Bone marrow sinusoidal endothelium controls terminal erythroid differentiation and reticulocyte maturation

Joschka Heil, Victor Olsavszky (), Katrin Busch, Kay Klapproth, Carolina Torre, Carsten Sticht, Kajetan Sandorski, Johannes Hoffmann, Hiltrud Schönhaber, Johanna Zierow, Manuel Winkler, Christian David Schmid, Theresa Staniczek, Deborah E. Daniels, Jan Frayne, Georgia Metzgeroth, Daniel Nowak, Sven Schneider, Michael Neumaier, Vanessa Weyer, Christoph Groden, Hermann-Josef Gröne, Karsten Richter, Carolin Mogler, Makoto Mark Taketo, Kai Schledzewski, Cyrill Géraud, Sergij Goerdt and Philipp-Sebastian Koch ()
Additional contact information
Joschka Heil: University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology
Victor Olsavszky: University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology
Katrin Busch: German Cancer Research Center (DKFZ)
Kay Klapproth: German Cancer Research Center (DKFZ)
Carolina Torre: Heidelberg University
Carsten Sticht: Heidelberg University
Kajetan Sandorski: University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology
Johannes Hoffmann: University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology
Hiltrud Schönhaber: University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology
Johanna Zierow: University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology
Manuel Winkler: University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology
Christian David Schmid: University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology
Theresa Staniczek: University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology
Deborah E. Daniels: University of Bristol
Jan Frayne: University of Bristol
Georgia Metzgeroth: Heidelberg University
Daniel Nowak: Heidelberg University
Sven Schneider: Heidelberg University
Michael Neumaier: Heidelberg University
Vanessa Weyer: Heidelberg University
Christoph Groden: Heidelberg University
Hermann-Josef Gröne: Philipps-University
Karsten Richter: German Cancer Research Center (DKFZ)
Carolin Mogler: Technical University Munich
Makoto Mark Taketo: Kyoto University
Kai Schledzewski: University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology
Cyrill Géraud: University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology
Sergij Goerdt: University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology
Philipp-Sebastian Koch: University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Within the bone marrow microenvironment, endothelial cells (EC) exert important functions. Arterial EC support hematopoiesis while H-type capillaries induce bone formation. Here, we show that BM sinusoidal EC (BM-SEC) actively control erythropoiesis. Mice with stabilized β-catenin in BM-SEC (Ctnnb1OE-SEC) generated by using a BM-SEC-restricted Cre mouse line (Stab2-iCreF3) develop fatal anemia. While activation of Wnt-signaling in BM-SEC causes an increase in erythroblast subsets (PII–PIV), mature erythroid cells (PV) are reduced indicating impairment of terminal erythroid differentiation/reticulocyte maturation. Transplantation of Ctnnb1OE-SEC hematopoietic stem cells into wildtype recipients confirms lethal anemia to be caused by cell-extrinsic, endothelial-mediated effects. Ctnnb1OE-SEC BM-SEC reveal aberrant sinusoidal differentiation with altered EC gene expression and perisinusoidal ECM deposition and angiocrine dysregulation with de novo endothelial expression of FGF23 and DKK2, elevated in anemia and involved in vascular stabilization, respectively. Our study demonstrates that BM-SEC play an important role in the bone marrow microenvironment in health and disease.

Date: 2021
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DOI: 10.1038/s41467-021-27161-3

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