한빛사논문
Jiseong Kim a,b,1, Myung Chul Lee a,m,1, Jieun Jeon a,b,1, Alejandra Rodríguez-delaRosa c,d,e, Yori Endo f, Da-Seul Kim a, Andrea Donaxi Madrigal-Salazar a,g, Jeong Wook Seo a, Hyeseon Lee a,h, Ki-Tae Kim i,j, Jae-I Moon i,j, Seung Gwa Park i,j, Mariana Carolina Lopez-Pacheco a,g, Abdulhameed F. Alkhateeb k, Nebras Sobahi k, Nicole Bassous a, Wenpeng Liu l, Jae Seo Lee a,n, Seongsoo Kim a, Dilara Yilmaz Aykut a, Mahmoud Lotfi Nasr l,o, Mohammad Asif Hussain k, Soo-Hong Lee b, Woo-Jin Kim i,j, Olivier Pourquié c,d,e, Indranil Sinha f, Su Ryon Shin a
aDivision of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, 02139, USA
bDepartment of Medical Biotechnology, Dongguk University, 32 Dongguk-ro, Goyang, 10326, Republic of Korea
cDepartment of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA
dDepartment of Genetics, Harvard Medical School, Boston, MA, 02115, USA
eHarvard Stem Cell Institute, Harvard University, Boston, MA, 02138, USA
fDepartment of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
gTecnológico de Monterrey, Escuela de Ingeniería y Ciencias, Campus Guadalajara, Av. Gral. Ramón Corona No 2514, Colonia Nuevo México, Zapopan, Jalisco, 45121, Mexico
hDepartment of Biomaterials Science (BK21 Four Program), Life and Industry Convergence Institute, Pusan National University, Miryang, 50463, Republic of Korea
iDepartment of Molecular Genetics & Dental Pharmacology, School of Dentistry and Dental Research Institute, Dental Multi-omics Center, Seoul National University, Seoul, 03080, Republic of Korea
jEpigenetic Regulation of Aged Skeleto-Muscular System Laboratory, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, 08826, Republic of Korea
kDepartment of Electrical and Computer Engineering, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
lDivision of Engineering in Medicine and Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
mMedicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
nHarvard Medical School and Wellman Center for Photomedicine, Massachusetts General Hospital, Cambridge, MA, 02139, USA
oCollege of Medicine, Mohamed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE
1These authors contributed equally to this work.
Corresponding authors: Indranil Sinha, Su Ryon Shin
Abstract
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.
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