mesenchymal stromal cells enhances short-term engraftment of cord blood cells in NOD/SCID mice. Cytotherapy. 2007;9:338–47.

    CAS  Google Scholar 

  63. 63.

    Flores-Guzman P, Flores-Figueroa E, Montesinos JJ, Martinez-Jaramillo G, Fernandez-Sanchez V, Valencia-Plata I, et al. Individual and combined effects of mesenchymal stromal cells and recombinant stimulatory cytokines on the in vitro growth of primitive hematopoietic cells from human umbilical cord blood. Cytotherapy. 2009;11:886–96.

    CAS  Google Scholar 

  64. 64.

    Peled T, Mandel J, Goudsmid RN, Landor C, Hasson N, Harati D, et al. Pre-clinical development of cord blood-derived progenitor cell graft expanded ex vivo with cytokines and the polyamine copper chelator tetraethylenepentamine. Cytotherapy. 2004;6:244–55.

    Google Scholar 

  65. 65.

    Delaney C, Heimfeld S, Brashem-Stein C, Voorhies H, Manger RL, Bernstein ID. Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat Med. 2010;16:232–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Fernandez-Sanchez V, Pelayo R, Flores-Guzman P, Flores-Figueroa E, Villanueva-Toledo J, Garrido E, et al. In vitro effects of stromal cells expressing different levels of Jagged-1 and Delta-1 on the growth of primitive and intermediate CD34+ cell subsets from human cord blood. Blood Cells Mol Dis. 2011;47:205–13.

    CAS  Google Scholar 

  67. 67.

    Peled T, Shoham H, Aschengrau D, Yackoubov D, Frei G, Rosenheimer GN, et al. Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment. Exp Hematol. 2012;40:342–55.

    CAS  Google Scholar 

  68. 68.

    Boitano AE, Wang J, Romeo R, Bouchez LC, Parker AE, Sutton SE, et al. Aryl hydrocarbon receptor antagonists promote the expansión of human hematopoietic stem cells. Science. 2010;329:1345–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Fares I, Chagraoui J, Gareau Y, Gingras S, Ruel R, Mayotte N, et al. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal. Science. 2014;345:1509–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Huang X, Lee MR, Cooper S, Hangoc G, Hong KS, Chung HM, et al. Activation of OCT4 enhances ex vivo expansion of human cord blood hematopoietic stem and progenitor cells by regulating HOXB4 expression. Leukemia. 2015;30:144–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Guo B, Huang X, Lee MR, Lee SA, Broxmeyer HE. Antagonism of PPAR-γ signaling expands hematopoietic stem and progenitor cells by enhancing glycolysis. Nat Med. 2018;24:36–7.

    Google Scholar 

  72. 72.

    Chaurasia P, Gajzer DC, Schaniel C, D’Souza S, Hoffman R. Epigenetic reprogramming induces the expansion of cord blood stem cells. J Clin Invest. 2014;124:2378–2395.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Shpall EJ, Quinones R, Giller R, Zeng C, Baron AE, Jones RB, et al. Transplantation of ex vivo expanded cord blood. Biol Bone Marrow Transpl. 2002;8:368–76.

    Google Scholar 

  74. 74.

    Jaroscak J, Goltry K, Smith A, Waters-Pick B, Martin PL, Driscoll TA, et al. Augmentation of umbilical cord blood (UCB) transplantation with ex vivo-expanded UCB cells: results of a phase I trial using the AastromReplicell System. Blood. 2003;101:5061–7.

    CAS  Google Scholar 

  75. 75.

    De Lima M, McMannis J, Gee A, Komanduri K, Couriel D, Andersson BS, et al. Transplantation of ex vivo expanded cord blood cells using the copper chelator tertraethylenepentamine: a phase I/II clinical trial. Bone Marrow Transpl. 2008;41:771–8.

    Google Scholar 

  76. 76.

