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Extrinsic regulation of haematopoietic stem cell self

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We have historically studied the intrinsic mechanisms that regulate stem cell self-renewal and tissue regeneration, focusing on the haematopoietic and nervous systems. In the past few years we have expanded the scope of these studies to include the extrinsic mechanisms that regulate haematopoietic stem cell self-renewal. By using functional genetic approaches in vivo, we have identified the cells in the bone marrow that are the physiologically important sources of factors that promote HSC maintenance. Contrary to the dogma of an osteoblastic niche, these studies demonstrated that HSCs reside in a perivascular niche in which endothelial cells and Leptin Receptor-expressing mesenchymal stromal cells secrete multiple key factors that promote HSC maintenance, including Stem Cell Factor and Cxcl12 (Nature 481:457; Nature 495:231; Nature 505:327). We have shown that this perivascular niche is necessary for the maintenance of quiescent HSCs (Cell Stem Cell 13:102) and that the microenvironment within this niche collaborates with long-range signals, such as estrogen, to regulate HSC function in response to both local changes within the tissue as well as overall physiological state (Nature 505:555). Finally, the LepR+ stromal cells that represent the major source of factors for HSC maintenance are also highly enriched for mesenchymal stem cells (MSCs) and are the major source of new bone and adipocytes that form throughout adult life in the bone marrow. New imaging approaches that we are developing enable high-throughput imaging of HSCs and their interactions with stromal cells throughout the three dimensional bone marrow compartment with confocal resolution.

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