Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2023.191
Extracellular Vesicles Derived from Adipose Stem Cells Alleviate Systemic Sclerosis by Inhibiting TGF-β Pathway
Eunae Kim1, Hark Kyun Kim1, Jae Hoon Sul1, Jeongmi Lee1, Seung Hyun Baek1, Yoonsuk Cho1, Jihoon Han1, Junsik Kim1, Sunyoung Park1, Jae Hyung Park2,3,4,5, Yong Woo Cho4,6 and Dong-Gyu Jo1,2,3,4,*
1School of Pharmacy, Sungkyunkwan University, Suwon 16419,
2Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science & Technology (SAIHST), Sungkyunkwan University, Suwon 06355,
3Biomedical Institute for Convergence, Sungkyunkwan University, Suwon 16419,
4ExoStemTech Inc., Ansan 15588,
5School of Chemical Engineering, Sungkyunkwan University, Suwon 16419,
6Department of Materials Science and Chemical Engineering, Hanyang University ERICA, Ansan 15588, Republic of Korea
*E-mail: jodg@skku.edu
Tel: +82-32-290-7782, Fax: +82-31-292-8800
Received: November 3, 2023; Revised: November 28, 2023; Accepted: November 30, 2023; Published online: June 5, 2024.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Systemic sclerosis is an autoimmune disease characterized by inflammatory reactions and fibrosis. Myofibroblasts are considered therapeutic targets for preventing and reversing the pathogenesis of fibrosis in systemic sclerosis. Although the mechanisms that differentiate into myofibroblasts are diverse, transforming growth factor β (TGF-β) is known to be a key mediator of fibrosis in systemic sclerosis. This study investigated the effects of extracellular vesicles derived from human adipose stem cells (ASC-EVs) in an in vivo systemic sclerosis model and in vitro TGF-β1-induced dermal fibroblasts. The therapeutic effects of ASC-EVs on the in vivo systemic sclerosis model were evaluated based on dermal thickness and the number of α-smooth muscle actin (α-SMA)- expressing cells using hematoxylin and eosin staining and immunohistochemistry. Administration of ASC-EVs decreased both the dermal thickness and α-SMA expressing cell number as well as the mRNA levels of fibrotic genes, such as Acta2, Ccn2, Col1a1 and Comp. Additionally, we discovered that ASC-EVs can decrease the expression of α-SMA and CTGF and suppress the TGF-β pathway by inhibiting the activation of SMAD2 in dermal fibroblasts induced by TGF-β1. Finally, TGF-β1-induced dermal fibroblasts underwent selective death through ASC-EVs treatment. These results indicate that ASC-EVs could provide a therapeutic approach for preventing and reversing systemic sclerosis.
Keywords: Systemic sclerosis, Extracellular vesicle, Exosome, Adipose stem cell, TGF-β


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