Review

Leukemia (2007) 21, 860–867. doi:10.1038/sj.leu.2404630; published online 8 March 2007

A hypothesis for an embryonic origin of pluripotent Oct-4+ stem cells in adult bone marrow and other tissues

M Z Ratajczak1, B Machalinski2, W Wojakowski3, J Ratajczak1 and M Kucia1

  1. 1Stem Cell Biology Program at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
  2. 2Department of Physiology, Pomeranian Medical University, Szczecin, Poland
  3. 3Third Department of Cardiology, Medical University of Silesia, Katowice, Poland

Correspondence: Dr MZ Ratajczak, Hoenig Endowed Chair in Cancer Biology, Professor and Director of Stem Cell Biology Program, University of Louisville, 580 S. Preston St, Baxter II, Rm. 119E, Louisville, KY 40202, Kentucky, USA. E-mail: mzrata01@louisville.edu

Received 13 January 2007; Revised 29 January 2007; Accepted 31 January 2007; Published online 8 March 2007.

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Abstract

Accumulating evidence demonstrates that adult tissues contain a population of stem cells that express early developmental markers such as stage-specific embryonic antigen and transcription factors Oct-4 and Nanog. These are the markers characteristic for embryonic stem cells, epiblast stem cells and primordial germ cells. The presence of these stem cells in adult tissues including bone marrow, epidermis, bronchial epithelium, myocardium, pancreas and testes supports the concept that adult tissues contain some population of pluripotent stem cells that is deposited in embryogenesis during early gastrulation. In this review we will discuss these data and present a hypothesis that these cells could be direct descendants of the germ lineage. The germ lineage in order to pass genes on to the next generations creates soma and thus becomes a 'mother lineage' for all somatic cell lineages present in the adult body.

Keywords:

Oct-4, Nanog, SSEA-4, VSELs, embryonic stem cells

'I feel quite optimistic about the possibility of someone discovering dormant embryonic totipotent stem cells in very small number, in all normal tissues....'
Dr Emilia Frindel, May 2000

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Introduction

Stem cells are endowed with the property of self-renewal and the ability to differentiate into cells that are committed to restricted developmental pathways. The compartment of stem cells is organized in a hierarchical manner from the (i) most primitive (totipotent) stem cells that are able to form both embryo and placenta, (ii) pluripotent stem cells (PSC) that are able only to form the embryo but has lost the capacity to form the trophoblast (which gives rise to the placenta), (iii) multipotent stem cells in particular three germ layers (endo-, meso- and ectoderm) to already (iv) differentiated tissue-committed (monopotent) populations of stem cells (Table 1).


According to the definition a PSC is a stem cell that is able to give rise to all cells present in the embryo during development. Therefore PSC contribute in in vitro cultures and in vivo after injection into the developing blastocyst (blastocyst complementation assay) to cells from all three germ layers, mesoderm, ectoderm and endoderm, but not to the trophoblast. The presence of PSC is very well documented during embryogenesis. The question remains if PSC exist in adult organisms and if so, are these primitive stem cells, functional in adult life?

Recently several groups reported the presence of Oct-4+ cells in bone marrow (BM),1, 2, 3 cord blood (CB),4, 5, 6, 7 epidermis,8, 9 heart (Mendez-Ferrer S, Prat, S, Lukic A, Diego A, Badimon JJ, Fuster, V, Nadal-Ginard, B. ES-like cells in the adult murine heart. Fourth ISSCR Annual Meeting, 2006), pancreas,10 testis11, 12 and bronchial epithelium.13 Oct-4 is an embryonic transcription factor that plays a determinant role in specification of mouse PSC in the inner cell mass (ICM) of a blastocyst and mouse embryos deficient in Oct-4 are unable to form mature blastocysts14 and die around the time of implantation.15 Oct-4 becomes downregulated during development, and the fact that Oct-4 had been identified in some rare cells present in adult tissues suggests that some embryonic stem cells (ESC) may persist into adulthood.