    De Lima M, McNiece I, Robinson SN, Munsell M, Eapen M, Horowitz M, et al. Cord-blood engraftment with ex vivo mesenchymal-cell coculture. New Engl J Med. 2012;367:2305–15.

    Google Scholar 

  77. 77.

    Horwitz ME, Chao NJ, Rizzieri DA, Long GD, Sullivan KM, Gasparetto C, et al. Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment. J Clin Invest. 2014;124:3121–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Wagner JE, Brunstein CG, Boitano AE, DeFor TE, McKenna D, Sumstad D, et al. Phase I/II trial of Stem Regenin-1 expanded umbilical cord blood hematopoietic stem cells supports testing as a stand-alone graft. Cell Stem Cell. 2016;18:144–55.

    CAS  Google Scholar 

  79. 79.

    Dircio-Maldonado R, Flores-Guzman P, Corral-Navarro J, Mondragon-Garcia I, Hidalgo-Miranda A, Beltran-Anaya FO, et al. Functional integrity and gene expression profiles of human cord blood-derived hematopoietic stem and progenitor cells generated in vitro. Stem Cells Transl Med. 2018;7:602–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Horwitz ME, Wease S, Blackwell B, Valcarcel D, Frassoni F, Boelens JJ, et al. Phase I/II study of stem-cell transplantation using a single cord blood unit expanded ex vivo with nicotinamide. J Clin Oncol.; 2018.

    CAS  PubMed  Google Scholar 

  81. 81.

    Heazlewood SY, Oteiza A, Cao H, Nilsson SK. Analyzing hematopoietic stem cell homing, lodgment, and engraftment to better understand the bone marrow niche. Ann NY Acad Sci. 2014;1310:119–28.

    CAS  Google Scholar 

  82. 82.

    Broxmeyer HE. Enhancing the efficacy of engraftment of cord blood for hematopoietic cell transplantation. Transfus Apher Sci. 2016;54:364–72.

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Van OsR, Ausema A, Dontje B, van Riesen M, van Dam G, de Hann G. Engraftment of syngeneic bone marrow is not more efficient after intrafemoral transplantation than after traditional intravenous administration. Exp Hematol. 2010;38:1115–23.

    Google Scholar 

  84. 84.

    Brunstein CG, Barker JN, Weisdorf DJ, Defor TE, McKenna D, Chong SY, et al. Intra-BM injection to enhance engraftment after myeloablative umbilical cord blood transplantation with two partially HLA-matched units. Bone Marrow Transpl. 2009;43:935–40.

    CAS  Google Scholar 

  85. 85.

    Frassoni F, Varaldo R, Gualandi F, Bacigalupo A, Sambuceti G, Sacchi N, et al. The intra-bone marrow injection of cord blood cells extends the possibility of transplantation to the majority of patients with malignant hematopoietic diseases. Best Pract Res Clin Haematol. 2010;23:237–44.

    Google Scholar 

  86. 86.

    Christopherson KW, Hangoc G, Broxmeyer HE. Cell surface peptidase CD26/DPPIV regulates CXCL12/SDF-1α mediated chemotaxis of human CD34+ progenitor cells. J Immunol. 2002;169:7000–8.

    CAS  Google Scholar 

  87. 87.

    Christopherson KW, Hangoc G, Mantel C, Broxmeyer HE. Modulation of hematopoietic stem cell homing and engraftment by CD26. Science. 2004;305:1000–3.

    CAS  Google Scholar 

  88. 88.

    Farag SS, Srivastava S, Messina-Graham S, Schwartz J, Robertson MJ, Abonour R, et al. In vivo DPP-4 inhibition to enhance engraftment of single-unit cord blood transplants in adults with hematological malignancies. Stem Cells Dev. 2013;22:1007–15.

    CAS  Google Scholar 

  89. 89.

