Stem cell repopulation efficiency but not pool size is governed by p27(kip1).
Sustained blood cell production requires preservation of a quiescent, multipotential stem cell pool that intermittently gives rise to progenitors with robust proliferative potential. The ability of cells to shift from a highly constrained to a vigorously active proliferative state is critical for maintaining stem cells while providing the responsiveness necessary for host defense. The cyclin-dependent kinase inhibitor (CDKI), p21(cip1/waf1) (p21) dominates stem cell kinetics. Here we report that another CDKI, p27(kip1) (p27), does not affect stem cell number, cell cycling, or self-renewal, but markedly alters progenitor proliferation and pool size. Therefore, distinct CDKIs govern the highly divergent stem and progenitor cell populations. When competitively transplanted, p27-deficient stem cells generate progenitors that eventually dominate blood cell production. Modulating p27 expression in a small number of stem cells may translate into effects on the majority of mature cells, thereby providing a strategy for potentiating the impact of transduced cells in stem cell gene therapy.
Cheng
T
T
Massachusetts General Hospital AIDS Research Center, Harvard Medical School, 149 13th Street, Room 5212 Boston, Massachusetts 02129, USA. cheng-tao@mgh.harvard.edu
Rodrigues
N
N
Dombkowski
D
D
Stier
S
S
Scadden
D T
DT
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D003433:Crosses, Genetic; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D005260:Female; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D006579:Heterozygote; D006720:Homozygote; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D025521:Tumor Suppressor Proteins
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases