| First Author | Shin JY | Year | 2014 |
| Journal | J Exp Med | Volume | 211 |
| Issue | 2 | Pages | 217-31 |
| PubMed ID | 24446491 | Mgi Jnum | J:208343 |
| Mgi Id | MGI:5562956 | Doi | 10.1084/jem.20131128 |
| Citation | Shin JY, et al. (2014) High c-Kit expression identifies hematopoietic stem cells with impaired self-renewal and megakaryocytic bias. J Exp Med 211(2):217-31 |
| abstractText | 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. |
