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. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK088334-05
Application #
8713978
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Bishop, Terry Rogers
Project Start
2010-09-30
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
$328,680
Indirect Cost
$123,255
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Sweeney, Elizabeth; Roberts, Douglas; Lin, Angela et al. (2013) Defective endochondral ossification-derived matrix and bone cells alter the lymphopoietic niche in collagen X mouse models. Stem Cells Dev 22:2581-95