What is a niche?

The word niche comes from the French; the literal meaning is a doghouse. The niche is not just a place, but has a functional dimension. For example, hematopoietic stem cells (HSCs) require a specific microenvironment for self-replication. The first example of the niche as specialized microenvironment was demonstrated in Drosophila.¹ In the Drosophila ovary, germ line stem cells maintain oocyte production. A small group of somatic cells located at the tip of the ovariole form a tubular structure that maintains and controls germ line stem cells. The cap cells may allow stem cells to adhere to the niche.

The hematopoietic stem cell niche

The HSC niche is a dynamic system. Cells, matrix glycoprotein and three-dimensional spaces provide the ultrastructure for a stem cell niche. HSCs circulate but do not function outside of specific locations. The ability of the niche to contribute to stem cell function makes the concept of the niche important for understanding human disease. Schofield and colleagues proposed the niche hypothesis; HSCs exist in a microenvironment; the microenvironment cells confer upon the HSCs self-renewal capabilities.²

Recently, the osteoblasts have been found to be important components of the niche. Osteopontin is a sialoprotein that interacts with receptors on HSCs, such as CD44, alpha4 and alpha5 beta1 integrins.^{3, 4} Osteopontin production varies with osteoblast activation and osteopontin serves to limit stem cell numbers. Osteopontin expression contributes to the migration of HSCs toward the endosteal region. Without osteopontin, increased stem cell expansion can occur. Bone also has a high concentration of calcium ions at the endosteal surface, a surface rich in HSCs.⁵ A calcium sensing receptor, expressed by HSCs, acts as a regulatory component of the HSC niche. The calcium sensing receptor is a potential target to manipulate the niche and increase stem cell numbers. Figure 1 illustrates the schema of this adult stem cell niche.

Figure 1.

The hematopoietic stem cell niche. Osteopontin serves to limit stem cell numbers.

Full figure and legend (78K)

Since the HSC niche appears to be a dynamic system, it may be amenable to manipulation for therapeutic uses. Mammalian bone marrow involves HSCs close to the endosteal surfaces, with the more differentiated cells closer to the central axis of the bone.⁶ This organized structure of the marrow suggests a relationship between HSCs and osteoblasts and osteogenic cells lining the endosteal surface. Osteoblasts produce hematopoietic growth factors and are activated by parathyroid hormone (PTH) or the locally produced, PTH-related protein, through the PTH/PTHrP receptor (PRP).^{7, 8}

The close proximity of the stem cells to bone raises the possibility of using compounds that affect bone and mineral metabolism. Drugs that affect osteoblast or osteoclast function, drugs that target calcium receptor, osteopontin, or Notch may be useful.

Murine studies

Murine studies have been undertaken to try to understand the stem cell niche, and thereby increase stem cell numbers. Dr David Scadden and colleagues tested whether osteoblasts contribute to the unique microenvironment of the bone marrow in vivo using a constitutively active PRP (coll-caPRP) in osteoblastic cells in a transgenic mouse model.⁹ Hematopoietic cells were found in small regions between trabeculae. The bony change was restricted to the metaphyseal area and there was no substantial alteration in the overall hematopoietic content of the bone marrow.

The Notch signaling pathway regulates cell fate in a variety of cellular systems.¹⁰ The Notch genes encode for transmembrane glycoprotein receptors. The binding of Notch ligands, such as Jagged1, Jagged2 and Delta initiates the activation of Notch signaling.¹¹

By changing the balance of daughter cell self-renewal versus differentiation, Notch signaling has been shown to increase stem cell numbers without expanding mature cells. Studies in recombination activation gene 1 deficient bone marrow cells have shown that Notch 1 activation inhibits differentiation of HSCs.¹² In addition, Notch 1 activation preferentially favors lymphoid cells, suggesting that manipulation of this system may have the potential to affect T lineage maturation after transplantation.¹³

To study whether PRP stimulation could have a meaningful physiologic effect, a model relevant to the clinical use of stem cells in humans was selected. PTH (1–34) was administered to animals undergoing a myeloablative bone marrow transplant using a limiting number of donor cells to mimic a therapeutic clinical setting. Survival at 28 days was 100% in the PTH-treated mice, compared to 27% in the control group.⁹ Bone marrow histology in the PTH-treated group demonstrated an increase in cellularity and a decrease in fat cells. Therefore, PTH alteration of the bone marrow microenvironment can result in improved engraftment. These data suggest that manipulating the microenvironment may be a means to influence engraftment in patients.

