Circulation and Chemotaxis of Fetal Hematopoietic Stem Cells

The major site of hematopoiesis transitions from the fetal liver to the spleen and bone marrow late in fetal development. To date, experiments have not been performed to evaluate functionally the migration and seeding of hematopoietic stem cells (HSCs) during this period in ontogeny. It has been proposed that developmentally timed waves of HSCs enter the bloodstream only during distinct windows to seed the newly forming hematopoietic organs. Using competitive reconstitution assays to measure HSC activity, we determined the localization of HSCs in the mid-to-late gestation fetus. We found that multilineage reconstituting HSCs are present at low numbers in the blood at all timepoints measured. Seeding of fetal bone marrow and spleen occurred over several days, possibly while stem cell niches formed. In addition, using dual-chamber migration assays, we determined that like bone marrow HSCs, fetal liver HSCs migrate in response to stromal cell-derived factor-1α (SDF-1α); however, unlike bone marrow HSCs, the migratory response of fetal liver HSCs to SDF-1α is greatly increased in the presence of Steel factor (SLF), suggesting an important role for SLF in HSC homing to and seeding of the fetal hematopoietic tissues. Together, these data demonstrate that seeding of fetal organs by fetal liver HSCs does not require large fluxes of HSCs entering the fetal bloodstream, and that HSCs constitutively circulate at low levels during the gestational period from 12 to 17 days postconception. Newly forming hematopoietic tissues are seeded gradually by HSCs, suggesting initial seeding is occurring as hematopoietic niches in the spleen and bone marrow form and become capable of supporting HSC self-renewal. We demonstrate that fetal and adult HSCs exhibit specific differences in chemotactic behavior. While both migrate in response to SDF-1α, fetal HSCs also respond significantly to the cytokine SLF. In addition, the combination of SDF-1α and SLF results in substantially enhanced migration of fetal HSCs, leading to migration of nearly all fetal HSCs in this assay. This finding indicates the importance of the combined effects of SLF and SDF-1α in the migration of fetal HSCs, and is, to our knowledge, the first demonstration of a synergistic effect of two chemoattractive agents on HSCs.

[1]  K. Tokoyoda,et al.  Long-term hematopoietic stem cells require stromal cell-derived factor-1 for colonizing bone marrow during ontogeny. , 2003, Immunity.

[2]  A. M. Morrison,et al.  Quantitative developmental anatomy of definitive haematopoietic stem cells/long-term repopulating units (HSC/RUs): role of the aorta-gonad-mesonephros (AGM) region and the yolk sac in colonisation of the mouse embryonic liver. , 2002, Development.

[3]  F. Wolber,et al.  Roles of spleen and liver in development of the murine hematopoietic system. , 2002, Experimental hematology.

[4]  I. Weissman,et al.  Myeloerythroid-restricted progenitors are sufficient to confer radioprotection and provide the majority of day 8 CFU-S. , 2002, The Journal of clinical investigation.

[5]  U. V. von Andrian,et al.  Total body irradiation causes profound changes in endothelial traffic molecules for hematopoietic progenitor cell recruitment to bone marrow. , 2002, Blood.

[6]  Irving L. Weissman,et al.  Hematopoietic Stem Cells Are Uniquely Selective in Their Migratory Response to Chemokines , 2002, The Journal of experimental medicine.

[7]  Irving L. Weissman,et al.  Physiological Migration of Hematopoietic Stem and Progenitor Cells , 2001, Science.

[8]  R. Alon,et al.  The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34(+) cells: role in transendothelial/stromal migration and engraftment of NOD/SCID mice. , 2000, Blood.

[9]  H. Nakauchi,et al.  Expansion of hematopoietic stem cells in the developing liver of a mouse embryo. , 2000, Blood.

[10]  M. Le Bousse-Kerdilès,et al.  Chemokine SDF-1 enhances circulating CD34(+) cell proliferation in synergy with cytokines: possible role in progenitor survival. , 2000, Blood.

