Bone marrow stromal cells (BMSCs) play pivotal roles in tissue maintenance and regeneration. Their origins, however, remain incompletely understood. Here we identify rare LNGFR+ cells in human fetal and regenerative bone marrow that co-express endothelial and stromal markers. This endothelial subpopulation displays transcriptional reprogramming consistent with endothelial-to-mesenchymal transition (EndoMT) and can generate multipotent stromal cells that reconstitute the bone marrow (BM) niche upon transplantation. Single-cell transcriptomics and lineage tracing in mice confirm robust and sustained contributions of EndoMT to bone precursor and hematopoietic niche pools. Interleukin-33 (IL-33) is overexpressed in subsets of EndoMT cells and drives this conversion process through ST2 receptor signaling. These data reveal generation of tissue-forming BMSCs from mouse and human endothelial cells and may be instructive for approaches to human tissue regeneration. Endothelial cells (ECs) may contribute to tissue development and regeneration. Kenswil et al. reveal a process of transition of ECs to bone marrow stromal cells (BMSCs), contributing to bone marrow and niche formation in mammals. IL-33 is identified as a driver of this process.

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Cell Stem Cell

Kenswil, K.J.G. (Keane Jared Guillaume), Pisterzi, P. (Paola), Sánchez-Duffhues, G. (Gonzalo), van Dijk, C. (Claire), Lolli, A, Knuth, C.A, … Raaijmakers, M.H.G.P. (2021). Endothelium-derived stromal cells contribute to hematopoietic bone marrow niche formation. Cell Stem Cell. doi:10.1016/j.stem.2021.01.006