Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, Mannheim, Germany.
European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Nat Commun. 2021 Nov 29;12(1):6963. doi: 10.1038/s41467-021-27161-3.
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) 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 hematopoietic stem cells into wildtype recipients confirms lethal anemia to be caused by cell-extrinsic, endothelial-mediated effects. Ctnnb1 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.
在骨髓微环境中，内皮细胞（EC）发挥着重要的作用。动脉 EC 支持造血，而 H 型毛细血管则诱导骨形成。在这里，我们表明骨髓窦状内皮细胞（BM-SEC）可主动控制红细胞生成。使用骨髓内皮细胞特异性 Cre 小鼠系（Stab2-iCreF3）稳定 BM-SEC 中的 β-连环蛋白（Ctnnb1）的小鼠会发生致命性贫血。虽然 BM-SEC 中的 Wnt 信号激活会导致成红细胞亚群（PII-PIV）增加，但成熟的红细胞（PV）减少，表明末端红细胞分化/网织红细胞成熟受损。将 Ctnnb1 造血干细胞移植到野生型受体中证实，致命性贫血是由细胞外在的、内皮介导的效应引起的。Ctnnb1 BM-SEC 显示出异常的窦状分化，伴有 EC 基因表达和窦周 ECM 沉积的改变，以及血管生成调节紊乱，新出现的内皮细胞表达 FGF23 和 DKK2，前者在贫血中升高，后者参与血管稳定。我们的研究表明，BM-SEC 在骨髓微环境的健康和疾病中发挥着重要作用。