    Velez de Mendizabal N, Strother RM, Farag SS, Broxmeyer HE, Messina-Graham S, Chitnis SA, et al. Modelling the sitagliptin effect on dipeptidyl peptidase-4 activity in adults with haematological malignancies after umbilical cord blood haematopoietic cell transplantation. Clin Pharm. 2014;53:247–59.

    CAS  Google Scholar 

  90. 90.

    Farag SS, Nelson R, Cairo MS, O’Leary HA, Zhang S, Huntley C, et al. High-dose sitagliptin for systemic inhibition of dipeptidylpeptidase-4 to enhance engraftment of single cord umbilical cord blood transplantation. Oncotarget. 2017;8:110350–7.

    PubMed  PubMed Central  Google Scholar 

  91. 91.

    Xia L, McDaniel JM, Yago T, Doeden A, Mcever RP. Surface fucosylation of human cord blood cells augments binding to P-selectin and E-selectin and enhances engraftment in bone marrow. Blood. 2004;104:3091–6.

    CAS  Google Scholar 

  92. 92.

    Popat U, Mehta RS, Rezvani K, Fox P, Kondo K, Marin D, et al. Enforced fucosylation of cord blood hematopoietic cells accelerates neutrophil and platelet engraftment after transplantation. Blood. 2015;125:2885–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Pelus LM, Broxmeyer HE, Kurland JI, Moore MA. Regulation of macrophage and granulocyte proliferation: specificities of prostaglandin E and lactoferrin. J Exp Med. 1979;150:277–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    North TE, Goessling W, Walkley CR, Lengerke C, Kopani KR, Lord AM, et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature. 2007;447:1007–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Hoggatt J, Singh P, Sampath J, Pelus LM. Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation. Blood. 2009;113:5444–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Cutler C, Multani P, Robbins D, Kim HT, Le T, Hoggatt J, et al. Prostaglandin-modulated umbilical cord blood hematopoietic stem cell transplantation. Blood. 2013;122:3074–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Brunstein CG, McKenna DH, DeFor TE, Sumstad D, Paul P, Wiesdorf DJ, et al. Complement fragment 3a priming of umbilical cord blood progenitors: safety profile. Biol Blood Marrow Transpl. 2013;19:1474–9.

    CAS  Google Scholar 

  98. 98.

    Capitano ML, Hangoc G, Cooper S, Broxmeyer HE. Mild heat treatment primes human CD34+ cord blood cells for migration towards SDF-1α and enhances engraftment in an NSG mouse model. Stem Cells. 2015;33:1975–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Huang X, Guo B, Liu S, Wan J, Broxmeyer HE. Neutralizing negative epigenetic regulation by HDAC5 enhances human haematopoietic stem cell homing and engraftment. Nat Commun. 2018;9:2741

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Guo B, Huang X, Cooper S, Broxmeyer HE. Glucocorticoid hormone-induced chromatin remodeling enhances human hematopoietic stem cell homing and engraftment. Nat Med. 2017;23:424–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Lee CJ, Savani BN, Mohty M, Labopin M, Ruggeri A, Schmid C, et al. Haploidentical hematopoietic cell transplantation for adult acute myeloid leukemia: a position statement from the acute leukemia working party of the European Society for Blood and Marrow Transplantation. Haematologica. 2017;102:1810–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Bart T. Cost effectiveness of cord blood versus bone marrow and peripheral blood stem cells. Clin Outcomes Res. 2010;2:141–7.

    Google Scholar 

  103. 103.

    Majhail NS, et al. Cost of pediatric allogeneic hematopoietic-cell transplantation. Pedia Blood Cancer. 2010;54:138–43.

    Google Scholar 

  104. 104.

    Broxmeyer HE, Farag S. Background and future considerations for human cord blood hematopoietic cell transplantation, including economic concerns. Stem Cells Dev. 2013;22(suppl 1):103–10.

