Unique differentiation programs of human fetal liver stem cells shown bothin vitro and in vivo in NOD/SCID mice

Comparative measurements of different types of hematopoietic progenitors pr esent in human fetal liver, cord blood, and adult marrow showed a large (up to 250-fold), stage-specific, but lineage-unrestricted, amplification of t he colony-forming cell (CFC) compartment in the fetal liver, with a higher ratio of all types of CFC to long-term culture-initiating cells (LTC-IC) an d a lower ratio of total (mature) cells to CFC. Human fetal liver LTC-IC we re also found to produce more CFC in LTC than cord blood or adult marrow LT C-IC, and more of the fetal liver LTC-IC-derived CFC were erythroid. Human fetal liver cells regenerated human multilineage hematopoiesis in NOD/SCID mice with the same kinetics as human cord blood and adult marrow cells, but sustained a high level of terminal erythropoiesis not seen in adult marrow -engrafted mice unless exogenous human erythropoietin (Epo) was injected. T his may be due to a demonstrated 10-fold lower activity of murine versus hu man Epo on human cells, sufficient to distinguish between a differential Ep o sensitivity of fetal and adult erythroid precursors. Examination of human LTC-IC, CFC, and erythroblasts generated either in NOD/SCID mice and/or in LTC showed the types of cells and hemoglobins produced also to reflect the ir ontological origin, regardless of the environment in which the erythroid precursors were generated. We suggest that ontogeny may affect the behavio r of cells at many stages of hematopoietic cell differentiation through key changes in shared signaling pathways. (C) 1999 by The American Society of Hematology.