Several lines of evidence support the presence of Oct-4+ PSC in adult BM. First, the expression of typical PSC markers such as Oct-4,16 Nanog17 (another transcription factor expressed in the developing blastocyst) and stage-specific embryonic antigen (SSEA) (surface marker of early ESC),18 was reported at the protein and/or mRNA level in BM-derived stem cells isolated using various strategies. Accordingly, these embryonic markers were demonstrated in very small embryonic-like (VSEL)1, 7 multipotent adult progenitor cells (MAPC),19 mesenchymal stem cells (MSC)20 (in particular the so-called serum deprived (SD) fraction)21 and marrow-isolated adult mulitlineage inducible (MIAMI) cells.22 Second, the existence of PSC in hematopoietic tissues is somehow supported by 'plasticity' experiments demonstrating a robust contribution of for example BM- or CB-derived cells to regeneration of multiple non-hematopoietic organs and tissues.23, 24, 25, 26, 27, 28

Nevertheless, several questions remain. First, it is important to elucidate whether these Oct-4+ cells are functional in steady-state conditions or are merely a remnants from developmental embryogenesis that reside in a dormant state in the tissues. The dormant status of these cells could be the result of the fact that they are (i) located in non-physiological niches, (ii) exposed to inhibitors, (iii) deprived of some appropriate stimulatory signals and finally (iv) limited in pluripotency because of the erasure of the somatic imprint on some of the crucial somatically imprinted genes (e.g., H19 and IGF2). A proper methylation of these imprinted genes (different on maternal- and paternal-derived chromosomes) is the crucial mechanism that governs totipotency of the zygote and pluripotency of the PSC. These PSC deposited during early gastrulation could be activated after exposure to some appropriate signals that lead to epigenetic changes that affect the methylation status of their DNA and acetylation of histones – leading to, for example, a reestablishment of the proper somatic imprint in dormant PSC (e.g., during organ/tissue injury or oncogenesis).

Second it is important to know if these rare cells identified in BM and other tissues proliferate in steady-state conditions and contribute to the renewal of the pool of other monopotent tissue-specific stem cells. To support this possibility, for example, BM-derived stem cells were demonstrated to differentiate in vitro cultures to cells from different germ layers.19, 20, 21, 22, 23, 24, 25, 26, 27, 28

In this review we will present a hypothesis that the cells that express Oct-4, Nanog, SSEA-1 (mice) and SSEA-3/4 (human) identified in adult mammalian tissues are (i) a rare population of PSC, (ii) descendants from the germ lineage, (iii) are deposited during early gastrulation in the developing organs and (iv) may persists into adulthood.

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Germ lineage a mother lineage of all cell lineages in the body

From the developmental and evolutionary point of view the main goal of the multicellular organism is to pass genes to the next generations and this process is orchestrated by the appropriate interplay between germ and somatic cell lines.29, 30 The germ line carries the genome (nuclear and mitochondrial DNA) from one generation to the next generation and is the only cell lineage which retains true developmental totipotency. In this context we can envision that all somatic cell lines are descendants from the germ line and help germ cells to accomplish this mission effectively (Figure 1).

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

The cycle of life – from zygote to germ cells. From the developmental and evolutionary point of view the germ line (shown in red) carries the genome (nuclear and mitochondrial DNA) from one generation to the next and all somatic cell lines bud out (gray color) during ontogenesis from the germ line to help germ cells accomplish this mission effectively. The germ potential is established in the fertilized oocyte (zygote), and subsequently retained in the morula, ICM, EPSC, PGC and mature germ cells (oocytes and sperm). The first cells that bud out from the germ lineage are trophoectodermal cells that will give rise to the placenta. Subsequently during gastrulation EPSC are a source of PSC for all three germ layers (meso-, ecto- and endoderm) and PGC. We hypothesize that at this stage some EPSC could be deposited as Oct-4+ PSC in peripheral tissues/organs (red circles). Similarly, some migrating PGC could go astray from their major migratory route to the genital ridges and become deposited as well. Furthermore, it is also possible that similarly as PGC, other EPSC deposited in the developing tissues undergo erasure of their somatic imprint (yellow arrows). This mechanism of erasure will protect developing organism from the possibility of teratoma formation. However, it will affect some of the aspects of the pluripotentiality of these cells (e.g., potential of these cells to contribute to blastocyst development).

