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Introduction: The biologic basis of stem-cell therapy
Seminm
in
HEMATOLOGY Vol
Introduction:
37, No 1, Suppl 2, January 2000
The Biologic Basis of Stem-Cell Therapy
John F. DiPenio
T
HIS SUPPLEMENT TO Seminars in Hematology summarizes recent findings in basic stem-cell biology, including mechanisms of stem- and progenitor-cell mobilization, strategies for ex vivo manipulations of human CD34+ cells, and improvements in allogeneic blood stem-cell transplantation. These articles were based on presentations made at a Washington University School of Medicine satellite symposium of the 39th Annual Meeting of the American Society of Hematology on December 5, 1997. In this supplement, recent findings are discussed that have major implications for the conventional concept of hematopoiesis and lead to paradigm shifts in this field. G. Spangrude and D. Cooper discuss several important aspects of stem-cell biology. Examples include the awareness of hematopoietic stem cells that lack CD34 and the knowledge of limitations in the self-renewal potential. There is now the possibility that two general stem-cell compartments exist in the bone marrow, one that frequently cycles and is the primary source of blood production over time, and another that rarely cycles but represents the major source of engraftment post-transplant. This hypothesis is in line with the observation that primitive, noncycling stem cells are capable of rapidly engrafting an irradiated recipient, while the contribution of progenitor cells to early recovery after transplantation is rather limited. Finally, the recent description of a common lymphoid proSeminars
in Hematology,
genitor cell that can give rise to macrophages and dendritic cells, as well as a segregation of erythroid and megakaryocytic lineages from other myeloid lineages, requires a new concept of the hematopoietic hierarchy. Articles by T. Papayannopoulou, W. Fibbe, and D. Link provide insights into the molecules and mechanisms involved in stem- and progenitor-cell mobilization. Cross-talk between hematopoietic cells and the bone marrow microenvironment via cytoadhesive interactions, as well as the effects of hematopoietic growth factors, cytokines, and chemokines mediated via specific cellular receptors, play a major role. Dr Papayannopoulou, who has investigated the VLA4/VCAM-1 pathway, suggests that decreased expression of VLA-4 on mobilized CD34+ cells may play a role in mobilization. In addition, she observed that granulocyte colonystimulating factor (G-CSF) receptors are not required to elicit the anti-VLA-4 response, suggesting that the mobilizing effects of G-CSF and anti-VLA4 are due to additive effects of the two different treatment strategies. In conFrom the Division of Bone Marrow Transplantation and Stem Cell Biology, Washington University School of Medicine, St Louis, MO. Address reprint reqztests to John F. DiPersio, MD, PhD, Division of Bone Marrow Transplantation and Stem Cell Biology, Washington University School of Medicine, 660 S Euclid, St Louis, MO 63 110. Copyright 0 2000 by W.B. Saunders Company 003 7-l 963/00/3701-2001$10.00/0
Vol 37, No 1, Sup@ 2 (January),
2000:
pp l-2
1
2
John F. Dipersio
trast, data from Dr Link suggest that a functional G-CSF receptor is required for mobilization of progenitor cells in response to cytotoxic chemotherapy (eg, cyclophosphamide) and interleukin (IL)-& but not in responsetoJZt-3 ligand or IL-12. Lastly, Fibbe et al propose that the IL-8-induced mobilization of peripheral blood progenitor cells in mice and monkeys may be due to the rapid release of the metalloproteinase gelatinase-B, which in turn cleaves the extracellular matrix proteins to which progenitor and stem cells are attached in the bone marrow microenvironment. Collectively, these data argue for a multistep process, including a triggering event (eg, mediated by chemokines such asIL-8 and stromal-cellderived factor-l {SDF-1)) and an amplification step (mediated by hematopoietic growth factors). These lead to changesin the bone marrow microenvironment, which in turn leads to progenitorand stem-cell mobilization. The article by Brugger et al summarizes a number of ex vivo manipulations of human
CD34+ stem and progenitor cells, which have been made possible due to advancesin CD34-cell enrichment technology, as well as the identification of novel cytokines and hematopoietic growth factors. Using this technology, it is now possible to generate both primitive and more mature hematopoietic cells of various lineagesfrom purified CD34+ cells ex vivo, opening new perspectives in the cellular therapy of hematopoietic malignancies. Initial clinical experience with ex vivo-generated stem and progenitor cells is also discussed. Finally, I and my colleagues describe recent developments in allogeneic blood stem-/progenitor-cell transplantation. In conjunction with ex vivo manipulations of CD34+ progenitor cells, these advancesmay help to ameliorate pancytopenia following transplantation. Such innovative approaches,together with new knowledge in basic stem-cell biology, will certainly have profound implications for clinical stem-cell transplantation in the near future.
