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Cell Engineering for Neuromuscular Regeneration & Neural Reprogramming

  • Author(s): Li, LeeAnn Kai-Yin
  • Advisor(s): Li, Song
  • et al.
Abstract

Neurological disorders are the primary cause of disability and the second leading cause of deaths worldwide, with an ever-increasing burden as populations grow and age. The peripheral nervous system (PNS) possesses great regenerative capability, but even so, no effective therapy exists for severe peripheral nerve injuries (PNIs) and underlying mechanisms are incompletely understood. Conversely, treatment for central nervous system (CNS) disease is crippled by little innate regenerative ability of the brain and inaccessibility of patient neural tissue. Direct reprogramming or transdifferentiation of adult somatic cells into neuronal fate (“induced neurons”) has great potential for overcoming these barriers, but still suffers from low and variable efficiencies of conversion. My thesis harnessed principles of cell engineering, neuroengineering, and regenerative medicine to address these issues. In the PNS, we demonstrated a novel proof-of-concept that engineered synthetic neuromuscular tissue (SyNMT) can be used to guide development of and screening for stem cell therapies to treat denervation injuries. We compared neural crest stem cells (NCSCs) to bone marrow-derived mesenchymal stem cells (MSCs). Three-dimensional (3D) multicellular spheroids of NCSCs enhanced in vitro regenerative functions and dramatically increased in vivo longevity, with significant functional improvement in rat trials that recapitulated SyNMT findings of NCSC but not MSC improvements in neuromuscular junction innervation. In the CNS, we demonstrated that 3D spheroids promoted the direct reprogramming of human fibroblasts into neurons, increasing conversion efficiency by over 67 times. Moreover, reprogramming displayed distinct spatial patterns dependent on adhesive polarity that could be rescued by dual BMP & TGF-β pathway inhibition. Overall, this work demonstrated the significant impact of engineering biophysical cues to improve regeneration and survival of neuromuscular cell therapies as well as to improve neural reprogramming, enhancing translational potential for biomedical applications.

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