Deficiency of GRP94 in the Hematopoietic System Alters Proliferation Regulators in Hematopoietic Stem Cells

摘要: We have previously reported that acute inducible knockout of the endoplasmic reticulum chaperone GRP94 led to an expansion hematopoietic stem and progenitor cell pool. Here, we investigated effectors mechanisms for this phenomenon. observed increase in AKT activation freshly isolated GRP94-null HSC-enriched Lin(-) Sca-1(+) c-Kit(+) (LSK) cells, corresponding with higher production PI(3,4,5)P3, indicative PI3K activation. Treatment LSK cells inhibitor MK2206 compromised expansion, suggesting a causal relationship between elevated increased proliferation HSCs. Microarray analysis demonstrated 97% reduction expression cycle regulator Ms4a3 real-time quantitative PCR confirmed down-regulation but not total bone marrow (BM). A further examination comparing BM spleen as well cultured vitro, revealed specific cells. On examining surface proteins are known regulate proliferation, reduced connexin 32 (Cx32) plaques However, suppression Cx32 hemichannel activity wild-type through mimetic peptides did lead vitro. Two other important mediate HSC-niche interactions, specifically Tie2 CXCR4, were impaired by Grp94 deletion. Collectively, our study uncovers novel unique roles regulating HSC proliferation.