Combinational regenerative inductive effect of bio-adhesive hybrid hydrogels conjugated with hiPSC-derived myofibers and its derived EVs for volumetric muscle regeneration

• Published in: Bioactive materials Vol. 43; pp. 579 - 602
• Main Authors: Kim, Jiseong, Lee, Myung Chul, Jeon, Jieun, Rodríguez-delaRosa, Alejandra, Endo, Yori, Kim, Da-Seul, Madrigal-Salazar, Andrea Donaxi, Seo, Jeong Wook, Lee, Hyeseon, Kim, Ki-Tae, Moon, Jae-I, Park, Seung Gwa, Lopez-Pacheco, Mariana Carolina, Alkhateeb, Abdulhameed F., Sobahi, Nebras, Bassous, Nicole, Liu, Wenpeng, Lee, Jae Seo, Kim, Seongsoo, Aykut, Dilara Yilmaz, Nasr, Mahmoud Lotfi, Hussain, Mohammad Asif, Lee, Soo-Hong, Kim, Woo-Jin, Pourquié, Olivier, Sinha, Indranil, Shin, Su Ryon
• Format: Journal Article
• Language: English
• Published: China Elsevier B.V 01.01.2025; KeAi Publishing Communications Ltd; KeAi Publishing; KeAi Communications Co., Ltd
• Subjects: Adhesives; Angiogenesis; Bio-adhesive hydrogel; Cardiomyocytes; Crosslinking; Extracellular matrix; Extracellular vesicles; Gelatin; Harsh environments; Human induced pluripotent stem cells; Hydrogels; Mechanical properties; MicroRNAs; miRNA; Muscle regeneration; Muscles; Musculoskeletal system; Myogenesis; Nanomaterials; Phenotypes; Pluripotency; Regeneration (physiology); Regenerative medicine; Restoration; Stem cells; Tethering; Tissue engineering; Transplants & implants; Tyramine; Volumetric muscle loss; Human induced pluripotent stem cells; Extracellular vesicles; Bio-adhesive hydrogel; Volumetric muscle loss; Muscle regeneration
• ISSN: 2452-199X; 2097-1192; 2452-199X
• DOI: 10.1016/j.bioactmat.2024.09.013

In regenerative medicine, extracellular vesicles (EVs) possess the potential to repair injured cells by delivering modulatory factors. However, the therapeutic effect of EVs in large-scale tissue defects, which are subject to prolonged timelines for tissue architecture and functional restoration, remains poorly understood. In this study, we introduce EVs and cell-tethering hybrid hydrogels composed of tyramine-conjugated gelatin (GelTA) that can be in-situ crosslinked with EVs derived from human induced pluripotent stem cell-derived myofibers (hiPSC-myofibers) and hiPSC-muscle precursor cells. This hybrid hydrogel sustains the release of EVs and provides a beneficial nano-topography and mechanical properties for creating a favorable extracellular matrix. Secreted EVs from the hiPSC-myofibers contain specific microRNAs, potentially improving myogenesis and angiogenesis. Herein, we demonstrate increased myogenic markers and fusion/differentiation indexes through the combinatory effects of EVs and integrin-mediated adhesions in the 3D matrix. Furthermore, we observe a unique impact of EVs, which aid in maintaining the viability and phenotype of myofibers under harsh environments. The hybrid hydrogel in-situ crosslinked with hiPSCs and EVs is facilely used to fabricate large-scale muscle constructs by the stacking of micro-patterned hydrogel domains. Later, we confirmed a combinational effect, whereby muscle tissue regeneration and functional restoration were improved, via an in vivo murine volumetric muscle loss model. [Display omitted] •EVs extrated from hiPSC-myofibers contain specific miRNAs that promote myogenic differentiation and stimulate angiogenesis.•EVs support the survival and differentiation of hiPSC-myofibers in medium without myogenic differentiation reagents.•GelTA hydrogel sustains the releases of EVs and provides a favorable ECM via their unique physicochemical properties.•GelTA hydrogel in-situ crosslinked with hiPSCs and EVs improved muscle tissue regeneration and functional restoration.