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PDGFRα+ and HIC1+ mesenchymal progenitors in murine skeletal tissue ; roles in homeostasis and regeneration

University of British Columbia

Despite its rigid structure, bone is a highly dynamic tissue that is constantly remodeled throughout life to maintain its structure and function. Remodeling is mediated by bone resorbing osteoclasts and bone depositing osteoblasts. While the hematopoietic origins of osteoclasts are well understood, the identity of the skeletal mesenchymal progenitors that give rise to osteoblasts remains elusive. Understanding the identity and biology of these skeletal mesenchymal progenitors is critical to the development of therapeutics for the treatment of bone-related disorders from trauma and surgical-induced heterotopic ossification to osteoporosis-related fractures. Previous studies have attempted to identify skeletal stem and progenitor cell populations, however, though the periosteum is known to be a source of progenitors crucial to bone regeneration, none of the identified populations were periosteal. While PDGFRα expression has been identified in many putative skeletal progenitors, we show that it is expressed ubiquitously throughout skeletal tissues and therefore does not constitute a unique marker for skeletal progenitors. We identified HIC1 as a marker of a novel injury-inducible periosteal skeletal progenitor that contributes to bone homeostasis and regeneration, an important advancement in the understanding of skeletal biology. Contrary to skeletal tissues, in skeletal muscle, expression of PDGFRα is restricted to fibro-adipogenic progenitors (FAPs) which have been suggested as the cellular source of heterotopic ossification. Using a new inducible PDGFRαCreERT2 transgenic model, we confirmed that tissue resident PDGFRα+ FAPs give rise to HO in skeletal muscle and that they have inherent osteogenic potential that is induced by an altered inflammatory environment following muscle damage. This presents novel cellular and therapeutic targets for the prevention of acquired HO. The TGFβ and BMP pathways are well known for their effects on FAPs, inducing ectopic bone formation and fibrosis. Using a PDGFRαCreERT2/Smad4Flox transgenic model, we examined the role of mesenchymal TGFβ and BMP signaling in adult tissues. We found that impairment of SMAD-mediated TGFβ/BMP signaling in PDGFRα+ cells induced increased proliferation and uncoupling of bone formation and resorption resulting in high turnover bone loss. This suggests constitutive SMAD-mediated TGFβ/BMP signaling is required for adult murine skeletal homeostasis and deepens our scientific understanding of adult skeletal biology.

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2020-09-09

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/75937

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/