Role of thrombomodulin expression on hematopoietic stem cells

Area of Science:

• Hematology
• Stem Cell Biology
• Molecular Biology

Background:

• Protease-activated receptor 1 (PAR1) activation by thrombin or activated protein C (aPC) differentially regulates hematopoietic stem cell (HSC) quiescence and bone marrow (BM) retention.
• Murine HSCs co-express thrombomodulin (THBD), PAR1, and endothelial protein C receptor (EPCR), suggesting a quasi-cell-autonomous mechanism for HSC quiescence via thrombin-mediated THBD and aPC-EPCR complex activation of PAR1.

Purpose of the Study:

• To investigate the role of THBD expression on HSCs in maintaining stem cell quiescence and BM retention under homeostatic conditions.

Main Methods:

• Analysis of HSC function in mice with constitutive or temporally controlled complete THBD deficiency.
• Utilized flow cytometry, functional assays, and single-cell RNA profiling.

Main Results:

• THBD is expressed in mouse HSCs, progenitors, and immature B cells, but not in human HSCs; vascular endothelium expression is conserved.
• Mice lacking THBD showed altered BM morphology, reduced progenitors, extramedullary hematopoiesis, and increased HSC frequency, with near-normal engraftment.
• aPC supplementation partially restored HSC stemness but did not affect B cell progenitors or extramedullary hematopoiesis.

Conclusions:

• THBD expression on hematopoietic stem and progenitor cells (HSPCs) has minor effects on homeostatic hematopoiesis in mice.
• THBD's role on HSPCs is not conserved in humans.