[11]  I. Weissman,et al.  The Role of Apoptosis in the Regulation of Hematopoietic Stem Cells , 2000, The Journal of experimental medicine.

[12]  I. Weissman,et al.  Stem Cells Units of Development, Units of Regeneration, and Units in Evolution , 2000, Cell.

[13]  R. Alon,et al.  The chemokine SDF-1 stimulates integrin-mediated arrest of CD34(+) cells on vascular endothelium under shear flow. , 1999, The Journal of clinical investigation.

[14]  J. Hamada,et al.  Selective secretion of chemoattractants for haemopoietic progenitor cells by bone marrow endothelial cells: a possible role in homing of haemopoietic progenitor cells to bone marrow , 1999, British journal of haematology.

[15]  A. Cumano,et al.  Stem Cell Emergence and Hemopoietic Activity Are Incompatible in Mouse Intraembryonic Sites , 1999, The Journal of experimental medicine.

[16]  Y. Ito,et al.  Hepatic differentiation induced by oncostatin M attenuates fetal liver hematopoiesis. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[17]  T. Kishimoto,et al.  A cell-autonomous requirement for CXCR4 in long-term lymphoid and myeloid reconstitution. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[18]  T. Springer,et al.  The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. , 1999, Immunity.

[19]  J. Greenberger,et al.  Influence of cytokines on the growth kinetics and immunophenotype of daughter cells resulting from the first division of single CD34(+)Thy-1(+)lin- cells. , 1998, Blood.

[20]  J. Groopman,et al.  Stromal cell-derived factor-1 alpha and stem cell factor/kit ligand share signaling pathways in hemopoietic progenitors: a potential mechanism for cooperative induction of chemotaxis. , 1998, Journal of immunology.

[21]  Kouji Matsushima,et al.  The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract , 1998, Nature.

[22]  Masahiko Kuroda,et al.  Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development , 1998, Nature.

[23]  T. Kishimoto,et al.  A novel CXC chemokine PBSF/SDF-1 and its receptor CXCR4: their functions in development, hematopoiesis and HIV infection. , 1998, Seminars in immunology.

[24]  E. Butcher,et al.  Chemokines and the arrest of lymphocytes rolling under flow conditions. , 1998, Science.

[25]  J. Barker Early transplantation to a normal microenvironment prevents the development of Steel hematopoietic stem cell defects. , 1997, Experimental hematology.

[26]  T. Springer,et al.  The Chemokine SDF-1 Is a Chemoattractant for Human CD34+ Hematopoietic Progenitor Cells and Provides a New Mechanism to Explain the Mobilization of CD34+ Progenitors to Peripheral Blood , 1997, The Journal of experimental medicine.

[27]  E. Dzierzak,et al.  Characterization of the first definitive hematopoietic stem cells in the AGM and liver of the mouse embryo. , 1996, Immunity.

[28]  A. Medvinsky,et al.  Definitive Hematopoiesis Is Autonomously Initiated by the AGM Region , 1996, Cell.

[29]  S. Nishikawa,et al.  Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1 , 1996, Nature.

[30]  T. Holyoake,et al.  Ex vivo expansion with stem cell factor and interleukin-11 augments both short-term recovery posttransplant and the ability to serially transplant marrow. , 1996, Blood.

[31]  K. Koike,et al.  Chemotactic and chemokinetic activities of stem cell factor on murine hematopoietic progenitor cells. , 1996, Blood.

[32]  Cindy L. Miller,et al.  The repopulation potential of fetal liver hematopoietic stem cells in mice exceeds that of their liver adult bone marrow counterparts. , 1996, Blood.

[33]  J. García-Porrero,et al.  Potential intraembryonic hemogenic sites at pre-liver stages in the mouse , 1995, Anatomy and Embryology.

