Intermediate-term hematopoietic stem cells with extended but time-limited reconstitution potential.
Sustained blood cell production depends on divisions by hematopoietic stem cells (HSCs) that yield both differentiating progeny as well as new HSCs via self-renewal. Differentiating progeny remain capable of self-renewal, but only HSCs sustain self-renewal through successive divisions securely enough to maintain clones that persist life-long. Until recently, the first identified next stage consisted of "short-term" reconstituting cells able to sustain clones of differentiating cells for only 4-6 weeks. Here we expand evidence for a numerically dominant "intermediate-term" multipotent HSC stage in mice whose clones persist for 6-8 months before becoming extinct and that are separable from both short-term as well as permanently reconstituting "long-term" HSCs. The findings suggest that the first step in stem cell differentiation consists not in loss of initial capacity for serial self-renewal divisions, but rather in loss of mechanisms that stabilize self-renewing behavior throughout successive future stem cell divisions.
Benveniste
Patricia
P
Ontario Cancer Institute, Toronto, ON M5G 2M9, Canada.
Frelin
Catherine
C
Janmohamed
Salima
S
Barbara
Mary
M
Herrington
Robert
R
Hyam
Deborah
D
Iscove
Norman N
NN
D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D018952:Antigens, CD34 / Q000235:genetics; D002454:Cell Differentiation; D002455:Cell Division; D019070:Cell Lineage; D002469:Cell Separation; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D039421:Integrin alpha2 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D011956:Receptors, Cell Surface / Q000235:genetics; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D013997:Time Factors; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
D015703:Antigens, CD; D018952:Antigens, CD34; D039421:Integrin alpha2; D011956:Receptors, Cell Surface; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3