Role of thrombomodulin expression on hematopoietic stem cells.
hematopoiesis
hemostasis
stem cells
thrombomodulin
thrombosis
Journal
Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
05
06
2019
revised:
23
09
2019
accepted:
10
10
2019
pubmed:
20
10
2019
medline:
15
5
2021
entrez:
20
10
2019
Statut:
ppublish
Résumé
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. To determine the role of THBD expression on HSC for sustaining stem cell quiescence and BM retention under homeostatic conditions. 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. 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. THBD expression on HSPC has minor effects on homeostatic hematopoiesis in mice, and is not conserved in humans.
Sections du résumé
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.
Identifiants
pubmed: 31628891
doi: 10.1111/jth.14663
pmc: PMC6940513
mid: NIHMS1055745
pii: S1538-7836(22)01580-X
doi:
Substances chimiques
Receptor, PAR-1
0
Thrombomodulin
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
123-135Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL142975
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL104165
Pays : United States
Organisme : NHLBI NIH HHS
ID : K08 HL127187
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL130678
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL117132
Pays : United States
Organisme : National Institute of Allergy and Infectious Diseases
ID : AI133561
Pays : International
Organisme : NHLBI NIH HHS
ID : R01 HL148096
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL133348
Pays : United States
Informations de copyright
© 2019 International Society on Thrombosis and Haemostasis.
Références
Blood. 2018 Jul 12;132(2):123-131
pubmed: 29866813
Cell. 2015 May 21;161(5):1202-1214
pubmed: 26000488
Blood Adv. 2017 Jun 27;1(15):1148-1158
pubmed: 28920104
Blood. 2013 May 30;121(22):4463-72
pubmed: 23564910
Blood. 2013 Oct 10;122(15):2562-71
pubmed: 23982175
J Exp Med. 1997 Feb 17;185(4):755-66
pubmed: 9034153
Blood. 2018 Oct 11;132(15):1593-1603
pubmed: 30026184
Nat Med. 2012 Jul;18(7):1123-9
pubmed: 22729286
J Biol Chem. 2007 Apr 20;282(16):11849-57
pubmed: 17327234
PLoS One. 2014 Apr 16;9(4):e94993
pubmed: 24740120
Immunity. 2006 Dec;25(6):977-88
pubmed: 17174120
Proc Natl Acad Sci U S A. 1989 Oct;86(19):7547-51
pubmed: 2798426
Science. 2011 Jul 8;333(6039):218-21
pubmed: 21737740
Blood. 2015 Jul 30;126(5):673-82
pubmed: 26045607
Cell. 2013 May 23;153(5):1025-35
pubmed: 23706740
Leukemia. 2013 Sep;27(9):1928-30
pubmed: 23511127
Front Immunol. 2019 Jun 07;10:1292
pubmed: 31231394
Blood. 2009 Jul 2;114(1):49-59
pubmed: 19417209
Nat Biotechnol. 2018 Jun;36(5):411-420
pubmed: 29608179
Exp Hematol. 2001 Feb;29(2):146-55
pubmed: 11166453
Leukemia. 2014 Nov;28(11):2148-54
pubmed: 24667943
Nat Biotechnol. 2018 Dec 03;:null
pubmed: 30531897
Nat Med. 2015 Nov;21(11):1307-17
pubmed: 26457757
Cell Stem Cell. 2015 Jun 4;16(6):712-24
pubmed: 26004780
Blood. 2005 Aug 15;106(4):1232-9
pubmed: 15845900
Science. 2016 Apr 8;352(6282):189-96
pubmed: 27124452
Cell Immunol. 2014 Mar-Apr;288(1-2):47-52
pubmed: 24637088
Nat Med. 2007 Nov;13(11):1349-58
pubmed: 17982464