Endomucin marks quiescent long-term multi-lineage repopulating hematopoietic stem cells and is essential for their transendothelial migration
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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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 114475 |
| Tidsskrift | Cell Reports |
| Vol/bind | 43 |
| Udgave nummer | 7 |
| Antal sider | 22 |
| ISSN | 2211-1247 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
This project was funded by the European Union's Horizon 2020 Research and Innovation Programme under Marie Slodowska-Curie grant agreement no. 801481 and in part by a Clinical Academic Group grant provided by the University of Copenhagen and the Capital Region of Denmark. S.E. obtained additional financial support from the Danish Cancer Foundation. K.T.-M. is supported by a clinical research fellowship and a center grant from the Novo Nordisk Foundation (grant no. 100191, Novo Nordisk Foundation Center for Stem Cell Biology, DanStem; grant no. NNF17CC0027852). We thank the members of the K.T.M. group for useful discussions and Rajesh Somasundaram for his help and assistance at the FACS core facility. We are also grateful to the staff of the Department of Experimental Medicine for excellent animal care and thank Bo Porse for sharing the B6.SJL mice. Finally, we thank the Mouse Genetics Program of the Wellcome Sanger Institute and its funders and the European Mouse Mutant Archive (MRC Mammalian Genetics Unit in Harwell, UK) for providing the mutant mouse strain C57BL/6N-EMCNem1(IMPC)Wtsi/WtsiH. The following figures were generated with the BioRender scientific and illustration software (biorender.com): Figures 2A, S2E, 5A, 5E, S4F, S5A, 6A, 6F, 6I, S7A, and S7F and the graphical abstract. S.E. K.R. and K.T.-M. conceived and designed the study. S.E. with the support of M.E. S.Q. F.G.R.-G. K.R. and M.D. collected and assembled the data. K.T.-M. supervised and obtained funding for the study. J.M.-G. has conducted the derivation of the mouse model and contributed to in vivo work. S.E. F.G.R.-G. and C.A.E. processed and analyzed RNA sequencing data. S.E. K.R. and K.T.-M. analyzed and interpreted the data. S.E. made the figures. S.E. and K.T.-M. drafted and wrote the manuscript. M.E. F.G.R.-G. M.D. D.B. C.N. J.W. and K.R. interpreted the data and contributed to the writing of the manuscript. The authors declare no competing interests.
Funding Information:
This project was funded by the European Union\u2019s Horizon 2020 Research and Innovation Programme under Marie Slodowska-Curie grant agreement no. 801481 and in part by a Clinical Academic Group grant provided by the University of Copenhagen and the Capital Region of Denmark . S.E. obtained additional financial support from the Danish Cancer Foundation . K.T.-M. is supported by a clinical research fellowship and a center grant from the Novo Nordisk Foundation (grant no. 100191 , Novo Nordisk Foundation Center for Stem Cell Biology, DanStem; grant no. NNF17CC0027852 ). We thank the members of the K.T.M. group for useful discussions and Rajesh Somasundaram for his help and assistance at the FACS core facility. We are also grateful to the staff of the Department of Experimental Medicine for excellent animal care and thank Bo Porse for sharing the B6.SJL mice. Finally, we thank the Mouse Genetics Program of the Wellcome Sanger Institute and its funders and the European Mouse Mutant Archive (MRC Mammalian Genetics Unit in Harwell, UK) for providing the mutant mouse strain C57BL/6N-EMCN em1(IMPC)Wtsi /WtsiH. The following figures were generated with the BioRender scientific and illustration software ( biorender.com ): Figures 2 A, S2 E, 5 A, 5E, S4 F, S5 A, 6 A, 6F, 6I, S7 A, and S7F and the graphical abstract.
Publisher Copyright:
© 2024 The Authors
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