The endoplasmic reticulum as a determinant of hematopoietic niche homeostasis

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Hematopoietic stem cells (HSCs) produce all blood cell lineages in response to stressors. The bone marrow (BM) microenvironment (also called: the BM niche) maintains this multilineage repopulation (LTR) ability of HSCs for the life time of the organism. It is known that in chronic stress (infections or inflammation) and in aging, the LTR ability (LTR) of HSCs is strongly reduced. However, it remains largely unclear how outside signals from the BM niche trigger and maintain LTR ability and self-renewal of HSCs. We have established mouse models in which specific primary changes in the BM niche cause secondary reduction of LTRA in HSCs. In the mouse strain we will be using, we deleted the Sfrp1 gene in Osterix-expressing osteoprogenitor cells (OS1Del/Del mice). In this project, we will study how the changes in BM niche cells from these mice change their communication with HSCs and their ability to maintain the LTRA of these cells.Our preliminary data from the transcriptome of OS1Del/Del mice shows deregulation of endoplasmic proteostasis in sorted osteoprogenitors. Further validation studies confirmed downregulation of proteostatic factors at the protein level, and a strong reduction of protein degradation in BM niche cells from OS1Del/Del mice. Proteostasis is a critical cellular maintenance process, not only for removing misfolded proteins, but also for sorting of proteins for secretion to the extracellular space. As such, endoplasmic proteostasis would be a determining factor in regulating communication between BM niche cells and HSCs. In this project we will further investigate endoplasmic proteostasis in BM niche cells, as well as identify critical mediators in both the endoplasmic proteostatic process and in the secretome. Furthermore, we will treat OS1Del/Del mice with the aim to restore endoplasmic proteostasis in the BM niche and to improve the LTR ability of HSCs. A long-term goal of these experiments is to identify niche-directed strategies to prevent exhaustion of HSCs with LTR ability in chronic stress (infections or inflammation) and in aging.