Abstract
In adult mammalian bone marrow (BM), vascular endothelial cells and perivascular reticular cells control the function of haematopoietic stem and progenitor cells (HSPCs). During fetal development, the mechanisms regulating the de novo haematopoietic cell colonization of BM remain largely unknown. Here, we show that fetal and adult BM exhibit fundamental differences in cellular composition and molecular interactions by single cell RNA sequencing. While fetal femur is largely devoid of leptin receptor-expressing cells, arterial endothelial cells (AECs) provide Wnt ligand to control the initial HSPC expansion. Haematopoietic stem cells and c-Kit+ HSPCs are reduced when Wnt secretion by AECs is genetically blocked. We identify Wnt2 as AEC-derived signal that activates β-catenin-dependent proliferation of fetal HSPCs. Treatment of HSPCs with Wnt2 promotes their proliferation and improves engraftment after transplantation. Our work reveals a fundamental switch in the cellular organization and molecular regulation of BM niches in the embryonic and adult organism.
Highlights
1, Cong Xu1, In adult mammalian bone marrow (BM), vascular endothelial cells and perivascular reticular cells control the function of haematopoietic stem and progenitor cells (HSPCs)
We propose that arterial endothelial cells in the developing BM provide critical signals promoting the de novo colonization of fetal bone by HSPCs
Indicating that the reduction of HSPCs is not caused by the knock-in of CreER into the c-Kit locus itself, the number of HSPCs is not significantly altered in Ctnnb1iΔKit embryos without tamoxifen treatment (Supplementary Fig. 11e). The sum of these results indicates that arterial endothelial cells (AECs)-controlled Wnt/βcatenin signaling promotes HSPC expansion in fetal BM
Summary
1, Cong Xu1, In adult mammalian bone marrow (BM), vascular endothelial cells and perivascular reticular cells control the function of haematopoietic stem and progenitor cells (HSPCs). In adult BM, the behavior of haematopoietic stem and progenitor cells (HSPCs) is regulated by complex microenvironments involving multiple cell types, in particular vascular endothelial cells (ECs) and perivascular LepR+ reticular cells[11–17]. Both cell types are a critical source of stem cell factor (SCF; encoded by Kitl)[18,19], a cytokine that controls HSC self-renewal and maintenance through the activation of the receptor tyrosine kinase c-Kit. Reticular cells provide another cytokine, stromal cellderived factor-1 (Cxcl12)[20], which signals through the G-proteincoupled receptor Cxcr[4] and thereby regulates HSPC maintenance, trafficking and homing[21–23]. While several studies have investigated the transcriptional profile and differentiation of fetal and adult HSPCs at single cell resolution[35,45–47], the properties of the fetal BM stroma and the mechanisms mediating HSC engraftment and expansion in the initial stages of marrow development remain little understood
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