Full figure and legend (97K)

To support this concept, we can envision a zygote, which derives directly during conception from the fusion of two germ cells (female oocyte and male sperm) as the most primitive totipotent germ stem cell able to form both embryo and extra-embryonal tissues (placenta). In a zygote haploid DNA derived from an oocyte is combined with haploid DNA of a male germ cell, sperm, and the zygote could be envisioned as a mother cell to the germ lineage which 'down the road' will give rise to (i) more differentiated cells from the germ lineage (to ensure transfer of genome to the next generation) and (ii) other somatic lineages that will provide the body to fulfill this mission, which will derive/ 'bud out' from the germ lineage during embryogenesis. Figure 1 presents this concept showing a circle of reproductive life, which begins with the establishment of the most primitive germ line cell (zygote), somatic lineages (meso-, ecto- and endoderm) and most important germ cells (oocytes or sperm), which ensure transfer of DNA to the next generation. In this context the germ lineage in order to pass genes to the progeny must establish an adult organism that will provide a 'vehicle' soma/body to fulfill this mission.30, 31, 32

Figure 2 shows that the germ potential of the zygote is retained in the (i) first blastomers, (ii) cells that are present in the center of a developing morula and subsequently in the (iii) cells from the ICM of a blastocyst. At this time of development, however some level of specification already occurs and the trophoectoderm 'buds out' from the germ line (Figure 1). Trophoectoderm will form the placenta and the remaining part of the blastocyst – ICM will give rise to the epiblast.

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Retention of germ-cell potential during ontogenesis. Cells with germ potential are shown in red. The earliest and the most primitive cell in the germ line is the totipotent zygote. The germ potential is subsequently retained during development in cells located in the middle of the morula, ICM cells in the developing blastocyst, EPSC, PGC cells and germ cells in gonads. Germ potential could be also retained in rare Oct-4+ EPSC deposited during development in peripheral tissues as founders for monopotent tissue committed stem cells? or those rare PGC that may go astray from their major migratory and survive in peripheral tissues (e.g., in BM or adrenal glands).

Full figure and legend (67K)

Epiblast stem cells (EPSC) as demonstrated experimentally are also pluripotent and retain germ lineage potential as well.33 Shortly before the epiblast is about to give rise to all three germ layers (ectoderm, mesoderm and endoderm), the first morphologically identifiable precursors of primordial germ cells (PGC) in mice become specified approximately, 6.0–6.5 days post-coitum (d.p.c.) in the proximal part of the epiblast (Figure 2)34, 35 Thus precursors of PGC are the first population of stem cells that is specified in the embryo at the beginning of gastrulation. PGC in mice subsequently move for a short period of time first to the basis of alantois which is located in the extraembryonic mesoderm and then migrate into the embryo proper towards the genital ridges – where they will undergo developmental differentiation to oocytes or sperm, respectively36 (Figure 2). Therefore one individual life could be envisioned as one link in the chain of the consecutive events aimed at the transfer of the genome by germ cells from one generation to the next. In this context, the somatic cell lines that bud from the germ line (Figure 1) merely play a supportive role.

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Epiblast as a source of PSC in the developing embryo

As mentioned above PSC (Table 1) is a cell which in vitro at the single cell level can give rise to the cells from all three germ layers (meso-, ecto- and endoderm), however, the most valuable evidence for pluripotentiality of a stem cell is its contribution to the development of multiple organs and tissues in vivo after injection into the developing blastocyst. This had been very well demonstrated in the case of ESC isolated from embryos or established in vitro ESC lines37, 38, 39 However, it is very difficult to get such evidence in a reproducible manner for any type of putative PSC isolated from adult tissues.

As mentioned above, EPSC are pluripotent and express SSEA-1 (mice), SSEA-3/4 (human), Oct-4 and Nanog. They will give rise to all three germ layers, ecto-, meso- and endoderm including PGC (Figure 1). Thus, the epiblast, through the process of gastrulation, is the source of all stem cells for all the germ layers and stem cells in these layers will give rise to all of the tissues and organs in the embryo. Thus EPSC could be envisioned as a founder population of PSC for multipotent stem cells for ecto-, endo- or mesoderm that give rise to unipotent stem cells that will develop given cell lineages.