in
HEMATOLOGY Vol
Introduction:
37, No 1, Suppl 2, January 2000
The Biologic Basis of Stem-Cell Therapy
John F. DiPenio
T
HIS SUPPLEMENT TO Seminars in Hematology summarizes recent findings in basic stem-cell biology, including mechanisms of stem- and progenitor-cell mobilization, strategies for ex vivo manipulations of human CD34+ cells, and improvements in allogeneic blood stem-cell transplantation. These articles were based on presentations made at a Washington University School of Medicine satellite symposium of the 39th Annual Meeting of the American Society of Hematology on December 5, 1997. In this supplement, recent findings are discussed that have major implications for the conventional concept of hematopoiesis and lead to paradigm shifts in this field. G. Spangrude and D. Cooper discuss several important aspects of stem-cell biology. Examples include the awareness of hematopoietic stem cells that lack CD34 and the knowledge of limitations in the self-renewal potential. There is now the possibility that two general stem-cell compartments exist in the bone marrow, one that frequently cycles and is the primary source of blood production over time, and another that rarely cycles but represents the major source of engraftment post-transplant. This hypothesis is in line with the observation that primitive, noncycling stem cells are capable of rapidly engrafting an irradiated recipient, while the contribution of progenitor cells to early recovery after transplantation is rather limited. Finally, the recent description of a common lymphoid proSeminars
in Hematology,
genitor cell that can give rise to macrophages and dendritic cells, as well as a segregation of erythroid and megakaryocytic lineages from other myeloid lineages, requires a new concept of the hematopoietic hierarchy. Articles by T. Papayannopoulou, W. Fibbe, and D. Link provide insights into the molecules and mechanisms involved in stem- and progenitor-cell mobilization. Cross-talk between hematopoietic cells and the bone marrow microenvironment via cytoadhesive interactions, as well as the effects of hematopoietic growth factors, cytokines, and chemokines mediated via specific cellular receptors, play a major role. Dr Papayannopoulou, who has investigated the VLA4/VCAM-1 pathway, suggests that decreased expression of VLA-4 on mobilized CD34+ cells may play a role in mobilization. In addition, she observed that granulocyte colonystimulating factor (G-CSF) receptors are not required to elicit the anti-VLA-4 response, suggesting that the mobilizing effects of G-CSF and anti-VLA4 are due to additive effects of the two different treatment strategies. In conFrom the Division of Bone Marrow Transplantation and Stem Cell Biology, Washington University School of Medicine, St Louis, MO. Address reprint reqztests to John F. DiPersio, MD, PhD, Division of Bone Marrow Transplantation and Stem Cell Biology, Washington University School of Medicine, 660 S Euclid, St Louis, MO 63 110. Copyright 0 2000 by W.B. Saunders Company 003 7-l 963/00/3701-2001$10.00/0
Vol 37, No 1, Sup@ 2 (January),
2000:
pp l-2
1
2
John F. Dipersio
trast, data from Dr Link suggest that a functional G-CSF receptor is required for mobilization of progenitor cells in response to cytotoxic chemotherapy (eg, cyclophosphamide) and interleukin (IL)-& but not in responsetoJZt-3 ligand or IL-12. Lastly, Fibbe et al propose that the IL-8-induced mobilization of peripheral blood progenitor cells in mice and monkeys may be due to the rapid release of the metalloproteinase gelatinase-B, which in turn cleaves the extracellular matrix proteins to which progenitor and stem cells are attached in the bone marrow microenvironment. Collectively, these data argue for a multistep process, including a triggering event (eg, mediated by chemokines such asIL-8 and stromal-cellderived factor-l {SDF-1)) and an amplification step (mediated by hematopoietic growth factors). These lead to changesin the bone marrow microenvironment, which in turn leads to progenitorand stem-cell mobilization. The article by Brugger et al summarizes a number of ex vivo manipulations of human
CD34+ stem and progenitor cells, which have been made possible due to advancesin CD34-cell enrichment technology, as well as the identification of novel cytokines and hematopoietic growth factors. Using this technology, it is now possible to generate both primitive and more mature hematopoietic cells of various lineagesfrom purified CD34+ cells ex vivo, opening new perspectives in the cellular therapy of hematopoietic malignancies. Initial clinical experience with ex vivo-generated stem and progenitor cells is also discussed. Finally, I and my colleagues describe recent developments in allogeneic blood stem-/progenitor-cell transplantation. In conjunction with ex vivo manipulations of CD34+ progenitor cells, these advancesmay help to ameliorate pancytopenia following transplantation. Such innovative approaches,together with new knowledge in basic stem-cell biology, will certainly have profound implications for clinical stem-cell transplantation in the near future.