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J Exp Med. 2014 Feb 10;211(2):217-31. doi: 10.1084/jem.20131128. Epub 2014 Jan 20.

High c-Kit expression identifies hematopoietic stem cells with impaired self-renewal and megakaryocytic bias.

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Human Oncology and Pathogenesis Program and 2 Department of Pathology and 3 Department of Laboratory Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.


Hematopoietic stem cells (HSCs) are heterogeneous with respect to their self-renewal, lineage, and reconstitution potentials. Although c-Kit is required for HSC function, gain and loss-of-function c-Kit mutants suggest that even small changes in c-Kit signaling profoundly affect HSC function. Herein, we demonstrate that even the most rigorously defined HSCs can be separated into functionally distinct subsets based on c-Kit activity. Functional and transcriptome studies show HSCs with low levels of surface c-Kit expression (c-Kit(lo)) and signaling exhibit enhanced self-renewal and long-term reconstitution potential compared with c-Kit(hi) HSCs. Furthermore, c-Kit(lo) and c-Kit(hi) HSCs are hierarchically organized, with c-Kit(hi) HSCs arising from c-Kit(lo) HSCs. In addition, whereas c-Kit(hi) HSCs give rise to long-term lymphomyeloid grafts, they exhibit an intrinsic megakaryocytic lineage bias. These functional differences between c-Kit(lo) and c-Kit(hi) HSCs persist even under conditions of stress hematopoiesis induced by 5-fluorouracil. Finally, our studies show that the transition from c-Kit(lo) to c-Kit(hi) HSC is negatively regulated by c-Cbl. Overall, these studies demonstrate that HSCs exhibiting enhanced self-renewal potential can be isolated based on c-Kit expression during both steady state and stress hematopoiesis. Moreover, they provide further evidence that the intrinsic functional heterogeneity previously described for HSCs extends to the megakaryocytic lineage.

[Indexed for MEDLINE]
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