We hypothesize that some pluripotent EPSC could be deposited during gastrulation in peripheral tissues (Figures 1 and 2).30 Furthermore, there is also some additional evidence that some epiblast-derived PGC themselves during migration through the embryo proper on their way to the genital ridges might go astray and seed to peripheral tissues40, 41, 42 Therefore, it is very likely that the cells identified in adult tissues that express ICM/epiblast/PGC markers such as SSEA-1 (mice), SSEA-3/4 (human), Oct-4 and Nanog are populations of PSC that were deposited in these tissues early during gastrulation/embryogenesis.

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Regulation of pluripotency in the germ line – implications for other PSC in adult organs/tissues?

Interestingly PGC in contrast to EPSC do not reveal pluripotency. Namely, in cultures freshly isolated from embryos, PGC proliferate for a few days only, and then disappear either because they differentiate or die.43 Furthermore, while the nuclei of migrating PGC at 8.5–9.5 d.p.c. can be successfully used as donors for nuclear transfer, nuclei from PGC at 11.5 d.p.c. and later are incompetent to support full-term development.44 This is somehow intriguing, taking in consideration that PGC are the population of stem cells that carries 'developmental totipotency' for oocytes and sperm.

However, when PGC are cultured over murine embryonic fibroblasts and exposed ex vivo to three growth factors, kit ligand, leukemia inhibitory factor and basic fibroblast growth factor, they continue to proliferate and form large colonies of embryonic germ cells (EG) which similarly as ESC can be expanded indefinitely.45, 46, 47 EG had been derived from pre- and post-migratory as well as from migratory PGC in both mice and humans and are pluripotent.45, 46 Namely, EG in contrast to PGC fully contribute to blastocyst complementation giving rise in the developing embryo to all somatic lineages and germ cells.

To explain this phenomenon at the molecular level, it is known that the pluripotency of PGC nuclei depends on the methylation status of genomic imprinted genes (e.g. H19, Igf-2, Igf-2R and Snrpn).44, 48 PGC until 9.5 d.p.c. have a somatic imprint (paternal and maternal pattern of methylation) of H19, Igf-2, Igf-2R, Snrpn – that is crucial to maintain their pluripotency. A somatic type of imprint, however, is erased by demethylation whereas these cells migrate towards the genital ridges approximately 10.5 d.p.c.49 The erasing of the methylation (imprint) of H19, Igf-2, Igf-2R and Snrpn in early PGC could be envisioned as one of the mechanisms that shuts down PGC developmental pluripotency – and makes these cells resistant to parthenogenesis or formation of teratomas.50, 51 A proper somatic imprint is subsequently reestablished in sperm and oocytes, so that a fertilized egg expresses a developmentally proper somatic imprint of these crucial genes.

The fact that PGC-derived EG cells are pluripotent, demonstrates that the re-establishment of a proper somatic imprint is possible. We hypothesize that perhaps similar mechanism of somatic imprint erasure takes place during development not only in PGCs but also in other EPSC-derived PSCs that are deposited in the developing organs (Figure 1). It is also likely that similarly as PGC these cells under certain circumstances (e.g., tissue/organ injury) may regain a proper somatic imprint.

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Presence of Oct-4+ stem cells in the BM

Stem cells that express early embryonic stem cell markers including Oct-4, Nanog and SSEA-1 had been identified in BM in several potential multipotent/PSC isolated from the BM or CB such as VSELs1, 7 MSC20, 21 MAPC,19 MIAMI,22 unresticted somatic stem cells (USSC),52 precursors of oocytes/spermatogonia.53, 54 It is very likely that several investigators using different isolation strategies described the same populations of stem cells but gave them different names according to the circumstance.

