Skeletal development and the hematopoietic niche

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DESCRIPTION (provided by applicant): Certain immuno-osseous and hematopoietic disorders likely result from an impaired hematopoietic niche, which in turn may ensue from defective endochondral ossification (EO), where a cartilage skeletal blueprint is replaced by trabecular bone and marrow. This proposal will test our hypothesis that the EO- derived chondro-osseous junction (COJ), comprised of hypertrophic cartilage and trabecular bone, is a key hematopoietic niche within the marrow. This hypothesis stems from our transgenic (Tg) and null mice for collagen X, a matrix protein expressed in hypertrophic cartilage prior to EO. Mice with disrupted collagen X function display skeleto-hematopoietic defects including altered hypertrophic cartilage and trabecular bone in the COJ, marrow hypoplasia, diminished lymphopoiesis, and impaired immune function. We propose that these defects stem from an altered hematopoietic niche within the COJ, and that these mice provide an innovative system to identify the mechanistic basis for niche-mediated disorders. The goals of this proposal are to implicate a subset of COJ progenitors and collagen X as key regulators of the hematopoietic niche by: 1) Assessing by bone marrow transplantation if all hematopoietic defects in the collagen X mice could be attributed to niche impairment and whether homing of transplanted HSCs to the COJ niche could be visualized via two-photon microscopy; 2) Testing the ability of EO-progenitors from control and collagen X mice to reconstitute an ectopic COJ and HSC niche upon transplantation; and 3) Determining if EO-derived osteoprogenitors require collagen X for niche establishment and/or niche maintenance. PUBLIC HEALTH RELEVANCE: This proposal will test if the environment or "niche" in the marrow where blood cells form, is generated by a skeletal development process. We will use genetically engineered mice that have a niche defect to identify the skeletal components needed for proper formation and function of the blood cell niche. Data should yield insights into basic stem cell biology, as well as aid in diagnosis and treatment of niche-mediated diseases.