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Role of thrombomodulin expression on hematopoietic stem cells. J Thromb Haemost 2020 Jan;18(1):123-135

Date

10/20/2019

Pubmed ID

31628891

Pubmed Central ID

PMC6940513

DOI

10.1111/jth.14663

Scopus ID

2-s2.0-85074837812 (requires institutional sign-in at Scopus site)   3 Citations

Abstract

BACKGROUND: Activation of protease-activated receptor 1 (PAR1) by either thrombin or activated protein C (aPC) differentially regulate the quiescence and bone marrow (BM) retention of hematopoietic stem cells (HSC). Murine HSC co-express THBD, PAR1, and endothelial protein C receptor (EPCR), suggesting that HSC sustain quiescence in a quasi-cell autonomous manner due to the binding of thrombin present in the microenvironment to THBD, activation of EPCR-bound protein C by the thrombin-THBD-complex, and subsequent activation of PAR1 by the aPC-EPCR complex.

OBJECTIVE: To determine the role of THBD expression on HSC for sustaining stem cell quiescence and BM retention under homeostatic conditions.

METHODS: Hematopoietic stem cell function was analyzed in mice with constitutive or temporally controlled complete THBD-deficiency by flow cytometry, functional assays, and single cell RNA profiling.

RESULTS: THBD was expressed in mouse, but not human, HSC, progenitors, and immature B cells. Expression in vascular endothelium was conserved in humans' BM. Mice with constitutive THBD deficiency had a normal peripheral blood profile, altered BM morphology, reduced numbers of progenitors and immature B cells, pronounced extramedullary hematopoiesis, increased HSC frequency, and marginally altered transcriptionally defined HSC stemness. Transplantation experiments indicated near normal engraftment and repopulating ability of THBD-deficient HSC. Transgenic aPC supplementation normalized BM histopathology and HSC abundance, and partially restored transcriptional stemness, but had no effect on B cell progenitors and extramedullary hematopoiesis. Temporally controlled THBD gene ablation in adult mice did not cause the above abnormalities.

CONCLUSION: THBD expression on HSPC has minor effects on homeostatic hematopoiesis in mice, and is not conserved in humans.

Author List

Basu S, Liang HPH, Hernandez I, Zogg M, Fields B, May J, Ogoti Y, Wyseure T, Mosnier LO, Burns RT, Carlson K, Weiler H

Authors

Karen-Sue B. Carlson MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin
Hartmut Weiler PhD Associate Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Hematopoiesis
Hematopoietic Stem Cells
Mice
Mice, Inbred C57BL
Receptor, PAR-1
Signal Transduction
Thrombomodulin