- Email: [email protected]
mesenchymal stromal cell niche?
Cytotherapy, 2014; 16: 1e2
COMMENTARY
Does plerixafor destroy the hematopoietic progenitor cell/mesenchymal stromal cell niche?
IAN MCNIECE & ELIZABETH SHPALL The University of Texas MD Anderson Cancer Center, Houston Texas, USA
Tissue homeostasis is dependent on replacement of damaged and aged cells, and stem cells are the primary source of new cell generation. Most tissue and organs of the body contain stromal cells that are part of the stem cell niche and are essential for the maintenance, proliferation and differentiation of stem cells. Hematopoiesis is a well-characterized tissue system in which interactions between hematopoietic stem cells (HSCs) and stromal cells in the bone marrow (BM) have been clearly established (1e3). The BM environment is subject to complex regulation that is critical for hematopoiesis. Many studies have demonstrated the production of both stimulating and inhibitory factors by BM stromal cells (mesenchymal stromal cells, MSCs) (4e6). However, the full potential of MSCs and their role in control of the HSC proliferation and differentiation remains unclear. Critical to sustained hematopoiesis is the maintenance of stem cell quiescence. Without a niche in which a stem cell pool can reside unstimulated by proliferative and differentiation signals, hematopoiesis cannot be sustained life-long. There is evidence that HSC quiescence is at least in part regulated by direct contact between HSCs and MSCs. This contact is mediated through chemokine receptor 4 (CXCR4) on HSCs engaging stromal cellederived factor (SDF)-1 on MSCs (7). With the advent of plerixafor—a CXCR4 antagonist used to mobilize HSCs for stem cell transplantation—it is pertinent to ask how this agent interferes with HSC/MSC interactions. In this issue of Cytotherapy, Ludwig et al. (8) cocultured HSCs and MSCs with and without plerixafor, studying cell division kinetics and stem cell surface marker changes to explore the relationship between HSCs and MSCs and the role of the CXCR4/SDF-1 axis. They found that co-culture of
HSCs with MSCs increased cell division but with an increased proportion of cells retaining CD34 expression. These cells had a higher colony-forming capacity suggesting that the MSCs sustained and amplified the progenitor population. This effect was robust and maintained in different culture conditions. Surprisingly, HSCs cultured with MSCs had reduced CXCR4 expression. The addition of plerixafor did not reduce the colony-forming capacity but did reduce cell division kinetics. The authors conclude that the CXCR4/SDF-1 axis is critical for HSC/MSC interaction with respect to migration, adhesion and regulation of proliferation but not maintenance of primitive progenitor cells. These findings are of great interest but should be considered more as hypothesis-generating rather than definitive. A shortcoming of the study is that it was not powered to distinguish between hematopoietic stem cells and more committed progenitor cells. The literature clearly defines HSCs as more primitive than HPCs and that self-renewal (or stemness) is lost with differentiation of HSCs to HPCs (9,10). This question of the role of plerixafor on the true HSC progenitor of the HPC remains unresolved. Future studies evaluating HSC potential in vivo in non-obese diabetic/severe combined immune-deficient mice will shed more definitive light on this issue. Disclosure of interests: The authors have no commercial, proprietary, or financial interest in the products or companies described in this article. References 1. Lichtman MA. The ultrastructure of the hematopoietic microenvironment of the marrow: a review. Exp Hematol. 1981;9:391.
Correspondence: Elizabeth Shpall, MD, 1515 Holcombe, BLVE-423, Houston, TX 77030. E-mail: [email protected]
ISSN 1465-3249 Copyright Ó 2014, published by Elsevier Inc. on behalf of International Society for Cellular Therapy. http://dx.doi.org/10.1016/j.jcyt.2013.12.002
2
I. McNiece & E. Shpall
2. Bianco P, Riminucci M. The bone marrow stroma in vivo: ontogeny, structure, cellular composition and changes in disease. In: Beresford JN, Owens ME, editors. Marrow Stromal Cell Culture. Handbooks in Practical Animal Cell Biology. Cambridge, United Kingdom: Cambridge University Press; 1998. p. 1025. 3. Dexter TM. Stromal cell associated haemopoiesis. J Cell Physiol Suppl. 1982;1:87. 4. Deans RJ, Moseley AB. Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol. 2000;28:875. 5. Le Blanc K, Rasmusson I, Gotherstrom C, et al. Mesenchymal stem cells inhibit the expression of CD25 (interleukin2 receptor) and CD38 on phytohaemagglutinin-activated lymphocytes. Scand J Immunol. 2004;60:307e15. 6. Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and
7.
8.
9.
10.
prolong skin graft survival in vivo. Exp Hematol. 2002;30: 42e8. Devine SM, Vij R, Rettig M, et al. Rapid mobilization of functional donor of hematopoietic cells without G-CSF using AMD3100, an antagonist of the CXCR4/SDF-1 interaction. Blood. 2008;112:990e8. Ludwig A, Saffrich R, Eckstein V, et al. Functional potentials of human hematopoietic progenitor cells are maintained by mesenchymal stromal cells and not impaired by plerixafor. Cytotherapy. 2014;16:111e21. Jones RJ, Celano P, Sharkis SJ, Sensenbrenner LL. Two phases of engraftment established by serial bone marrow transplantation in mice. Blood. 1989;73:397. Shizuru JA, Negrin RS, Weissman IL. Hematopoietic stem and progenitor cells: clinical and preclinical regeneration of the hematolymphoid system. Stem Cells. 2004;22:1292.