VSEL stem cells

The homogenous population of rare (approx0.01% of BM MNC) Sca-1+ lin- CD45- cells was recently purified by fluorescence-activated cell sorting (FACS) from murine BM.1 They express (as determined by real-time quantitative PCR and immunhistochemistry) SSEA-1, Oct-4, Nanog and Rex-1 and Rif-1 telomerase protein, but do not express MHC-I and HLA-DR antigens and are CD90- CD105- and CD29-. Direct electron microscopical analysis revealed that these cells display several features typical for ESC such as (i) a small size (2–4 mum in diameter), (ii) a large nucleus surrounded by a narrow rim of cytoplasm and (iii) open-type chromatin (euchromatin). Despite their small size they posses diploid DNA and contain numerous mitochondria.

Interestingly approximately 5–10% of purified VSELs if plated over a C2C12 murine myoblast cell feeder layer are able to form spheres that resemble embryoid bodies. Cells from these VSEL-derived spheres (VSEL-DS) are composed of immature cells with large nuclei containing euchromatin, and like purified VSELs are CXCR4+SSEA-1+Oct-4+. Furthermore, cells from VSEL-DS, after re-plating over C2C12 cells, may again (up to 5–7 passages) grow new spheres or, if plated into cultures promoting tissue differentiation, expand into cells from all three germ cell layers. Similar spheres were also formed by VSELs isolated from murine fetal liver, spleen and thymus. Interestingly, formation of VSEL-DS was associated with a young age in mice, and no VSEL-DS were observed in cells isolated from old mice (>2 years). As VSELs express several markers of the germ cell line (fetal-type alkaline phosphatase, Oct-4, SSEA-1, CXCR4, Mvh, Stella, Fragilis, Nobox, Hdac6), they are probably closely related to a population of EPSC.

VSELs are mobile and respond robustly to an SDF-1 gradient, adhere to fibronectin and fibrinogen, and may interact with BM-derived stromal fibroblasts.55 Confocal microscopy and time laps studies revealed that these cells attach rapidly to, migrate beneath and undergo emperipolesis in marrow-derived fibroblasts.55 This robust interaction of VSELs with BM-derived fibroblasts has an important implication, namely that isolated BM stromal cells may be contaminated by these tiny cells from the beginning. This observation may somehow explain the unexpected 'plasticity' of marrow-derived cells with a fibroblastic morphology (e.g., MSC or MAPC). To support this, a similar population of SSEA-1+ Oct-4+ Nanog+ Sca-1+ lin- CD45- cells was also recently isolated from the BM by another team with the suggestion that these cells could be associated with MSC.3

MSC (multipotent mesenchymal stromal cells

MSC were initially identified as a population of BM-derived adherent bone/cartilage-forming progenitor cells.56, 57 In early passages of low-density plated MSC two morphologically distinct populations of cells were described, a population of more mature, large, flat and slowly replicating cells and one of rapidly self-renewing cells (RS cells) which are small and spindle shaped.20 Furthermore, serum deprivation of human MSC cultures selects for expansion of so- called SD MSC.21 These SD–MSC are small and express mRNA for embryonic markers such as Oct-4, ODC antizyme and hTERT, and proliferate more slowly than RS cells. It was postulated that these SD–MSC cells are the most primitive fraction of MSC from more mature MSC are derived. To support this further, there are recent reports that a subpopulation of undifferentiated MSC expanded from BM adherent cells could express embryonic stem cell and PSC markers such as Oct-4 and Rex1 or Oct-4 and Nanog.58 The relationship of these undifferentiated MSC with other populations of Oct-4+ cells in BM including VSELs requires further studies.

MAPC

MAPC are isolated from BM MNC as a population of CD45- GPA-A- adherent cells and they display a similar fibroblastic morphology to small MSC.19 Thus it has been postulated that MAPC could be more primitive cells than MSC; however, the potential relationship between MSC, in particular SD–MSC cells and MAPC has yet to be established. The colonies of cells enriched in murine MAPC express SSEA-1. Recently it was reported that MAPC isolated from porcine marrow are similarly as VSELs very small, embryonic-like and express SSEA-1, Oct-4 and Nanog.59 They are also negative for the expression of CD34, CD44, CD45, CD117 and MHC class I and class II. The growth of these rare cells depends on selected serum batches and is tightly regulated by oxygen tension. Interestingly MAPC are the only population of BM-derived stem cells that, so far as is known, contribute to all three germ layers after injection into a developing blastocyst, indicating their pluripotency.19 The contribution of MAPC to blastocyst development, however, requires confirmation by other, independent laboratories.

