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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.
Highlights
Within the bone marrow microenvironment, endothelial cells (EC) exert important functions
Here, we discovered that constitutive β-catenin activation in bone marrow (BM) sinusoidal EC (BM-SEC) caused aberrant sinusoidal endothelial differentiation with altered EC marker gene expression and increased periendothelial extracellular matrix (ECM) deposition as well as angiocrine dysregulation with de novo expression of FGF23 and DKK2
Aberrant sinusoidal differentiation and angiocrine dysregulation entailed lethal anemia due to a block in terminal erythroid differentiation resulting in defective reticulocyte maturation
Summary
Within the bone marrow microenvironment, endothelial cells (EC) exert important functions. Crosstalk between hematopoietic stem and progenitor cells (HSPCs) and cells of the bone marrow (BM) microenvironment is increasingly recognized to regulate normal hematopoiesis as well as development of myeloid disorders[1]. Distinct vessel types within the BM niche comprise arterial endothelial cells (AEC), H-type capillary vessels, and BM sinusoidal (L-type) endothelial cells (BM-SEC) that contribute to osteogenesis, bone angiogenesis, and HSPC maintenance and differentiation via angiocrine signaling[4,5,6,7,8,9]. Endothelial Notch activation can revert this process inducing arterialization and H-type capillary expansion[4,11] Despite these essential data on the involvement of BM-EC in normal hematopoiesis, evidence for the involvement of BM-EC in the pathogenesis of hematological disorders is scarce. Targeted driver Cre mice target all EC as well as hematopoietic stem cells and part of their progeny[22], and the EpoR-Cre driver used to target BM-SEC is expressed in erythroid cells[10]
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