RNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells

The self-renewal potential of hematopoietic stem cells (HSCs) is essential for maintaining tissue and blood homeostasis after stress. Previous studies have identified RNA Binding Proteins (RBPs) as central regulators of HSC fate and promotion of self-renewal, with SYNCRIP being one such RBP upregulated in HSPCs. Using a conditional Cre-lox system to deplete SYNCRIP in HSCs, the authors observed that knocking out SYNCRIP resulted in decreased in vitro colony formation and in vivo engraftment activity, suggesting that SYNCRIP is necessary for HSC self-renewal potential. To test the hypothesis that loss of SYNCRIP alters HSC proliferation, the researchers utilized Cell Microsystem’s CellRaft AIR system to directly image wild type and SYNCRIP KO cells and monitor single cell division in vitro. As the CellRaft arrays allow for single cell segregation in flask-like culture conditions, single HSCs were identified, and their division was tracked with CellRaft Cytometry software. While there was a slight increase in time to first cell division in the SYNCRIP KO cells compared to WT, there was no significant difference in the percent of cumulative dividing cells over 60hrs, indicating that the loss of self-renewing potential of SYNCRIP KO HSCs is not due to a deficit in HSC proliferation. Further investigation found that loss of SYNCRIP resulted in increased unfolded protein response and Endoplasmic Reticulum stress leading to dysregulated proteostasis in KO HSCs. Interestingly, as SYNCRIP is an RBP, it is required for translating CDC42 and a decrease in this RHO-GTPase’s expression resulted in dysregulated HSC polarity and asymmetric segregation with a loss of self-renewal. These studies highlight the role of SYNCRIP in HSC maintenance and repopulation which is necessary for blood homeostasis as well as engraftment following transplantation.