IMPROVING THE CLINICAL UTILITY OF MESENCHYMAL STEM CELLSTHROUGH ENHANCING CELL SURVIVAL: ENGINEERED AND CELLULARAPPROACHES

[摘要] For decades, mesenchymal stem cells have been touted as highly promising cells for usein regenerative medicine. Their flexibility in differentiation to other cell types, paracrine abilitiesin supporting angiogenesis, and modulatory behavior in inflammation have led to researchersapplying 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 therapieshas been a lack of survival for implanted cells, preventing them from carrying out their manybeneficial functions. We have examined strategies to improve this MSC survival dilemma,hypothesizing that a combination of engineered approaches to activate survival signaling andmodulation of autophagy to generate energy for the cell would act to improve MSC survival andfunction in the face of stressors. Our results show that cell surface restriction of EGFR toconstitutively activate downstream survival signaling improves MSC longevity in two systems:physical tethering of soluble EGF on bone regeneration scaffolds, and EGFR tethering throughEGF-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 aremobilized for degradation during the stress of differentiation and can be tuned to affect MSCfunction in relation to differentiation. Ultimately, these strategies to alter MSC signaling andfunction will be of considerable use for attempts to apply the great potential utility of MSCs towound healing and other contexts in biomedical science.

[发布机构] the University of Pittsburgh