PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells

Abstract

Retention of long-term repopulating hematopoietic stem cells (LT-HSCs) in the bone marrow is essential for hematopoiesis and for protection from myelotoxic injury. We report that signaling cascades that are traditionally viewed as coagulation-related also control retention of EPCR+ LT-HSCs in the bone marrow and their recruitment to the blood via two different protease activated receptor 1 (PAR1)-mediated pathways. Thrombin-PAR1 signaling induces nitric oxide (NO) production, leading to TACE-mediated EPCR shedding, enhanced CXCL12-CXCR4-induced motility, and rapid stem and progenitor cell mobilization. Conversely, bone marrow blood vessels provide a microenvironment enriched with protein C that retain EPCR+ LT-HSCs by limiting NO generation, reducing Cdc42 activity and enhancing VLA4 affinity and adhesion. Inhibition of NO production by activated protein C (aPC)-EPCR-PAR1 signaling reduces progenitor cell egress, increases NOlow bone marrow EPCR+ LT-HSCs retention and protects mice from chemotherapy-induced hematological failure and death. Our study reveals new roles for PAR1 and EPCR that control NO production to balance maintenance and recruitment of bone marrow EPCR+ LT-HSCs with clinical relevance.

Osteopontin attenuates aging‐associated phenotypes of hematopoietic stem cells

“…Elucidation of the mechanisms by which aging of the niche affects HSC aging will support the design of rationale therapeutic interventions to attenuate aging in hematopoiesis (Khong et al , 2015; Khatri et al , 2016). While mechanisms through which the niche regulates young HSCs have started to be elucidated (Visnjic et al , 2004; Xie et al , 2009; Méndez‐Ferrer et al , 2010; Nombela‐Arrieta et al , 2013; Bruns et al , 2014; Acar et al , 2015; Gur‐Cohen et al , 2015), data on the extent of aging of the niche and the contribution to aging of HSCs are rare. Changes in the niche composition or function upon aging involve decreased bone formation, enhanced adipogenesis and changes in extracellular matrix (ECM) components (Calvi et al , 2003; Zhang et al , 2003; Naveiras et al , 2009; Geiger et al , 2013).…”

Extracellular molecules in hematopoietic stem cell mobilisation

“…Although thrombin can induce HSPC mobilization in mice [66], whether it is involved in G-CSF, chemotherapy or plerixafor-mediated mobilization is not clear with G-CSF making small but significant increases in some prothrombotic features while reducing others [67].…”

Bidirectional Pathologic Effects of Thrombin

“…The opposing effects of thrombin and aPC via PAR1 and EPCR reportedly control hematopoietic stem cell differentiation [58,59]. Thrombomodulin, which is essential for the activation of protein C, maintains hematopoietic stem cells in a quiescent state and causes retention of them in the bone marrow.…”