Transcription factor induction of vascular blood stem cell niches in vivo
Elliott J. Hagedorn, Julie R. Perlin, Rebecca J. Freeman, Samuel J. Wattrus, Tianxiao Han, Clara Mao, Ji Wook Kim, Inés Fernández-Maestre, Madeleine L. Daily, Christopher R. D'Amato, Michael J. Fairchild, Raquel Riquelme, Brian Li, Dana A.V.E. Ragoonanan, Khaliun Enkhbayar, Emily L. Henault, Helen G. Wang, Shelby E. Redfield, Samantha H. Collins, Asher Lichtig, Song Yang, Yi Zhou, Balvir Kunar, Jesús M. Gómez-Salinero, Thanh Theresa Dinh, Junliang Pan, Karoline Holler, Henry A. Feldman, Eugene C. Butcher, Alexander van Oudenaarden, Shahin Rafii, Jan Philipp Junker, Leonard I. Zon
Abstract
The hematopoietic niche is a supportive microenvironment composed 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 in zebrafish, we define a conserved gene expression signature and cis-regulatory landscape that are unique to sinusoidal endothelial cells in the HSPC niche. Using enhancer mutagenesis and transcription factor overexpression, we elucidate a transcriptional code that involves members of the Ets, Sox, and nuclear hormone receptor families and 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.