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

• DOI: 10.1084/jem.20131128
• Publication Date: 2014-01-21T02:35:13Z
• Authors: Joseph Y. Shin; Wenhuo Hu; Mayumi Naramura; Christopher Y. Park
• Keywords: Proto-Oncogene Proteins c-kit

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