MIAMI cells

This population of cells was isolated from human adult BM by culturing BM MNC in low oxygen tension conditions on fibronectin.22 Colonies of small adherent cells express the embryonic stem cell markers Oct-4 and Rex-1 and differentiate into cells from multiple germ layers. The potential relationship of these cells to MSC and MAPC described above is not clear, although it is possible that these are overlapping populations of cells identified by slightly different isolation/expansion strategies.

BM-derived oocytes and spermatogonia

Recently somewhat unexpectedly BM was also identified as a source of oocyte-53 and spermatogonia-like cells.54 This observation supports to some extent the concept that during embryonic development some of the stem cells from the germ lineage (Figures 1 and 2) may go astray on their way to the genital ridges and colonize fetal liver, and subsequently by the end of the second trimester of gestation together with fetal liver-derived HSC move to the BM tissue. Accordingly, oocyte-generating germ line stem cells were found in murine BM in a set of elegant experiments in which BM transplantation restored oocyte production in normal animals sterilized by chemotherapy as well as in ataxia teleangiectasia-mutated gene-deficient mice, which are otherwise incapable of making oocytes.53 Direct sorting analysis revealed in BM the presence of c-kit+Sca-1-lin- cells that expressed PGC markers such as Oct-4, Mvh, Dazl, Stella and Fragillis. Expression of all of these markers correlated with an adherent fraction of BM cells. Based on these observations the authors concluded that BM could be a potential source of germ cells that could sustain oocyte production in adulthood.

Another independent group also recently reported that BM cells may also be a source of male germ cells.54 These cells expressed PGC markers such as Fragillis, Stella, Rnf17, Mvh and Oct-4, as well as molecular markers of spermatogonial stem cells and spermatogonia including Rbm, c-Kit, Tex18, Stra8, Piwil2, Dazl and Hsp90alpha. Thus BM unexpectedly is emerging as a potential source of germ cells for reproductive medicine. So far, however, evidence is lacking that these BM-derived oocytes or spermatogonia are fully functional, capable of fertilization and can give rise to embryos.

Oct3/4+ precursors of cardiomyocytes in BM

It was recently demonstrated that BM cells may form culture aggregates of Oct3/4+ cells which in vitro cultures in the presence of platelet-derived growth factor (PDGF)-AB may differentiate into cardiomyocytes.2 These cells were identified in BM from young and old mice, however, their potential to differentiate into cardiomyocytes by PDGF-AB-mediated paracrine/juxtacrine pathway decreased with animal age.

Oct-4+ stem cells in CB

Neonatal CB is an important source of non-hematopoietic stem cells. Generally, we can envision CB as neonatal PB mobilized by the stress related to delivery. Release of several cytokines and growth factors, as well as hypoxic conditions during labor, may mobilize neonatal marrow cells into circulation.

It is well known that CB-derived cells contribute to skeletal muscle60, 61 liver62, 63, 64 neural tissue,65 and myocardium regeneration66, 67 and more importantly recent multiorgan engraftment and differentiation has been achieved in goats after transplantation of human CB CD34+lin- cells.68 Furthermore, several groups of investigators described the presence of Oct-4+, Nanog+ and SSEA-3/4+ stem cells in human CB and umbilical cord matrix.69 They were enriched by different approaches employing (i) immunomagnetic beads against CD133,4 (ii) expansion of hematopoietic cell depleted adherent population of CB cells in the presence of thrombopoietin, kit ligand and flt3-ligand6 or (iii) isolation of mononuclear cells by Ficoll gradient centrifugation.5

