Stem Cells: The Lessons from Hematopoieses

The driving force that led to the isolation of hematopoietic stem cells (HSCs) was primarily medical, and not simply biological, inquiry. Following the massive exposure of the civilian populations to ionizing radiation in 1945, experimental animal models of whole body lethal radiation soon revealed that the deaths that occur at the lowest lethal doses were the result of a disrupted hematopoietic system: the loss of granulocytes led to infection, the loss of platelets led to bleeding, and the loss of red blood cells led to fatal anemias. This fatal radiation syndrome could be prevented by shielding a single long bone, or by injecting bone marrow from identical twin mice into the irradiated host. Two sets of discoveries set the stage for the isolation of HSCs: 1) In 1956 three groups demonstrated that bone marrow (chromosomally marked) injected into lethally irradiated hosts saved the hosts by reconstituting the host hematolymphoid system with donor-derived cells (Ford et al. 1956; Makinodan 1956; Nowell et al. 1956). 2) In 1961 while seeking an assay to understand the potential different effects of x-rays on normal versus neoplastic cells, Till and McCulloch (1961) observed that limiting doses of bone marrow injected into lethally irradiated mice resulted in the appearance of spleen colonies, each colony containing several different cell types in the myelo- erythroid series. Pre-irradiation of the donor resulted in random chromosomal translocations in donor bone marrow (BM); limiting doses of that marked BM resulted in a spleen colony (CFU-S) within which all cells bear the same unique translocation.