Endomucin marks quiescent long-term multi-lineage repopulating hematopoietic stem cells and is essential for their transendothelial migration
Sophia Engelhard,
Montserrat Estruch,
Shuyu Qin,
Christoph A. Engelhard,
Francisco G. Rodriguez-Gonzalez,
Martine Drilsvik,
Javier Martin-Gonzalez,
Jeng-Wei Lu,
David Bryder,
Claus Nerlov,
Joachim Weischenfeldt,
Kristian Reckzeh,
Kim Theilgaard-Mönch
Affiliations
Sophia Engelhard
Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Finsen Laboratory, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
Montserrat Estruch
Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Finsen Laboratory, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
Shuyu Qin
Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Finsen Laboratory, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
Christoph A. Engelhard
Center for Physical Activity Research, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department for Biochemistry and Molecular Biology (BMB), University of Southern Denmark, Odense, Denmark
Francisco G. Rodriguez-Gonzalez
Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Finsen Laboratory, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
Martine Drilsvik
Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Finsen Laboratory, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
Javier Martin-Gonzalez
Core Facility for Transgenic Mice, Department of Experimental Medicine, University of Copenhagen, Copenhagen, Denmark
Jeng-Wei Lu
Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Finsen Laboratory, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
David Bryder
Division of Molecular Hematology, Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden
Claus Nerlov
MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, UK
Joachim Weischenfeldt
Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Finsen Laboratory, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
Kristian Reckzeh
Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Finsen Laboratory, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Symphogen, Ballerup, Denmark; Corresponding author
Kim Theilgaard-Mönch
Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Finsen Laboratory, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Hematology, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark; Corresponding author
Summary: Endomucin (EMCN) currently represents the only hematopoietic stem cell (HSC) marker expressed by both murine and human HSCs. Here, we report that EMCN+ long-term repopulating HSCs (LT-HSCs; CD150+CD48−LSK) have a higher long-term multi-lineage repopulating capacity compared to EMCN− LT-HSCs. Cell cycle analyses and transcriptional profiling demonstrated that EMCN+ LT-HSCs were more quiescent compared to EMCN− LT-HSCs. Emcn−/− and Emcn+/+ mice displayed comparable steady-state hematopoiesis, as well as frequencies, transcriptional programs, and long-term multi-lineage repopulating capacity of their LT-HSCs. Complementary functional analyses further revealed increased cell cycle entry upon treatment with 5-fluorouracil and reduced granulocyte colony-stimulating factor (GCSF) mobilization of Emcn−/− LT-HSCs, demonstrating that EMCN expression by LT-HSCs associates with quiescence in response to hematopoietic stress and is indispensable for effective LT-HSC mobilization. Transplantation of wild-type bone marrow cells into Emcn−/− or Emcn+/+ recipients demonstrated that EMCN is essential for endothelial cell-dependent maintenance/self-renewal of the LT-HSC pool and sustained blood cell production post-transplant.