Further work assessed the ability of PTH to increase the number of stem cells mobilized into the circulation after treatment with G-CSF. C57B1/6 mice were treated with PTH or vehicle alone for 5 weeks. The mice then underwent a standard G-CSF mobilization for 5 days. At the end of the treatment period, white blood count and colony forming units were assessed. There was no difference in the number of CFU-Cs mobilized in the mock or PTH mobilized mice, demonstrating that PTH has no direct effect on progenitor cells. However, there was an increase in frequency of HSC, defined as the population of lin-Sca-1+c-Kit+Flk-2 cells.¹⁴ This work suggests that the increased number of HSCs in the bone marrow following PTH treatment can be mobilized into the peripheral blood circulation with a standard mobilization regimen. The proposed effects of PTH on the stem cell niche are illustrated in Figure 2.

Figure 2.

The role of PTH on the HSC niche. Proposed PTH effects on mobilization and engraftment.

Full figure and legend (73K)

Stimulation of the hematopoetic stem cell niche during multiple rounds of chemotherapy was tested to mimic the situation in patients receiving repetitive rounds of chemotherapy. Mice received cyclophosphamide every 2 weeks for four cycles. On the day after chemotherapy, mice were treated with either saline alone, G-CSF, PTH alone, or a combination of PTH and G-CSF.¹⁵ At the end of the treatment period, half of the mice were killed and preservation of the HSC pool assessed by competitive repopulation assays. The other half of the mice had mobilization of stem cells into the peripheral blood assessed by competitive repopulation assays. PTH led to an increase in the HSC pool in mice that did not receive G-CSF and a preservation of the stem cell pool in G-CSF-treated mice. These studies demonstrate that targeting the stem cell niche can protect and expand the HSC pool during myelotoxic chemotherapy.

In an allogeneic murine transplant model, the osteoblasts promote engraftment across HLA barriers.¹⁶ Lin negative, T-cell depleted hematopoietic progenitor cells engraft HLA matched, but not HLA mismatched, lethally irradiated mice. Addition of dendritic cells did not support engraftment. Osteoblasts, purified from donor murine long bones, were transplanted with marrow stem cells into fully allogeneic mice. The recipient mice showed full donor reconstitution of hematopoietic elements, suggesting the role for osteoblasts in engraftment across HLA boundaries.

Large animal studies

Preliminary data in monkeys suggest that PTH may be useful for engraftment and immune reconstitution after allogeneic stem cell transplantation.¹⁷ Six monkeys received conditioning with rabbit antithymocyte globulin (Thymoglobulin), melphalan, fludarabine and rituximab followed by MHC mismatched bone marrow transplantation, with no post-transplant immunosuppressant. Three mice received PTH from day -7 to day +49 after transplant. Bone marrow at 4 weeks in the PTH-treated animals had increased cellularity. There were remarkable increases in CD4 counts (14 000 cells/ml vs 0), CD 19 counts (10 000 cells/ml vs 0) and platelet counts (385 10⁹/l vs 50 10⁹/l) in the treated vs untreated animals. Although the number of animals tested was small, these data suggest a role for PTH manipulation of the stem cell microenvironment.

Clinical uses of PTH

Background

Human PTH 1–34 is an approved drug that has recently been used in large studies to treat osteoporosis.^{18, 19} The actions of PTH are associated with the N-terminal portion of PTH; fragments of amino acids 1–34 have been shown to have the same effects and pharmacologic profile as the full-length PTH (1–84).²⁰

There have been several studies suggesting a benefit of PTH for the treatment of osteoporosis; the doses used ranged from 15 to 100 g per day using different preparations of PTH.²¹ Adverse side effects in these studies included hypercalcemia, usually <11.2 mg/dl, local injection site reactions, mild headaches and arthralgias. Recently, PTH was shown to decrease the risk of vertebral fracture in postmenopausal women.²² Side effects included mild hypercalcemia (3%), leg cramps, nausea and injection site irritation.

In the osteoporosis study of 83 men, the dose used was 40 g sq daily of PTH 1–34; the men took the drug for 24 months. Four percent of the men had elevated calcium levels, but none above 11.5 mg/dl.¹⁸ Other reported side effects included heartburn, joint pain, back pain and muscle aches. The dose used in the study of 238 postmenopausal women was 100 g of the full-length PTH 1–84 sq daily.¹⁹ This dose is roughly equivalent to 40 g of PTH 1–34. Twelve percent of the women had an elevated serum calcium level; the level was above 11.2 mg/dl in five patients. Three women developed gout. Reported side effects included injection site pain, joint pain, muscle aches, nausea, fatigue and headaches.

