Translational Cell-Specific Tissue Remodeling for Osteoarthritis
Matthew P. Murphy, MD, Lauren S. Koepke, BS, Michael Lopez, BS, Gunsagar Gulati, BS, Ryan C. Ransom, BS, Thomas H. Ambrosi, PhD, Xinming Tong, PhD, Charles KF Chan, PhD, Michael T. Longaker, MD, MBA.
Stanford, Stanford, CA, USA.
Purpose:The ability to regenerate stable hyaline cartilage following a diagnosis of Osteoarthritis (OA) has eluded many plastic and orthopedic surgeons. While there are preliminary pilot studies attempting to assess functional outcomes with "stem cell" therapies, there is no evidence at a cellular level of their efficacy. We have recently identified both mouse and human Skeletal Stem Cells (SSC) with the ability to form bone cartilage and stromal tissue. Methods:Mouse Data:Groups included: P3 Pups, 2 week old, 6 week old and 1 year old mice male mice. Clonality was assessed using our Actin Cre ER mouse model. FACS analysis was performed using our published mSSC profile. SSC activation was performed using Microfracture surgery. Proliferation was assessed using EdU assays by IHC and intracellular FACS. Cellular origin was assessed with our parabiosis model. Gene expression was assessed using Microarray. Differentiation capacity was assessed in vitroand in vivo(both subcapsular and orthotopic). Biochemical manipulation used hydrogel and collagen scaffolds orthotopically. Outcomes were assessed by pentachrome staining.Human Data:Freshly isolated cartilage was isolated from fetal and adult articular cartilage. A novel xenograft model was used to assess MF surgery and fate skewing using hydrogel application. Results:With skeletal maturity there is a significant reduction in articular SSC, with a concomitant reduction in proteoglycan production at the articular surface in mouse and human. Following MF surgery there is a significant activation of local SSC in mouse and human tissues. In mouse tissue, MF surgery leads to an intrinsic genetic alteration leading to formation of fibrocartilage. With niche augmentation using BMP2 and VEGFr1 the regenerate forms articular cartilage (distinct from the fibrous scarred tissue) repeatedly which remains stable in both mouse and human tissues.Conclusions: We are the first group to show that MF surgery has any effect on SSC in mouse and human tissue. We show that local application of BMP2 and VEGFr1 leads to cartilage differentiation of SSC in both species providing an exciting new clinically relevant approach for treating OA.
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