Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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Cell-based Muscle Regeneration by utilizing Epigenetic Drug and Hydrogel
ShihJye Tan, MS, Zhi Yang, MD, Josephine Fang, MS, Yichen Wu, MS, Marcel Nimni, PhD, Mark Urata, MD. DDS, Bo Han, PhD.
USC, Los Angeles, CA, USA.

Purpose: The loss of a portion of a skeletal muscle poses a unique challenge for regeneration of muscle tissue and restoration of its normal structure and function. Our in vitro results demonstrated that hydrogel combined with the optimal dosage of epigenetic drug would effectively trans-differentiate adipose derived stem cells (ADSCs) into myoblasts-like cells. Therefore, in this study, we aim to investigate the capability of 5-aza-CR on reprogramming ADSCs that is administered by transglutaminase crosslnked gelatin gel (Col-Tgel) to repair the loss of a portion of skeletal muscle in animal models.
Methods: Thirty six 2-month-old retired breeder Fischer-344 rats were randomly divided into 4 groups: vehicle, ADSCs only, ADSCs with Col-Tgel, and ADSCs with 5-aza-CR Col-Tgel. A 5 mm diameter myectomy lesion was created in the tibialis anterior (TA) muscle of each rat and was infused with 100 µl of each sample. Rats were euthanized on day 5 and 14 post-op, and their muscles were removed for histological studies including a semi-quantitative histological score scale of the new muscle formation, maturation and alignment. Statistical differences were determined using ANOVA, followed by a Tukey-Kramer honestly significant difference (HSD) test for pair-wise comparisons (SAS). A statistical significance was accepted at p < 0.05.
Results: ADSCs treated with 5-aza-CR initially were greatly trans-differentiated into muscle cells compared to those without 5-aza-CR. On day 14, significant infiltration of fibroblasts, inflammatory cells, neovessel invasion, and the least amount of new muscle formation were observed for the vehicle and ADSCs groups. In contrary, significant amount of new muscle formation was identified by MyoD1 immunohistochemistry in the ADSCs with Col-Tgel and the ADSCs with 5-aza-CR Col-Tgel groups. Besides, the combination of 5-aza-CR with Col-Tgel showed a much greater area of muscle formation than those without 5-aza-CR. Moreover, the newly formed muscle in this group was well aligned and paralleled to the intact muscle at the repair site.
Conclusions: ADSCs treated with 5-aza-CR provided not only the precursors that led to trans-differentiate of functioning muscle cells, but also allowed the recruitment of cells, mediation of inflammatory response, remodeling of the extracellular matrix (ECM), and prevention of deleterious downstream effects of fibrotic scar tissue formation through the paracrine effects. The Col-Tgel that was used in this study not only provides pliable handling properties that allows it to conform to any irregular shaped defect, but it also controls the release rate of chemical stimuli (i.e. 5-aza-CR) to amplify the regenerative capacity. The study suggested this cell-based therapy was able to significantly boost the regenerative capacity of severe injured muscle and induce self-regeneration function that is lost due to ageing. Furthermore, the results obtained from this study encouraged the translation of cell-based therapy to clinical treatments for patients.


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