Grb2 Regulates Proliferation and Survival of Hematopoietic Stem Cells

Although HSC proliferation, survival and expansion have been shown to be supported by the cooperative action of different cytokines, little is known about the intracellular signaling pathways that are activated by cytokines upon binding to their receptors. Growth factor receptor-bound protein 2 (Grb2) is a ubiquitous adaptor protein known to be involved in signaling induced by a variety of growth factors and cytokines; however, its physiological role in HSC has never been characterized. Our study has shown that Grb2 mRNAs are highly expressed in HSC relative to more differentiated cells of the myeloid and erythroid lineages. Conditional deletion of Grb2 induced a progressive decline of long-term (LT-) HSC numbers and cytopenia with animal aging. While Grb2 deletion did not modify LT-HSC quiescence, it impaired HSC regenerative and self-renewing abilities in a cell-autonomous fashion. We revealed that Grb2 deletion impaired LT-HSC proliferative response to 5-FU treatment in vivo.

Our findings position Grb2 as a key adaptor protein governs cytokines signaling in cycling LT-HSC and a master regulator of LT-HSC transplantation, proliferation and survival.