Novel differential calcium regulation of hematopoietic stem and progenitor cells under physiological low oxygen conditions

Low oxygen bone marrow (BM) niches (similar to 1%-4% low O-2) provide critical signals for hematopoietic stem/progenitor cells (HSC/HSPCs). Our presented data are the first to investigate live, sorted HSC/HSPCs in their native low O-2 conditions. Transcriptional and proteomic analysis uncovered differential Ca2+ regulation that correlated with overlapping phenotypic populations consisting of robust increases of cytosolic and mitochondrial Ca2+, ABC transporter (ABCG2) expression and sodium/hydrogen exchanger (NHE1) expression in live, HSC/HSPCs remaining in constant low O-2. We identified a novel Ca2+ high population in HSPCs predominantly detected in low O-2 that displayed enhanced frequency of phenotypic LSK/LSKCD150 in low O-2 replating assays compared to Ca2+ low populations. Inhibition of the Ca2+ regulator NHE1 (Cariporide) resulted in attenuation of both the low O-2 induced Ca2+ high population and subsequent enhanced maintenance of phenotypic LSK and LSKCD150 during low O-2 replating. These data reveal multiple levels of differential Ca2+ regulation in low O-2 resulting in phenotypic, signaling, and functional consequences in HSC/HSPCs.