[34]  I. Weissman,et al.  The purification and characterization of fetal liver hematopoietic stem cells. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[35]  F. Ruscetti,et al.  Steel factor (c-kit ligand) promotes the survival of hematopoietic stem/progenitor cells in the absence of cell division. , 1995, Blood.

[36]  N. Wolf,et al.  Developmental hematopoiesis from prenatal to young-adult life in the mouse model. , 1995, Experimental hematology.

[37]  I. Weissman,et al.  The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. , 1994, Immunity.

[38]  J. Strouboulis,et al.  Development of hematopoietic stem cell activity in the mouse embryo. , 1994, Immunity.

[39]  I. Weissman,et al.  Evidence that hematopoietic stem cells express mouse c-kit but do not depend on steel factor for their generation. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[40]  N. Nicola,et al.  Direct proliferative actions of stem cell factor on murine bone marrow cells in vitro: effects of combination with colony-stimulating factors. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[41]  D. Williams,et al.  Effect of murine mast cell growth factor (c-kit proto-oncogene ligand) on colony formation by human marrow hematopoietic progenitor cells. , 1991, Blood.

[42]  A. Reith,et al.  The murine W/c-kit and Steel loci and the control of hematopoiesis. , 1991, Seminars in hematology.

[43]  Timothy A. Springer,et al.  Adhesion receptors of the immune system , 1990, Nature.

[44]  D. Chui,et al.  Hemopoietic stem cells in murine embryonic yolk sac and peripheral blood. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[45]  I. Weissman,et al.  A cell-surface molecule involved in organ-specific homing of lymphocytes , 1983, Nature.

[46]  E. Houssaint Differentiation of the mouse hepatic primordium. II. Extrinsic origin of the haemopoietic cell line. , 1981, Cell differentiation.

[47]  T. Dexter,et al.  In vitro duplication and ‘cure’ of haemopoietic defects in genetically anaemic mice , 1977, Nature.

[48]  M. Moore,et al.  Role of stem cell migration in initiation of mouse foetal liver haemopoiesis , 1975, Nature.

[49]  W. Fried,et al.  Studies on the Defective Haematopoietic Microenvironment of Sl/Sld Mice , 1973, British journal of haematology.

[50]  H. Vogel,et al.  Hemopoietic stem cell distribution in tissues of fetal and newborn mice , 1970, Journal of cellular physiology.

[51]  M. Moore,et al.  Ontogeny of the Haemopoietic System: Yolk Sac Origin of In Vivo and In Vitro Colony Forming Cells in the Developing Mouse Embryo * , 1970, British journal of haematology.

[52]  J. Till,et al.  The cellular basis of the genetically determined hemopoietic defect in anemic mice of genotype Sl-Sld. , 1965, Blood.

[53]  I. Weissman,et al.  Lymphoid development from stem cells and the common lymphocyte progenitors. , 1999, Cold Spring Harbor symposia on quantitative biology.

[54]  H. Broxmeyer,et al.  In vitro behavior of hematopoietic progenitor cells under the influence of chemoattractants: stromal cell-derived factor-1, steel factor, and the bone marrow environment. , 1998, Blood.

[55]  A. Cumano,et al.  Circulation of hematopoietic progenitors in the mouse embryo. , 1996, Immunity.

[56]  C. E. van der Schoot,et al.  Constitutive expression of E-selectin and vascular cell adhesion molecule-1 on endothelial cells of hematopoietic tissues. , 1996, The American journal of pathology.

[57]  G. Johnson,et al.  Stem cell factor enhances the survival but not the self-renewal of murine hematopoietic long-term repopulating cells. , 1994, Blood.

[58]  I. Weissman,et al.  Cellular, genetic, and evolutionary aspects of lymphocyte interactions with high-endothelia venules. , 1980, Ciba Foundation symposium.

[59]  E. Russell Hereditary anemias of the mouse: a review for geneticists. , 1979, Advances in genetics.

[60]  L. Smith,et al.  Distribution of injected 59fe in mice. , 1970 .