| For decades, mesenchymal stem cells have been touted as highly promising cells for use in regenerative medicine. Their flexibility in differentiation to other cell types, paracrine abilities in supporting angiogenesis, and modulatory behavior in inflammation have led to researchers applying the cells across a wide variety of treatments, including skin healing, bone regeneration, myocardial infarction repair, and others. However, a fundamental limitation in all MSC therapies has been a lack of survival for implanted cells, preventing them from carrying out their many beneficial functions. We have examined strategies to improve this MSC survival dilemma, hypothesizing that a combination of engineered approaches to activate survival signaling and modulation of autophagy to generate energy for the cell would act to improve MSC survival and function in the face of stressors. Our results show that cell surface restriction of EGFR to constitutively activate downstream survival signaling improves MSC longevity in two systems: physical tethering of soluble EGF on bone regeneration scaffolds, and EGFR tethering through EGF-like repeats of the ECM protein Tenascin C in a polymer for skin wound healing. Additionally, we found that MSCs have a high accumulation of autophagosomes, which are mobilized for degradation during the stress of differentiation and can be tuned to affect MSC function in relation to differentiation. Ultimately, these strategies to alter MSC signaling and function will be of considerable use for attempts to apply the great potential utility of MSCs to wound healing and other contexts in biomedical science. |