In 2002, the Food and Drug Administration approved PTH (teriparatide) at a dose of 20 g for the treatment of osteoporosis in postmenopausal women who are at high risk for fracture, and to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture.²³ Approval was accompanied by a black box warning indicating an increased incidence of osteosarcoma in rats treated with high doses of teriparatide over their lifespan. This warning was based on data in rats that were given lifetime daily injection of PTH and had an increased incidence of osteosarcoma. This effect was not seen in the primate model of monkeys.

The use of parathyroid hormone in the autologous setting

The initial step in proceeding with clinical trials with PTH was to determine an optimal dose and regimen in cancer patients. The approved dose is 20 g, and the dose used in several of the clinical osteoporosis studies was 40 g. Because the dose used in the murine studies was higher, a Phase I study was undertaken at Massachusetts General Hospital, the Dana Farber Cancer Institute, Beth Israel Deaconess Medical Center and MD Anderson Hospital to determine the safety of higher doses of PTH, enrolling patients who were candidates for autologous stem cell transplantation but had not been able to mobilize stem cells well.

Autologous stem cell transplantation is a curative therapy for many patients with non-Hodgkin's lymphoma and Hodgkin's disease, and has been shown to prolong survival in multiple myeloma.²⁴ Peripheral blood stem cells can be collected after mobilization; regardless of the mobilization strategy used, approximately 20% of patients are unable to mobilize sufficient peripheral blood stem cells to proceed safely to autologous stem cell transplant.²⁵

Several different strategies have been tried for second mobilization, including the use of G-CSF alone or in combination with other agents or the use of bone marrow cells collected after bone marrow harvest.²⁶ These salvage strategies are successful in approximately 40% of patients.²⁷ Recently, the CXCR4 antagonist, AMD 3100, has been tested in clinical trial in patients with lymphoma.²⁸ Thus, patients who do not have an adequate first stem cell collection are often not likely to have a good second stem cell mobilization or bone marrow harvest and better strategies are needed for the 20% of patients who are 'poor mobilizers'.

Patients with hematologic malignancies who met usual transplant indications were candidates for this Phase I study of PTH.²⁹ Patients had to have failed one or two earlier mobilization attempts, defined as peripheral blood CD34 <5/Ul or <2.0 10⁶ CD34+ cells/kg after four aphereses. All patients received PTH subcutaneously for days 1–14 of the study or until apheresis was complete. Patients were treated in a standard Phase I format at doses of either 40, 60, 80 or 100 g daily. All patients received G- CSF 10 g/kg daily on days 10–14 of the study or until the end of apheresis. Preliminary results suggest no dose limiting toxicity (defined as hypercalcemia, hypotension or hypophosphatemia) at doses of up to 100 g. These data suggest that PTH is well tolerated in doses up to 100 g; further investigation is needed to determine the efficacy in this setting.

The use of PTH after cord blood transplantation

Umbilical cord blood is a useful stem cell alternative for patients without matched-related or -unrelated donors.³⁰ Given the size of most American families, only 30% of patients will have a matched sibling donor. It is particularly difficult for black patients and other minorities to find matched unrelated bone marrow donors.³¹ More than 5000 patients have received umbilical cord blood transplants for malignant or non-malignant disease.³⁰

Several studies have indicated an improvement in engraftment and survival with an infused stem cell dose >3 10⁷ NC/kg.³² Most single cord blood units are only acceptable (>3 10⁷ NC/kg) for children and small adults, resulting in problems with graft failure, infection and poor immune reconstitution. Thus, the limiting number of stem cells in the cord blood product may be analogous to the limiting dilution experiments performed in the mouse model discussed above. These problems triggered investigation into ways of improving engraftment such as with stem cell expansion, infusion of multiple cord blood units, manipulation of homing and adhesion molecules or modulation of the stem cell niche.

The Minnesota group has employed the double cord blood strategy using both reduced intensity and myeloablative conditioning regimens.^{33, 34} Even with the use of two cord blood units, transplant-related mortality was 28% for the reduced intensity conditioning regimen, with infection being the primary cause of death. The myeloablative preparative regimen was cyclophosphamide, total body radiation and fludarabine. Neutrophil engraftment occurred at a median of 23 days. With a median follow-up of 10 months, the predicted 1-year survival was 57%.

A Phase I study of double cord blood transplantation using a reduced intensity conditioning regimen was completed at Massachusetts General Hospital and the Dana Farber Cancer Institute in Boston.³⁵ The conditioning regimen was fludarabine, melphalan and rabbit antithymocyte globulin. Patients received two cord blood units on the same day, with the GVHD prophylaxis of cyclosporine and mycophenolate mofetil. Twenty-one patients were treated, with the majority of patients having leukemia or lymphoma. The median days to ANC >0.5 10⁹/l were 20 and the median days to platelet count >20 10⁹/l unsupported were 41. The incidence of Grades II–IV GVHD was 40%. The median follow-up of survivors is 18 months. The 1-year overall and disease-free survivals are 71 and 67%, respectively. Deaths were related to fungal infection, bacterial infection, post-transplant lymphoproliferative disorder and bleeding. Other non-fatal infections included aspergillus, mucor, herpes encephalitis and CMV reactivation. While these preliminary results are encouraging, poor immune reconstitution leading to serious infections and post-transplant lymphoproliferative disorders remain barriers to more optimal transplant results. Therefore, our current strategy is to seek ways to improve immune reconstitution after cord blood transplantation in adults.

Since infection remains a major problem after umbilical cord blood transplantation, cell commitment and immune reconstitution are clinically useful goals. One approach is to manipulate the engrafted stem cells to undergo myeloid vs lymphoid differentiation. In the context of Notch activation there is preferential lymphoid differentiation.^{11, 13} This lymphoid differentiation may be helpful as many of the infections in cord blood recipients occur after engraftment, presumably related to poor T-cell function. The effect of PTH on immune reconstitution and engraftment will be examined in cord blood recipients receiving PTH post-transplant.

Our current multicenter cord blood transplantation study is enrolling patients who are between the ages of 18 and 45 and who meet the usual indications for allogeneic transplantation. Patients receive a myeloablative conditioning regimen. Patients will receive PTH at a dose of 100 g per day for 28 days post-transplant or until engraftment. The primary end point will be days to neutrophil engraftment.

The intent of this study is to mimic the excellent results in the murine and monkey system in a clinical scenario in which slow immune reconstitution and poor engraftment remain limiting factors. Although results with cord blood transplantation in adults are improving with the double cord blood approach, infection continues to be an important concern that may be improved by using PTH to manipulate the stem cell niche.

Future applications

The role of the stem cell niche as a target for therapy is just beginning to be explored. Traditionally, it was believed that somatic stem cells could only differentiate into their tissue of origin. Recent data suggests that stem cells have plasticity; they can differentiate into different types of cells, with signals from the microenvironment. Stem cells have been shown to help repair cardiac and neural damage in injured tissue in an animal model. Cord blood cells are a more primitive population than adult bone marrow, and have increased capacity for multilineage differentiation. In a mouse model, cord blood cells injected into the tail vein migrated to infarcted myocardial tissue.³⁶ Infarct size was smaller in the mice treated with cord blood cells. Cord blood cells can be expanded in culture and induced to differentiate into cells with neural markers.³⁷ Recently, cord blood cells have been shown to improve functional recovery in rats that have been subjected to strokes, by middle cerebral artery occlusion. Infarct volume was reduced and behavioral performance increased when a higher dose of cells was infused. Improved understanding of the stem cell niche, and modulation of the stem cell niche, will have impact outside of oncology. The molecular profile of a stem cell niche has been elucidated in a murine fetal liver cell line, using functional genomics.³⁸ A gene expression profile of a stem cell supporting phenotype has been characterized in stromal cell lines.

Human mesenchymal stem cells (MSC), derived from the bone marrow, may be an appropriate source for cellular therapy for degenerative diseases, and as a target for gene therapy. These cells can differentiate into osteogenic cells, in the presence of steroids, or insulin-like growth factor I.³⁹ Clinical studies with human MSC are proceeding in patients after myocardial infarction. Human MSC treated with PTH and vitamin D (3) expressed high levels of osteocalcin and alkaline phosphates, two markers of bone formation.⁴⁰ Calcium formation in MSC was increased by PTH and vitamin D (3), suggesting a future role for altering the stem cell microenvironment.

The marrow microenvironment provides a critical role as a supporting structure for stem cells. The schema for this microenvironment is illustrated in Figure 3. Regulation of the stem cell niche may occur by saturating the place of the niche, moving toward or away from the niche, or by pharmacologic means. Murine and monkey data suggests that improvement of the marrow microenvironment may alter survival after transplantation. Over the next 5 years, targeting this microenvironment and defining its role in humans will be the subject of provocative clinical investigations.

Figure 3.

Regulation of the stem cell microenvironment schema of the dynamic stem cell niche.

Full figure and legend (122K)

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Acknowledgements

I thank Dr Gregor Adams for preparation of figures and Drs Joseph Antin, Henry Kronenberg, David Scadden and Thomas Spitzer for helpful discussions and critical review of the manuscript.