Stem Cell Surface Modification to Promote Nerve Regeneration

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Project Summary Peripheral nerve injury, especially critical-sized nerve gap injury, often results in poor recovery of function and impaired quality of life for the patient. Stem cell therapy holds significant promise; however, its clinical application has been largely hampered by limited stem cell adhesion and the lack of efficient differentiation. We have shown that our stem cell surface modification technique is able to profoundly influence specific cell-cell and cell-matrix interactions. Therefore, our specific aims are to develop and optimize novel candidate analogs to promote human adipose stem cell (hASC) adhesion and differentiation in vitro; to incorporate the cell surface modification technique into hASC-based therapies to improve peripheral nerve regeneration; and to investigate related mechanisms underlying improved nerve regeneration. Aim1: To develop and optimize novel analogs by metabolic glycoengineering (MGE) technology to promote hASC's cell adhesion and cell differentiation in vitro. We will optimize the cell surface modification with thiolated sugar analogs (ManNAc), evaluate the effects, and thoroughly characterize them to promote hASCs adhesion, proliferation, and differentiation. Aim2: To incorporate MGE into hASC-based therapies to improve peripheral nerve regeneration. With optimized ManNAc analogs, we will systemically evaluate the effect of glycoengineered hASCs on nerve regeneration after nerve repair and further optimize the therapy. Aim 3: To examine the mechanism by which thiol-derivatized ManNAc analogs contribute to nerve regeneration . With expected improvements in nerve regeneration, we will evaluate signaling pathways (e.g., Wnt / β after MGE'ed hASC transplantation. -catenin) modulated by MGE The innovation lies in our hypothesis to modify stem cell surface glycan properties with sugar analogs to improve cell survival and differentiation, our novel and effective technology, and the new application of these technologies in a fully translational nerve repair model to develop a novel treatment. The significance lies in the novel cell-based therapy with surface modification to address one of the most challenging aspects of nerve regeneration for critical-sized nerve gap repair, and the expected discovery of the mechanism underlying improved survival and differentiation by transplanted MGE'ed hASC. Our technology and protocols are highly translatable to the clinical environment. Success in this project will have direct translational implications for patients with peripheral nerve trauma requiring surgical repair. The clinical study of ManNAc has demonstrated the safety of single oral doses up to 6 g, and the FDA has approved the use of ManNAc to treat GNE Myopathy. Our study will lead to the development of novel therapeutic strategies for nerve repair that can contribute to future clinical interventions and maximize the benefits of stem cell therapy based on the new findings.