Transcription factor induction of vascular blood stem cell niches in vivo

Abstract

The hematopoietic niche is a supportive microenvironment comprised of distinct cell types, including specialized vascular endothelial cells that directly interact with hematopoietic stem and progenitor cells (HSPCs). The molecular factors that specify niche endothelial cells and orchestrate HSPC homeostasis remain largely unknown. Using multi-dimensional gene expression and chromatin accessibility analyses, we define a conserved gene expression signature and cis-regulatory landscape unique to sinusoidal endothelial cells in the HSPC niche. Using enhancer mutagenesis and transcription factor overexpression, we elucidate a transcriptional code involving members of the Ets, Sox and Nuclear Hormone Receptor families that is sufficient to induce ectopic niche endothelial cells that associate with mesenchymal stromal cells and support the recruitment, maintenance and division of HSPCs in vivo. These studies set forth an approach for generating synthetic HSPC niches, in vitro or in vivo, and for effective therapies to modulate the endogenous niche.

Quality assurance of hematopoietic stem cells by macrophages determines stem cell clonality

“…HSPCs rapidly expand in the CHT for 3 to 4 days before migrating to the kidney marrow, the adult hematopoietic niche. In both niches, HSPCs interact with a variety of cell types, including vascular endothelial cells, mesenchymal stromal cells, and macrophages (MFs) (3)(4)(5)(6). In vivo clonal labeling shows that 20 to 30 of the hematopoietic stem cell (HSC) clones born in the VDA ultimately give rise to the adult blood system (7).…”

Quality assurance of hematopoietic stem cells by macrophages determines stem cell clonality

“…HSPCs rapidly expand in the CHT for a few days before migrating to the kidney marrow, the adult hematopoietic niche. In the niche, HSPCs interact with a variety of cell types, including vascular endothelial cells, mesenchymal stromal cells, and macrophages [3][4][5][6]. In vivo clonal labeling studies show that 20 -30 of the hematopoietic stem cell (HSC) clones born in the VDA ultimately give rise to the adult blood system [7].…”