Identification of a new intrinsically timed developmental checkpoint that reprograms key hematopoietic stem cell properties

Hematopoietic stem cells (HSCs) execute self-renewal divisions throughout fetal and adult life, although some of their properties do alter. Here we analyzed the magnitude and timing of changes in the self-renewal properties and differentiated cell outputs of transplanted HSCs obtained from different sources during development. We also assessed the expression of several “stem cell” genes in corresponding populations of highly purified HSCs. Fetal and adult HSCs displayed marked differences in their self-renewal, differentiated cell output, and gene expression properties, with persistence of a fetal phenotype until 3 weeks after birth. Then, 1 week later, the HSCs became functionally indistinguishable from adult HSCs. The same schedule of changes in HSC properties occurred when HSCs from fetal or 3-week-old donors were transplanted into adult recipients. These findings point to the existence of a previously unrecognized, intrinsically regulated master switch that effects a developmental change in key HSC properties.

[1]  David G Kent,et al.  Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defect. , 2006, The Journal of clinical investigation.

[2]  T. Rando.  Stem cells, ageing and the quest for immortality , 2006, Nature.

[3]  Eric Jervis,et al.  High-resolution video monitoring of hematopoietic stem cells cultured in single-cell arrays identifies new features of self-renewal. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[4]  G. de Haan,et al.  Cellular Memory and Hematopoietic Stem Cell Aging , 2006, Stem cells.

[5]  Yan Liu,et al.  The transcription factor MEF/ELF4 regulates the quiescence of primitive hematopoietic cells. , 2006, Cancer cell.

[6]  Mark A. Hall,et al.  In vivo fate-tracing studies using the Scl stem cell enhancer: embryonic hematopoietic stem cells significantly contribute to adult hematopoiesis. , 2004, Blood.

[7]  B. Hadland,et al.  A requirement for Notch1 distinguishes 2 phases of definitive hematopoiesis during development. , 2004, Blood.

[8]  Elaine Dzierzak,et al.  GATA-2 Plays Two Functionally Distinct Roles during the Ontogeny of Hematopoietic Stem Cells , 2004, The Journal of experimental medicine.

[9]  S. E. Jacobsen,et al.  Enforced expression of cyclin D2 enhances the proliferative potential of myeloid progenitors, accelerates in vivo myeloid reconstitution, and promotes rescue of mice from lethal myeloablation. , 2004, Blood.

[10]  Mark A. Hall,et al.  SCL is required for normal function of short-term repopulating hematopoietic stem cells. , 2004, Blood.

[11]  S. Ogawa,et al.  AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis , 2004, Nature Medicine.

[12]  C. Eaves,et al.  Different in vivo repopulating activities of purified hematopoietic stem cells before and after being stimulated to divide in vitro with the same kinetics. , 2003, Experimental hematology.

[13]  Cindy L. Miller,et al.  The marrow homing efficiency of murine hematopoietic stem cells remains constant during ontogeny. , 2003, Experimental hematology.

[14]  E. Dzierzak.  Hematopoietic stem cells and their precursors: developmental diversity and lineage relationships , 2002, Immunological reviews.

[15]  H. Nakauchi,et al.  Age-Associated Characteristics of Murine Hematopoietic Stem Cells , 2000, The Journal of experimental medicine.

[16]  I. Weissman,et al.  In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Cindy L. Miller,et al.  Impaired steel factor responsiveness differentially affects the detection and long-term maintenance of fetal liver hematopoietic stem cells in vivo. , 1997, Blood.

[18]  C. Eaves,et al.  Evidence of both ontogeny and transplant dose-regulated expansion of hematopoietic stem cells in vivo. , 1996, Blood.

[19]  Andrew W. Murray,et al.  Association of Spindle Assembly Checkpoint Component XMAD2 with Unattached Kinetochores , 1996, Science.

[20]  C. Begley,et al.  The scl gene product is required for the generation of all hematopoietic lineages in the adult mouse. , 1996, The EMBO journal.

[21]  Hiromitsu Nakauchi,et al.  Long-Term Lymphohematopoietic Reconstitution by a Single CD34-Low/Negative Hematopoietic Stem Cell , 1996, Science.

[22]  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.

[23]  S. Orkin,et al.  Hematopoiesis: how does it happen? , 1995, Current opinion in cell biology.

[24]  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.

[25]  Ihor R. Lemischka,et al.  Developmental potential and dynamic behavior of hematopoietic stem cells , 1986, Cell.

[26]  G. Keller,et al.  Expression of a foreign gene in myeloid and lymphoid cells derived from multipotent haematopoietic precursors , 1985, Nature.

[27]  D. Boggs,et al.  The total marrow mass of the mouse: A simplified method of measurement , 1984, American journal of hematology.

[28]  D. Harrison,et al.  Loss of stem cell repopulating ability upon transplantation. Effects of donor age, cell number, and transplantation procedure , 1982, The Journal of experimental medicine.

[29]  C. F. Wandel.  Progress in nuclear energy, series II: Reactors, Vol. 2, H.R. McK. Hyder (Ed.). Pergamon Press, Oxford (1961), vi-576 p. 105s , 1962 .