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Battling Osteoarthritis through the Activation of Tissue-resident Stem Cells

Review of “Articular cartilage regeneration by activated skeletal stem cells” from Nature Medicine by Stuart P. Atkinson

The many limitations associated with current therapeutic approaches to conditions such as osteoarthritis have led to the exploration of stem cell therapies as a means to regenerate cartilage [1]. While many studies and trials have focused on the potential of mesenchymal stem cells, other groups, including those of Michael T. Longaker and Charles K. F. Chan (Stanford University School of Medicine, Stanford, CA, USA), have begun to evaluate the potential of tissue-resident skeletal stem cells instead [2, 3]. Skeletal stem cells can contribute to the bone, cartilage, and stroma and proliferate following injury, at which point they take on an enhanced skeletogenic potential [4].

Recently, the Longaker and Chan teams sought to explore the activation of tissue-resident skeletal stem cells as a novel approach to the regeneration of cartilage and the treatment of conditions such as osteoarthritis. In their recent Nature Medicine article [5], Murphy et al. now report that activated skeletal stem cells exposed to bone morphogenetic protein 2 (BMP2) and a vascular endothelial growth factor receptor 1 (VEGF1R) antagonist can prompt the regeneration of articular cartilage.

The authors first described the gradual loss of skeletal stem cell numbers and overall chondrogenic activity during the normal aging process following the flow cytometry-mediated isolation of functional skeletal stem cells from adult and juvenile/fetal tissues of mice and humans. Interestingly, the induction of a localized, acute injury via microfracture surgery in the chondral surface of adult mouse limb joints prompted the local expansion of skeletal stem cells and the induction of a regenerative response suggesting that mature articular cartilage still hosts stem cell reservoirs.  Unfortunately, activated adult skeletal stem cells only formed fibrous tissue, even though they possessed chondrogenic potential; however, the localized delivery of BMP2 and a VEGFR1 antagonist within a hydrogel to repress osteogenic and fibroblastic fates [6, 7] and enhance chondrogenesis [2, 3], prompted these microfracture-activated adult skeletal stem cells to form articular cartilage instead. 

While other studies have shown how their stem cell-therapies can halt the progression of diseases such as osteoarthritis [8], these fascinating findings represent one of the few examples of effective, stable articular cartilage regeneration induced through the induced activity of tissue-resident stem cells.

For more on the regenerative power of tissue-resident stem cells, stay tuned to the Stem Cells Portal!


  1. Piuzzi NS, Ng M, Chughtai M, et al., Accelerated Growth of Cellular Therapy Trials in Musculoskeletal Disorders: An Analysis of the NIH Clinical Trials Data Bank. Orthopedics 2019;42:e144-e150.
  2. Chan Charles KF, Seo Eun Y, Chen James Y, et al., Identification and Specification of the Mouse Skeletal Stem Cell. Cell 2015;160:285-298.
  3. Chan CKF, Gulati GS, Sinha R, et al., Identification of the Human Skeletal Stem Cell. Cell 2018;175:43-56.e21.
  4. Marecic O, Tevlin R, McArdle A, et al., Identification and characterization of an injury-induced skeletal progenitor. Proceedings of the National Academy of Sciences 2015;112:9920.
  5. Murphy MP, Koepke LS, Lopez MT, et al., Articular cartilage regeneration by activated skeletal stem cells. Nature Medicine 2020.
  6. Steinberg J and Zeggini E, Functional genomics in osteoarthritis: Past, present, and future. Journal of Orthopaedic Research 2016;34:1105-1110.
  7. Prockop DJ, Brenner M, Fibbe WE, et al., Defining the risks of mesenchymal stromal cell therapy. Cytotherapy 2010;12:576-578.
  8. Glyn-Jones S, Palmer AJR, Agricola R, et al., Osteoarthritis. The Lancet 2015;386:376-387.