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.
| Original language | English |
|---|---|
| Article number | 6963 |
| Journal | Nature Communications |
| Volume | 12 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 29 Nov 2021 |
Bibliographical note
Funding Information:We thank Emrah Gümüs, Johanna Flach, Sven Schäfer, Jochen Weber, and Stephanie Riester for excellent technical support. We thank Dr Stefan Liebner (Goethe University Frankfurt, Frankfurt am Main, Germany) for providing the Ctnnb1(ex3)fl/wt mouse line from Prof. Makoto Mark Taketo (Kyoto University, Kyoto, Japan). We are grateful to Prof. Hans-Reimer Rodewald (German Cancer Research Center (DKFZ), Heidelberg, Germany) for support throughout the project, especially by providing flow cytometry chemicals and machines and the Cesium 137GammaCell40 Irradiator. We thank Dr Anjali Kusumbe (Kennedy Institute of Rheumatology, University of Oxford, UK) for providing us a proctocol for bone marrow endothelial cell isolation. D. N. is an endowed Professor of the “Deutsche José Carreras Leukaemie Stiftung” (DJCLS H 03/01). This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project number 259332240 – RTG 2099 (to C. Géraud, S. G., and P.-S. K.), project number 5454871 – SFB TR 23 (to C. Géraud and S. G.), project number 394046768 – SFB 1366 (to C. Géraud, S. G., and P.-S. K.) and project number 314905040 – SFB-TR 209 (to S. G.). The authors gratefully acknowledge the data storage service SDS@hd supported by the Ministry of Science, Research and the Arts Baden-Württemberg (MWK), and the German Research Foundation (DFG) through grant INST 35/1314-1 FUGG and INST 35/1503-1 FUGG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2021, The Author(s).