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    Bari S, Zhong Q, Fan X, Poon Z, Lim AST, Lim TH, et al. Ex vivo expansion of CD34+ CD90+ CD49f+ hematopoietic stem and progenitor cells from non-enriched umbilical cord blood with azole compounds. Stem Cells Transl Med. 2018;7:376–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Mokhtari S, Baptista PM, Vyas DA, Freeman CJ, Moran E, Brovold M, et al. Evaluating interaction of cord blood hematopoietic stem/progenitor cells with functionally integrated three-dimensional microenvironments. Stem Cells Transl Med. 2018;7:271–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Csaszar E, Kirouac DC, Yu M, Wang W, Qiao W, Cooke MP, et al. Rapid expansion of human hematopoietic stem cells by automated control of inhibitory feedback signaling. Cell Stem Cell. 2012;10:218–29.

    CAS  Google Scholar 

  108. 108.

    Kurtzberg J, Buntz S, Gentry T, Noeldner P, Ozamiz A, Rusche B, et al. Preclinical characterization of DUOC-01, a cell therapy product derived from banked umbilical cord blood for use as an adjuvant to umbilical cord blood transplantation for treatment of inherited metabolic diseases. Cytotherapy. 2015;17:803–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Sun JM, Kurtzberg J. Cell therapy for diverse central nervous system disorders: inherited metabolic diseases and autism. Pedia Res. 2018;83:364–71.

    CAS  Google Scholar 

  110. 110.

    Saha A, Buntz S, Scotland P, Xu L, Noeldner P, Patel S, et al. A cord blood monocyte-derived cell therapy product accelerates brain remyelination. JCI Insight. 2016;1:e86667.

    PubMed  PubMed Central  Google Scholar 

  111. 111.

    Achyut BR, Varma NR, Arbab AS. Application of umbilical cord blood derived stem cells in diseases of the nervous system. J Stem Cell Res Ther. 2014;4:1000202.

    PubMed  PubMed Central  Google Scholar 

  112. 112.

    Fleiss B, Guillot PV, Titomanlio L, Baud O, Hagberg H, Gressens P. Stem cell therapy for neonatal brain injury. Clin Perinatol. 2014;41:133–48.

    Google Scholar 

  113. 113.

    Garbuzova-Davis S, Ehrhart J, Sanberg PR. Cord blood as a potential therapeutic for amyotrophic lateral sclerosis. Expert Opin Biol Ther. 2017;17:837–51.

    Google Scholar 

  114. 114.

    Chez M, Lepage C, Parise C, Dang-Chu A, Hankins A, Carroll M. Safety and observations from a placebo-controlled, crossover study to assess use of autologous umbilical cord blood stem cells to improve symptoms in children with autism. Stem Cells Transl Med. 2018;7:333–41.

    PubMed  PubMed Central  Google Scholar 

  115. 115.

    Carpenter KLH, Major S, Tallman C, Chen LW, Franz L, Sun J, et al. White matter tract changes associated with clinical improvement in an open-label trial assessing autologous umbilical cord blood for treatment of young children with autism. Stem Cells Transl Med. 2019;8:138–47.

    PubMed  PubMed Central  Google Scholar 

  116. 116.

    Laskowitz DT, Bennett ER, Durham RJ, Volpi JJ, Wiese JR, Frankel M, et al. Allogeneic umbilical cord blood infusion for adults with ischemic stroke: clinical outcomes from a phase I safety study. Stem Cells Transl Med. 2018;7:521–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Park EH, Lim H-S, Lee S, Roh K, Seo KW, Kang KS, et al. Intravenous infusion of umbilical cord blood-derived mesenchymal stem cells in rheumatoid arthritis: a phase 1a clinical trial. Stem Cells Transl Med.; 2018.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Huang L, Zhang C, Gu J, Wu W, Shen Z, Zhou X, et al. A randomized placebo-controlled trial of human cord blood-derived mesenchymal stem cell infusion for children with cerebral palsy. Cell Transpl. 2018;27:325–34.

