Endothelium-derived stromal cells contribute to hematopoietic bone marrow niche formation

Abstract

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.

Deciphering Tumor Niches: Lessons From Solid and Hematological Malignancies

“…Furthermore, EndMT has been described as a tumor arm to resist chemo-and radiotherapies (191,192). Recent data support such a transition process in regenerative human BM, as a subset of ECs in trabecular sinusoid vessels has been shown to display an EndMT transcriptional signature (193). Importantly, this endothelial derived-mesenchymal population harbors properties of pluripotent stromal cells, with multi-lineage differentiation capacity (adipocyte, osteoblast, chondrocyte) and supportive capacity of hematopoiesis.…”

“…Importantly, this endothelial derived-mesenchymal population harbors properties of pluripotent stromal cells, with multi-lineage differentiation capacity (adipocyte, osteoblast, chondrocyte) and supportive capacity of hematopoiesis. Whether EndMT plays a role in hematological cancer is not confirmed yet, but this process surely could participate in the reconstitution of the hematopoietic BM niche after therapy ( 193 ). In the BM and spleen of PMF patients, the presence of microvascular ECs showing functional and morphologic changes associated with the MSC phenotype is in agreement with the potential contribution of EndMT to the BM fibrosis process that characterizes this disease ( 194 ).…”

Regulation of Partial and Reversible Endothelial-to-Mesenchymal Transition in Angiogenesis

“…Cell subpopulations that co-express endothelial-and mesenchymal-markers -indicating cells in an intermediate state of EndoMT -have been reported in cardiac (Widyantoro et al, 2010), pulmonary (Mendoza et al, 2016), and dermal (Manetti et al, 2017) fibrosis, as well as in fetal valve endothelial progenitor cells (Paruchuri et al, 2006). Furthermore, pseudotime analysis of single cell transcriptomic and epigenomic data shows a spectrum of intermediate EndoMT cells, as well as ECs undergoing apparent transition to other nonmesenchymal cell types (Andueza et al, 2020;Kenswil et al, 2021). Given this, partial EndoMT is most likely not its own distinct process.…”

“…Lastly, blood vessels reorganize and mature into a hierarchal network architecture (remodeling and specification). During these processes as well as in the context of certain diseases, ECs undergo diversification, and some even take on a new non-EC identity (Welch-Reardon et al, 2015;Gritz and Hirschi, 2016;Piera-Velazquez and Jimenez, 2019;Qiu and Hirschi, 2019;Kenswil et al, 2021). In complete endothelial-to-mesenchymal transition (EndoMT), for example, activation of a central EndoMT program -similar to the program that drives epithelial-to-mesenchymal transition (EMT) in epithelial cells -induces a subpopulation of ECs to fully abandon their EC identity and transition to a mesenchymal cell phenotype (Welch-Reardon et al, 2015;Piera-Velazquez and Jimenez, 2019).…”

Hematopoiesis during Ontogenesis, Adult Life, and Aging

“…More specifically, HSCs in bone marrow are associated with the stromal microenvironment termed "niches", which support and regulate stem cell function through cellular interactions and secreted factors [69,70]. Niche formation involves a number of nonhematopoietic stromal cells (mesenchymal stem cells (MSC), osteoblasts, adipocytes, CXCL12-producing cells, fibroblasts) [71], endothelial cells [72], osteoclasts, macrophages [69], and nonmyelinating Schwann cells [73,74].…”