1. Transcription factor induction of vascular blood stem cell niches in vivo
- Author
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Michael J. Fairchild, Rebecca J. Freeman, Khaliun Enkhbayar, Samantha H. Collins, Samuel J. Wattrus, Eugene C. Butcher, Helen G. Wang, Jesus M. Gomez-Salinero, Elliott J. Hagedorn, Julie R. Perlin, Yi Zhou, Inés Fernández-Maestre, Brian Li, Christopher D’Amato, Emily L. Henault, Henry A. Feldman, Thanh Theresa Dinh, Alexander van Oudenaarden, Leonard I. Zon, Shelby E. Redfield, Raquel Riquelme, Shahin Rafii, Asher Lichtig, Song Yang, Karoline Holler, Junliang Pan, Clara Mao, Balvir Kunar, Tianxiao Han, Dana A.V.E. Ragoonanan, Ji Wook Kim, J. Philipp Junker, and Madeleine L. Daily
- Subjects
Haematopoiesis ,Cell type ,Nuclear receptor ,Mesenchymal stem cell ,Progenitor cell ,Biology ,Enhancer ,Transcription factor ,Cell biology ,Chromatin - 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.
- Published
- 2021
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