Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Nov 26, 2019; 11(11): 990-1004
Published online Nov 26, 2019. doi: 10.4252/wjsc.v11.i11.990
Ameliorating liver fibrosis in an animal model using the secretome released from miR-122-transfected adipose-derived stem cells
Kee-Hwan Kim, Jae Im Lee, Ok-Hee Kim, Ha-Eun Hong, Bong Jun Kwak, Ho Joong Choi, Joseph Ahn, Tae Yun Lee, Sang Chul Lee, Say-June Kim
Kee-Hwan Kim, Jae Im Lee, Department of Surgery, Uijeongbu St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 11765, South Korea
Kee-Hwan Kim, Ok-Hee Kim, Ha-Eun Hong, Say-June Kim, Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
Ok-Hee Kim, Ha-Eun Hong, Bong Jun Kwak, Ho Joong Choi, Joseph Ahn, Tae Yun Lee, Say-June Kim, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
Sang Chul Lee, Department of Surgery, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 34943, South Korea
Author contributions: Kim SJ was responsible for planning the study, data interpretation, and manuscript preparation; Kim KH and Kim SJ wrote paper, complemented in vivo experiments, and data interpretation; Kim OK and Hong HE performed in vitro experiments; Lee JI, Kwak BJ, Choi HJ, Ahn J, Lee TR and Lee SC were involved in various in vivo experiments and data interpretation. All authors read and approved the manuscript.
Supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT), No. NRF-2015R1D1A1A01060721.
Institutional review board statement: This research was approved by Institutional Review Board, IRB No. 700069-201407-BR-002-01, of Hurim BioCell Co. Ltd. (Seoul, Korea).
Institutional animal care and use committee statement: Animal studies were carried out in compliance with the guidelines of the Institute for Laboratory Animal Research, Korea, IRB No: CUMC-2017-0317-04.
Conflict-of-interest statement: The authors have declared no potential conflicts of interest.
Data sharing statement: Requests for access to data should be addressed to the corresponding author.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Say-June Kim, MD, PhD, Professor, Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, South Korea. sayjunekim@gmail.com
Telephone: +82-2-22587636 Fax: +82-2-5350070
Received: March 12, 2019
Peer-review started: March 15, 2019
First decision: July 31, 2019
Revised: September 2, 2019
Accepted: September 13, 2019
Article in press: September 13, 2019
Published online: November 26, 2019
Processing time: 238 Days and 1.4 Hours
Abstract
BACKGROUND

Recently, the exclusive use of mesenchymal stem cell (MSC)-secreted molecules, called secretome, rather than cells, has been evaluated for overcoming the limitations of cell-based therapy, while maintaining its advantages. However, the use of naïve secretome may not fully satisfy the specificity of each disease. Therefore, it appears to be more advantageous to use the functionally reinforced secretome through a series of processes involving physico-chemical adjustments or genetic manipulation rather than to the use naïve secretome.

AIM

To determine the therapeutic potential of the secretome released from miR-122-transfected adipose-derived stromal cells (ASCs).

METHODS

We collected secretory materials released from ASCs that had been transfected with antifibrotic miR-122 (MCM) and compared their antifibrotic effects with those of the naïve secretome (CM). MCM and CM were intravenously administered to the mouse model of thioacetamide-induced liver fibrosis, and their therapeutic potentials were compared.

RESULTS

MCM infusion provided higher therapeutic potential in terms of: (A) Reducing collagen content in the liver; (B) Inhibiting proinflammatory cytokines; and (C) Reducing abnormally elevated liver enzymes than the infusion of the naïve secretome. The proteomic analysis of MCM also indicated that the contents of antifibrotic proteins were significantly elevated compared to those in the naïve secretome.

CONCLUSION

We could, thus, conclude that the secretome released from miR-122-transfected ASCs has higher antifibrotic and anti-inflammatory properties than the naïve secretome. Because miR-122 transfection into ASCs provides a specific way of potentiating the antifibrotic properties of ASC secretome, it could be considered as an enhanced method for reinforcing secretome effectiveness.

Keywords: Adipose-derived stem cells; Liver fibrosis; MicroRNAs; miR-122; Mesenchymal stem cells; Secretome

Core tip: We herein intended to determine the antifibrotic effects of the secretome released from miR-122-transfected adipose-derived stromal cells (miR-122-secretome). miR122-secrectome and naïve secretome were intravenously administered to the mice with liver fibrosis, respectively. miR122-secrectome infusion provided higher therapeutic potential in terms of reducing collagen content in the liver, inhibiting proinflammatory cytokines, and reducing abnormally elevated liver enzymes than the infusion of the naïve secretome. Proteomic analysis of the miR122-secrectome indicated that the contents of antifibrotic proteins were significantly elevated compared to those in the naïve secretome. Our results demonstrate that miR122-secrectome has higher antifibrotic and anti-inflammatory properties than the naïve secretome.