COMMENTARY
Does plerixafor destroy the hematopoietic progenitor cell/mesenchymal stromal cell niche?
IAN MCNIECE & ELIZABETH SHPALL The University of Texas MD Anderson Cancer Center, Houston Texas, USA
Tissue homeostasis is dependent on replacement of damaged and aged cells, and stem cells are the primary source of new cell generation. Most tissue and organs of the body contain stromal cells that are part of the stem cell niche and are essential for the maintenance, proliferation and differentiation of stem cells. Hematopoiesis is a well-characterized tissue system in which interactions between hematopoietic stem cells (HSCs) and stromal cells in the bone marrow (BM) have been clearly established (1e3). The BM environment is subject to complex regulation that is critical for hematopoiesis. Many studies have demonstrated the production of both stimulating and inhibitory factors by BM stromal cells (mesenchymal stromal cells, MSCs) (4e6). However, the full potential of MSCs and their role in control of the HSC proliferation and differentiation remains unclear. Critical to sustained hematopoiesis is the maintenance of stem cell quiescence. Without a niche in which a stem cell pool can reside unstimulated by proliferative and differentiation signals, hematopoiesis cannot be sustained life-long. There is evidence that HSC quiescence is at least in part regulated by direct contact between HSCs and MSCs. This contact is mediated through chemokine receptor 4 (CXCR4) on HSCs engaging stromal cellederived factor (SDF)-1 on MSCs (7). With the advent of plerixafor—a CXCR4 antagonist used to mobilize HSCs for stem cell transplantation—it is pertinent to ask how this agent interferes with HSC/MSC interactions. In this issue of Cytotherapy, Ludwig et al. (8) cocultured HSCs and MSCs with and without plerixafor, studying cell division kinetics and stem cell surface marker changes to explore the relationship between HSCs and MSCs and the role of the CXCR4/SDF-1 axis. They found that co-culture of
HSCs with MSCs increased cell division but with an increased proportion of cells retaining CD34 expression. These cells had a higher colony-forming capacity suggesting that the MSCs sustained and amplified the progenitor population. This effect was robust and maintained in different culture conditions. Surprisingly, HSCs cultured with MSCs had reduced CXCR4 expression. The addition of plerixafor did not reduce the colony-forming capacity but did reduce cell division kinetics. The authors conclude that the CXCR4/SDF-1 axis is critical for HSC/MSC interaction with respect to migration, adhesion and regulation of proliferation but not maintenance of primitive progenitor cells. These findings are of great interest but should be considered more as hypothesis-generating rather than definitive. A shortcoming of the study is that it was not powered to distinguish between hematopoietic stem cells and more committed progenitor cells. The literature clearly defines HSCs as more primitive than HPCs and that self-renewal (or stemness) is lost with differentiation of HSCs to HPCs (9,10). This question of the role of plerixafor on the true HSC progenitor of the HPC remains unresolved. Future studies evaluating HSC potential in vivo in non-obese diabetic/severe combined immune-deficient mice will shed more definitive light on this issue. Disclosure of interests: The authors have no commercial, proprietary, or financial interest in the products or companies described in this article. References 1. Lichtman MA. The ultrastructure of the hematopoietic microenvironment of the marrow: a review. Exp Hematol. 1981;9:391.
Correspondence: Elizabeth Shpall, MD, 1515 Holcombe, BLVE-423, Houston, TX 77030. E-mail: [email protected]
ISSN 1465-3249 Copyright Ó 2014, published by Elsevier Inc. on behalf of International Society for Cellular Therapy. http://dx.doi.org/10.1016/j.jcyt.2013.12.002
2
I. McNiece & E. Shpall
2. Bianco P, Riminucci M. The bone marrow stroma in vivo: ontogeny, structure, cellular composition and changes in disease. In: Beresford JN, Owens ME, editors. Marrow Stromal Cell Culture. Handbooks in Practical Animal Cell Biology. Cambridge, United Kingdom: Cambridge University Press; 1998. p. 1025. 3. Dexter TM. Stromal cell associated haemopoiesis. J Cell Physiol Suppl. 1982;1:87. 4. Deans RJ, Moseley AB. Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol. 2000;28:875. 5. Le Blanc K, Rasmusson I, Gotherstrom C, et al. Mesenchymal stem cells inhibit the expression of CD25 (interleukin2 receptor) and CD38 on phytohaemagglutinin-activated lymphocytes. Scand J Immunol. 2004;60:307e15. 6. Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and
7.
8.
9.
10.
prolong skin graft survival in vivo. Exp Hematol. 2002;30: 42e8. Devine SM, Vij R, Rettig M, et al. Rapid mobilization of functional donor of hematopoietic cells without G-CSF using AMD3100, an antagonist of the CXCR4/SDF-1 interaction. Blood. 2008;112:990e8. Ludwig A, Saffrich R, Eckstein V, et al. Functional potentials of human hematopoietic progenitor cells are maintained by mesenchymal stromal cells and not impaired by plerixafor. Cytotherapy. 2014;16:111e21. Jones RJ, Celano P, Sharkis SJ, Sensenbrenner LL. Two phases of engraftment established by serial bone marrow transplantation in mice. Blood. 1989;73:397. Shizuru JA, Negrin RS, Weissman IL. Hematopoietic stem and progenitor cells: clinical and preclinical regeneration of the hematolymphoid system. Stem Cells. 2004;22:1292.