Identification of Unique Hematopoietic Stem Cell Properties

Hematopoietic stem cells (HSC) are sufficient and required for life long production of all blood cell lineages. Steady state HSCs are largely quiescent and we demonstrate that the kinetics of HSC cell cycling are slower compared to more committed progenitor cells also during expansion and self-renewal ex vivo and in physiological conditions. Such slow kinetics during cell division might reflect a unique cell cycle transit of HSCs that could be critical for maintenance of the indispensable HSC pool and explain the observed loss of engraftment capacity of dividing cells in bone marrow populations enriched for HSCs.

Recent studies have suggested that HSCs might possess a much broader differentiation potential but in most cases the reported efficiency of such developmental plasticity has been rather low. We demonstrate that HSCs efficiently engraft within the infarcted myocardium following transplantation. However, engraftment is transitory and hematopoietic in nature. Our findings challenge the experimental basis for ongoing extensive clinical bone marrow transplantation trials of myocardial infarction patients, as these trials were largely initiated on the assumption that HSCs could generate high levels of cardiomyocytes through transdifferentiation. In contrast, low frequency HSC-derived cardiomyocytes were observed outside the infarcted myocardium, but were exclusively derived through cell fusion. Although such heterotypic cell fusion with hematopoietic cells and cardiomyocytes, Purkinje neurons, skeletal muscle and hepatocytes could be detected following injury induction of adult mice it did not occur in steady state tissues. On the other hand during fetal development lymphocyte-derived hepatocytes and Purkinje neurons demonstrate for the first time that the hematopoietic system might contribute toward non-hematopoietic cell lineages through fusion during normal fetal development.