High c-Kit expression identifies hematopoietic stem cells with impaired self-renewal and megakaryocytic bias Journal Article
| Authors: | Shin, J. Y.; Hu, W.; Naramura, M.; Park, C. Y. |
| Article Title: | High c-Kit expression identifies hematopoietic stem cells with impaired self-renewal and megakaryocytic bias |
| Abstract: | 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-Kitlo) and signaling exhibit enhanced self-renewal and long-term reconstitution potential compared with c-Kithi HSCs. Furthermore, c-Kitlo and c-Kithi HSCs are hierarchically organized, with c-Kithi HSCs arising from c-Kitlo HSCs. In addition, whereas c-Kithi HSCs give rise to long-term lymphomyeloid grafts, they exhibit an intrinsic megakaryocytic lineage bias. These functional differences between c-Kitlo and c-Kithi HSCs persist even under conditions of stress hematopoiesis induced by 5-fluorouracil. Finally, our studies show that the transition from c-Kitlo to c-Kithi 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. © 2014 Shin et al. |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 211 |
| Issue: | 2 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2014-02-10 |
| Start Page: | 217 |
| End Page: | 231 |
| Language: | English |
| DOI: | 10.1084/jem.20131128 |
| PROVIDER: | scopus |
| PMCID: | PMC3920569 |
| PUBMED: | 24446491 |
| DOI/URL: | |
| Notes: | Export Date: 3 March 2014 -- CODEN: JEMEA -- Source: Scopus |
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