Proteinase 3 Limits the Number of Hematopoietic Stem and Progenitor Cells in Murine Bone Marrow

Abstract

Summary: Hematopoietic stem and progenitor cells (HSPCs) undergo self-renewal and differentiation to guarantee a constant supply of short-lived blood cells. Both intrinsic and extrinsic factors determine HSPC fate, but the underlying mechanisms remain elusive. Here, we report that Proteinase 3 (PR3), a serine protease mainly confined to granulocytes, is also expressed in HSPCs. PR3 deficiency intrinsically suppressed cleavage and activation of caspase-3, leading to expansion of the bone marrow (BM) HSPC population due to decreased apoptosis. PR3-deficient HSPCs outcompete the long-term reconstitution potential of wild-type counterparts. Collectively, our results establish PR3 as a physiological regulator of HSPC numbers. PR3 inhibition is a potential therapeutic target to accelerate and increase the efficiency of BM reconstitution during transplantation. : In this article, Luo and colleagues show that Proteinase 3 (PR3), a member of neutrophil serine proteases, is expressed in HSPCs and regulates HSPC numbers in murine bone marrow. Their results suggest that PR3 deficiency does not affect HSPC proliferation but reduces the rate of spontaneous HSPC apoptosis by cleaving and activating caspase-3. Keywords: Proteinase 3, hematopoiesis, hematopoietic stem cell, hematopoietic progenitor cell, apoptosis