    Google Scholar 

  119. 119.

    Abo-Elkheir W, Hamza F, Elmofty AM, Emam A, Abdl-Moktader M, Elsherefy S, et al. Role of cord blood and bone marrow mesenchymal stem cells in recent deep burn: a case-control prospective study. Am J Stem Cells. 2017;6:23–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Ahn SY, Chang YS, Kim JH, Sung SL, Park WS. Two-year follow-up outcomes of premature infants enrolled in the phase I trial of mesenchymal stem cells transplantation for Bronchopulmonary dysplasia. J Pedia. 2017;185:49–54.

    Google Scholar 

  121. 121.

    Kim HS, Lee JH, Roh KH, Jun HJ, Kang KS, Kim TY. Clinical trial of human umbilical cord blood-derived stem cells for the treatment of moderate-to-severe atopic dermatitis: phase I/IIa studies. Stem Cells. 2017;35:248–55.

    CAS  Google Scholar 

  122. 122.

    Mattar P, Bieback K. Comparing the immunomodulatory properties of bone marrow, adipose tissue, and birth-associated tissue mesenchymal stromal cells. Front Immunol. 2015;6:560.

    PubMed  PubMed Central  Google Scholar 

  123. 123.

    Mukai T, Nagamura-Inoue T, Shimazu T, Mori Y, Takahashi A, Tsunoda H, et al. Neurosphere formation enhances the neurogenic differentiation potential and migratory ability of umbilical cord-mesenchymal stromal cells. Cytotherapy. 2016;18:229–41.

    CAS  Google Scholar 

  124. 124.

    Donders R, Bogie JFJ, Ravanidis S, Gervois P, Vanheusden M, Marée R, et al. Human Wharton’s jelly-derived stem cells display a distinct immunomodulatory and proregenerative transcriptional signature compared to bone marrow-derived stem cells. Stem Cells Dev. 2018;27:65–84.

    CAS  Google Scholar 

  125. 125.

    Singh AK, Kashyap MP, Jahan S, Kumar V, Tripathi VK, Siddiqui MA, et al. Expression and inducibility of cytochrome P450s (CYP1A1, 2B6, 2E1, 3A4) in human cord blood CD34+ stem cell-derived differentiating neuronal cells. Toxicol Sci. 2012;129:392–410.

    CAS  Google Scholar 

  126. 126.

    Giorgetti A, Marchetto MC, Li M, Yu D, Fazzina R, Mu Y, et al. Cord blood-derived neuronal cells by ectopic expression of Sox2 and c-Myc. Proc Natl Acad Sci USA. 2012;109:12556–61.

    CAS  Google Scholar 

  127. 127.

    Giorgetti A, Montserrat N, Aasen T, Gonzalez F, Rodriguez-Piza L, Vassena R, et al. Generation of induced pluripotent stem cells from human cord blood using OCT4 and SOX2. Cell Stem Cell. 2009;5:353–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Lee MR, Prasain N, Chae H-D, Kim YJ, Mantel C, Yoder MC, et al. Epigenetic regulation of Nanog by miR-302 cluster-MBD2 completes induced pluripotent stem cell reprogramming. Stem Cells. 2013;31:666–81.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


Research in the Mayani laboratory is supported by grants from the Mexican Institute of Social Security (IMSS) and the National Council of Science and Technology (CONACYT), Mexico. Publications reported from the Broxmeyer lab were supported by Public Health Service Grants from the National Institutes of Health: R35 HL139599, R01 DK109188, R01 HL056416, R01 HL112669, and U54 DK106846.

Author information



Corresponding author

Correspondence to Hector Mayani.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mayani, H., Wagner, J.E. & Broxmeyer, H.E. Cord blood research, banking, and transplantation: achievements, challenges, and perspectives. Bone Marrow Transplant 55, 48–61 (2020).

Download citation

Further reading


Quick links