Engineered human myogenic cells in hydrogels generate functional myofibers within dystrophic mouse muscle

Kowala, A.; Meng, J.; Pourquie, O.; Connelly, J.; Morgan, J. E.; Lin, Y.-Y.

doi:10.1101/2023.09.05.556335

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bioRxiv · 10.1101/2023.09.05.556335

Engineered human myogenic cells in hydrogels generate functional myofibers within dystrophic mouse muscle

Kowala, A.·Meng, J.·Pourquie, O.·Connelly, J.·Morgan, J. E.·Lin, Y.-Y.

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Abstract

Transplantation of human myogenic progenitor cells (MPCs) is a promising therapeutic strategy for treating muscle-wasting diseases, e.g., Duchenne muscular dystrophy (DMD). To increase engraftment efficiency of donor stem cells, modulation of host muscles is required, significantly limiting their clinical translation. Here we develop a clinically relevant transplantation strategy synergising hydrogel-mediated delivery and engineered human MPCs generated from CRISPR-corrected DMD patient-derived pluripotent stem cells (PSCs). We demonstrate that donor-derived human myofibers produce full-length dystrophin at 4 weeks and 5 - 6 months (long-term) post transplantation in the unmodulated muscles of the dystrophin-deficient mouse model of DMD. Remarkably, human myofibers are innervated by mouse motor neurons forming neuromuscular junctions and supported by vascularisation after long-term engraftment in dystrophic mice. PAX7+ cells of human origin replenish the satellite cell niche. There was no evidence of tumorigenesis in mice engrafted with hydrogel-encapsulated human MPCs. Our results provide a proof-of-concept in developing hydrogel-based cell therapy for muscle-wasting diseases.

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Kowala, A., Meng, J., Pourquie, O., Connelly, J., Morgan, J. E., Lin, Y.-Y.. 2023-09-05. Engineered human myogenic cells in hydrogels generate functional myofibers within dystrophic mouse muscle. https://doi.org/10.1101/2023.09.05.556335

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