Bone marrow sinusoidal endothelium controls terminal erythroid differentiation and reticulocyte maturation
Joschka Heil, Victor Olsavszky, Katrin Busch, Kay Klapproth, Carolina De La 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 M. Taketo, Kai Schledzewski, Cyrill Géraud, Sergij Goerdt, Philipp‐Sebastian Koch
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 ( Ctnnb1 OE-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 Ctnnb1 OE-SEC hematopoietic stem cells into wildtype recipients confirms lethal anemia to be caused by cell-extrinsic, endothelial-mediated effects. Ctnnb1 OE-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.