Multimodal manipulation of the Skeletal Stem Cell for Articular Cartilage Regeneration
Matthew P. Murphy, MD, Lauren S. Koepke, BS, Michael Lopez, BS, Ryan C. Ransome, BS, Rachel Brewer, BS, Owen Marecic, BA, Charles FK Chan, PhD, Michael T. Longaker, MD, MBA.
Stanford, Stanford, CA, USA.
Purpose: With an aging population, degenerative diseases such as osteoarthritis are expected to increase. Hyaline cartilage has a poor propensity to regenerate. To ameliorate its healing capacity patients are being offered multiple “stem cell” therapies with little or no evidence behind their claims. With a unique insight into the Skeletal Stem Cell we aim to share new insights into our manipulation of the SSC through surgical, biochemical and cellular treatments. Methods: (Figure 1) Skeletally mature mice were used throughout. An N=10 was used for each group unless stated. Clonality was assessed using Actin and Sox9 Cre-ER Rainbow mouse models induced with tamoxifen. Cell number was assessed with FACS using previously published FACS gating profiles. Proliferation was assessed using EdU assays by IHC and intracellular FACS. Cellular origin was assessed with our parabiosis model. Differentiation capacity was assessed in vitro and in vivo (both subcapsular and orthotopic). Biochemical manipulation used hydrogel and collagen scaffolds. Cellular treatments used labelled cell population transplantation orthotopically. Results: Following surgical manipulation, clonality was confirmed within the regenerate. A significant increase (p<0.05) in the number of SSC was seen at 1 and 2 weeks post operatively. The regenerate contained proliferating cells. There was a significant increase (p<0.05) in SSC proliferation following surgery. The significant increase in SSC within the area was due to a local increase of SSC. The fate of those SSC is affected by our temporal biochemical factors following injury. Addition of prospective FACS isolated cellular subpopulations augments the native SSC population. Conclusions: Our approach to manipulating SSC fate towards hyaline cartilage regeneration is a novel, cell-specific, targeted therapy. We now aim to translate this research into the clinical setting and optimize our protocol for regenerating hyaline cartilage.
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