Recently, the small cells resembling a population of murine BM-derived VSELs was purified from CB and demonstrated at the single cell level by employing a novel two-step isolation procedure – removal of erythrocytes by hypotonic lysis combined with multiparameter FACS.7 These CB-isolated VSELs (CB–VSEL) are very small (3–5 mum) and highly enriched in a population of CXCR4+AC133+CD34+lin- CD45- CB mononuclear cells, possess large nuclei containing unorganized euchromatin, express nuclear embryonic transcription factors Oct-4 and Nanog and surface embryonic antigen SSEA-4. Further studies are needed to see if human CB-isolated VSELs similarly as their murine BM-derived counterparts are endowed with pluripotency. It is also not clear at this point the potential relationship of these cells to so-called CB-derived USSC. USSC are very rare cells that are detectable in approximately 40% of CB units at the frequency 1–11 cells/CB unit.52 Unfortunately, the markers which are expressed on the founder cells for these colonies are not described. In vitro cultures unrestricted somatic stem cells differentiate into osteoblasts, chondroblasts, adipocytes, hematopoietic and neural cells.52

Oct-4+ stem cells in other tissues

A population of stem cells that express markers of ESC/epiblast/PGC cells was recently described in several non-hematopoietic organs for example, in epidermis8, 9, 70 bronchial epithelium,13 myocardium (Mendez-Ferrer S, Prat, S, Lukic A, Diego A, Badimon JJ, Fuster, V, Nadal-Ginard, B ES-like cells in the adult murine heart. Fourth ISSCR Annual Meeting, 2006), pancreas,10, 71 testis11, 12 retina72 and amniotic fluid.73

Oct-4+ cells in bronchial epithelium

The Oct-4+ long-term BrdU label-retaining cells were described at the bronchoalveolar junction of neonatal lung with the suggestion that these could be putative neonatal lung stem/progenitor cells.13 Furthermore, lung-derived cells if cultured on collagen in serum-free conditions develop Oct-4+, SSEA-1+ and Sca-1+ epithelial colonies with a surrounding mesenchymal stroma. These cells, presumably a subpopulation of so called Clara cells74 could be kept for weeks in primary cultures and undergo terminal differentiation to alveolar type-2- and type-1-like pneumocytes sequentially when removed from the stroma.

Oct-4+ cells in adult murine heart

By employing transgenic mice that express green fluorescence protein under a Oct-4 promoter, the presence of embryonic-like Oct-4-expressing stem cells through out the murine myocardium in particular in the atria region was demonstrated (Mendez-Ferrer S, Prat, S, Lukic A, Diego A, Badimon JJ, Fuster, V, Nadal-Ginard, B. ES-like cells in the adult murine heart. Fourth ISSCR Annual Meeting, 2006). Gene expression profile studies performed by microarrays and semiquantitative reverse transcriptase-polymerase chain reaction revealed that they express gene profiles resembling ESC. Furthermore, these cells if expanded in cultures and injected into the amniotic cavity of a developing chick embryo or a gastrulating mouse embryo confirmed wide developmental potential of these cells.

Oct-4+ cells in pancreas

It was demonstrated that stem cells isolated from exocrine rat pancreas are able to differentiate in culture in vitro into cells from all three germ layers, have the propensity to form three-dimensional, teratoma-like structures in vitro and show extensive self-renewal ability and are able to expand in long-term cultures.10 Cells isolated from these cultures express embryonic markers such as Oct-4, SSEA-1 and fetal alkaline phosphatase. Some of the clones derived from these cells were also found to differentiate into oocyte-like cells. It was shown that the expression of germ line markers such as SSEA-1, Mvh increases in these cells and in addition they acquire meiosis-specific markers such as SCP3 and DMC1.

Oct-4+ stem cells in epidermis

Very small Oct-4+ Nanog+ stem cells distinctively different from known epithelial or melanocytic stem cells were identified in the bulge region of human hair follicles.8 These cells if cultured in vitro in human embryonic stem cell medium formed so-called hair spheres that contain cells with the ability to differentiate into neurons, muscle cells, endothelial cells, adipocytes and osteoblasts. Furthermore, somehow surprisingly it was also reported that porcine fetal skin was found to be a potential source of Oct-4+ germ cells that are able to differentiate into like oocyte-cumulus complexes that secreted ovarian steroid hormones and responded to gonadotropin stimulation.70 More importantly, some of these aggregates extruded large oocyte-like cells that expressed oocyte markers. Thus these data support the concept that epidermis may contain Oct-4+ stem cells endowed with germ lineage potential.

