Changes in the cytokine regulation of stem cell self-renewal during ontogeny.
The last 10 years have seen the development of a quantitative assay that is specific for transplantable totipotent murine hematopoietic cells with durable in vivo blood-forming ability. Recently, this assay has been successfully adapted to allow the detection and enumeration of an analogous population of human hematopoietic stem cells using myelosuppressed immunodeficient (nonobese diabetic/severe-combined immunodeficiency) mice as recipients. Characterization of the cells detected by this assay indicates their close relationship in both mice and humans with cells detected in vitro as long-term culture-initiating cells (LTC-IC). Culture conditions have now been identified that support a significant net expansion of these cells from both species. More detailed analyses of the cytokine requirements for this response indicate that the viability, mitogenesis and maintenance of LTC-IC function by human CD34+ CD38- cells can be independently regulated by exogenous factors. Superimposed on this uncoupling of hematopoietic stem cell "self-renewal" and proliferation control is a change during ontogeny in the particular cytokines that regulate their responses. These findings unite stochastic and deterministic models of hematopoietic stem cell control through the concept of a molecular mechanism that actively blocks stem cell differentiation and must be maintained when these cells are stimulated to divide by exposure to certain types and concentrations of cytokines.
Eaves
C
C
Terry Fox Laboratory, British Columbia Cancer Agency, Canada.
Zandstra
P
P
Conneally
E
E
Miller
C
C
Cashman
J
J
Petzer
A
A
Piret
J
J
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002454:Cell Differentiation; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014183:Transplantation, Heterologous
D016207:Cytokines