The ultimate source of human hematopoietic stem cells: Thinking outside the marrow

The ability to reconstitute cellular components of the hematopoietic system has immense utility in several areas of clinical medicine. These include replacement of cells responsible for innate and acquired immunity, providing red cells for oxygen transport, and ultimately the ability to recover hematopoietic function by repopulating all lineages comprising the entire blood system. This latter property functionally defines the mammalian hematopoietic stem cell (HSC). Recently, human embryonic stem cells (ESCs) have been suggested to be a viable source of transplantable hematopoietic cells. Although the number of human ESCs is virtually unlimited, the ability to efficiently differentiate adequate numbers of cells that possess hematopoietic repopulating ability remains to be determined. Achieving this goal is confounded by the difficulty of experimentally generating murine hematopoietic cell types capable of in vivo reconstitution from mouse ESC, suggesting that similar limitations may arise using human counterparts. Although the use of human ESCs and adult somatic HSCs have their independent merits, a direct comparison between HSCs derived from each source using similar assays will ultimately be required to determine the best source for clinical use. Here we will summarize the results from efforts to differentiate and assay primitive hematopoietic cells derived from ESCs, and compare these findings to similar parameters using putative mammalian HSCs harvested from the adult.