HEMATOPOIETIC STEM-CELLS - INFERENCES FROM IN-VIVO ASSAYS

Mice and humans both contain a population in their marrow which can pe rmanently regenerate all of the hematopoietic lineages, This developme ntal potential was first demonstrated in myeloablated mice transplante d with genetically marked marrow obtained from congenic donors, More r ecently, this approach has been used to devise an in vivo limiting dil ution assay for ''competitive (lymphomyeloid) repopulating units'' (CR U) that allows murine hematopoietic stem cells to be quantitated, Meas urements of murine CRU have shown that this population expands concomi tantly with the total hematopoietic system during ontogeny and to some extent post-transplant. During these periods of expansion, defective c-kit function can be seen to preferentially compromise CRU self-renew al more than early CRU detection (which requires differentiation and a mplification of the progeny of CRU, but may not require extensive CRU self-renewal). In humans, a similar cell type with transplantable lymp homyeloid differentiation potential can be identified in cord blood on the basis of its ability to engraft sublethally irradiated immunodefi cient nonobese diabetic/severe combined immunodeficient mice, Quantita tion of these human CRU by limiting dilution analysis of unseparated, highly purified (CD34(+)CD38(-)) and cultured (CD34(+)CD38(-)) human c ord blood cells indicates that their numbers (like the long-term cultu re-initiating cell [LTC-IC] population) can be slightly expanded in cy tokine-supplemented serum-free media, although not as extensively as a nticipated from analogous studies of human marrow LTC-IC cultured unde r the same conditions. Taken together, the results of our studies sugg est that the self-renewal of mitotically activated hematopoietic stem cells can be enhanced by their interactions with particular cytokine c ombinations whose effectiveness in this regard may change during ontog eny.