Skeletal Stem Cell-based Cartilage Regeneration in Aged and Osteoarthritic Niches

About This Grant

Project Summary Osteoarthritis (OA) is a degenerative disease resulting in irreversible, progressive destruction of hyaline cartilage lining articular joints. A critical challenge for OA management is the development of an effective treatment that reverses cartilage damage. Our previous work indicates the existence of adult skeletal stem cells (SSCs) in postnatal cartilage. These SSCs are dormant yet can potentially repair damaged cartilage when stimulated by surgical procedures such as Microfracture (MF). While MF typically results in the formation of inferior fibrocartilage, we have demonstrated that MF-activated tissue-resident SSCs can be expanded and directed towards the formation of healthy chondrocytes and hyaline cartilage to regenerate full-thickness cartilage defects by pharmacologically modulating SSC activity and the microenvironment surrounding them. This method we termed Growth-factor Enhanced Microfracture (GEM). Our published studies and preliminary data demonstrate that GEM works well in young animals but is less effective in aged mice. Our data supported by recent findings of others further suggest that FGF7 (Fibroblast Growth Factor 7) expression in the SSC lineage is induced by an inflammatory aged and osteoarthritic bone marrow niche, which leads to pro-fibrotic lineage-skewing resulting in cartilage loss. We now build on additional preliminary results showing that direct and indirect blockade of FGF7 during GEM can reinstate stem cell-based cartilage formation in joints of aged and OA mice. The gained insights from the proposed study will help us to develop strategies to efficiently apply GEM even in impaired settings with a cellular microenvironment less conducive to articular cartilage regeneration. To that end, we are elucidating the cellular dynamics and molecular mechanisms that underlie SSC mediated cartilage repair. In Aim 1, we will expand our preliminary findings to confirm and mechanistically dissect how inhibiting FGF7 locally during GEM in aged and osteoarthritic mice can promote hyaline cartilage formation. In Aim 2, we will determine if epigenetic rewiring of local SSCs by a novel therapeutic compound is sufficient to overcome age-related impairments of GEM mediated cartilage regeneration. Our experiments will use state-of-the-art structural and functional readouts at the tissue level as well as latest technology to unravel cellular and molecular changes at the single cell level to assess regenerative properties and provide new biological insights into OA. Our team brings together expertise in skeletal stem cell biology, in-depth basic science and clinical knowledge of OA as well as bioengineering competency. We are using cutting-edge methods to pursue hypothesis-driven questions aimed at unlocking endogenous stem cells for cartilage repair. By taking advantage of a therapeutic window to skew local MF-activated SSC fate we want to generate new cartilage for the resurfacing of OA joints independent of age and disease state. Eventually, we wish to translate these preclinical studies.