SSEA-1+ cells in murine retina

A population of SSEA-1+ stem cells was isolated from the murine retina.72 These cells were highly expressed in the developing retina, but also detectable in newborn animals and their number decreases dramatically after birth.

Oct-4+ cells in amniotic fluid

A population of non-hematopoietic (CD45-) SSEA+ Oct-4+ stem cells was recently isolated from human amniotic fluid.73 These cells were able to differentiate into cells from all three germ layers. These data together with the observation that Oct-4+ PSC could be also isolated from placental cords raises the possibility that extra-embryonic tissues could be a source of embryonic-like cells for regeneration.

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Do ESC-like Oct-4+ cells shuttle between BM and peripheral tissues?

Evidence accumulated that during organ damage non-hematopoietic stem cells (including VSELs) are mobilized from the BM and perhaps other tissue-specific niches into peripheral blood where they circulate in order, what we believe, to 'home' to damaged tissues and participate in tissue repair.55 We reported that the number of these cells in peripheral blood increases also after heart infarct75, 76 and stroke.77 Other groups found that cells expressing markers for early tissue committed stem/progenitor cells circulate during skeletal muscle78, 79 and retina epithelium damage,80 lung injuries,81 bone fracture,82 ischemic damage of the kidney83 and injury of the liver.84 We noticed that the number of circulating non-hematopoietic stem cells expressing pluripotent/tissue committed markers (e.g., Oct-4+) in peripheral blood could be increased by some mobilizing agents, for example, G-CSF.85 in combination with compounds that block CXCR4 (e.g., T140 or AMD3100)86, 87

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Do ESC-like Oct-4+ cells initiate tumor development?

In 1855 Virchow proposed the 'embryonal – rest hypothesis' of tumor formation, based on histological similarities between tumors and embryonic tissues.88 This theory was later expanded by another pathologist Julius Conheim, who suggested that tumors develop from residual embryonic remnants 'lost' during developmental organogenesis.

The Oct-4+ stem cells recently identified in adult tissues could fully support Virchow's concept. In Table 2 we proposed different scenarios how these stem cells expressing embryonic markers could contribute to tumor development.89, 90 First, if the genomic imprint in these cells is not erased they may retain post-developmental in vivo pluripotency and grow teratomas and teratocarciomas91, 92 Second, if they are closely related to migratory PGC, which go astray from the major migratory route to the genital ridges they may ultimately give rise to for example, germinomas and seminomas.50, 51 Third, if these cells acquire critical mutations, they may develop into the several types of pediatric sarcomas (e.g., rhabdomyosarcoma, neuroblastoma, Ewing sarcoma and Willms tumor). In support of this there is a strong correlation with the number of these Oct-4+ cells which persist in postnatal tissues and the coincidence with these types of tumors in pediatric patients.93 Finally, it is possible that these cells if mobilized at the wrong time into peripheral blood, and deposited in areas of chronic inflammation, instead of playing a role in regeneration may contribute to the development of malignancies (e.g., stomach cancer).94


To support this further several tumor types may express embryonic markers including Oct-4 and as reported BM-derived stem cells that may develop in the presence of cancerogens several sarcomas including teratomas.95

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Do adult tissue-derived Oct-4+ stem cells hold promise for regenerative medicine?

Humanity continually searches for the 'holy grail' to prevent sufferings caused by aging-related illnesses, and improve a quality of life in advancing age. Adult tissue-isolated Oct-4+ stem cells could potentially provide a real therapeutic alternative to the controversial use of human ES cells and therapeutic cloning. Hence, while the ethical debate on the application of ES cells in therapy continues, the potential of Oct-4+ stem cells is ripe for exploration. Researchers must determine whether these cells could be efficiently employed in the clinic or whether they are merely developmental remnants found in the BM and other tissues that cannot be harnessed for regeneration. The coming years will bring important answers to this question.

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References

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Acknowledgements

This work was supported by NIH Grant R01 CA106281-01 to MZR.