Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Jan 26, 2020; 12(1): 70-86
Published online Jan 26, 2020. doi: 10.4252/wjsc.v12.i1.70
Generation of induced secretome from adipose-derived stem cells specialized for disease-specific treatment: An experimental mouse model
Ok-Hee Kim, Ha-Eun Hong, Haeyeon Seo, Bong Jun Kwak, Ho Joong Choi, Kee-Hwan Kim, Joseph Ahn, Sang Chul Lee, Say-June Kim
Ok-Hee Kim, Ha-Eun Hong, Haeyeon Seo, Kee-Hwan Kim, Sang Chul Lee, 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, Haeyeon Seo, Bong Jun Kwak, Ho Joong Choi, Joseph Ahn, Say-June Kim, Department of Surgery, Division of Hepato-biliary Pancreatic Surgery, Seoul St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul 06591, South Korea
Kee-Hwan Kim, Department of Surgery, Uijeongbu St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul 11765, 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: All authors contributed to manuscript preparation; Kim SJ designed the research and analyzed data; Kim OH wrote the paper, performed in vitro experiment, and analyzed data; Hong HE and Seo H performed in vitro experiments; Kwak BJ, Choi HJ, Kim KH, Ahn J, and Lee SC performed in vivo experiments and analyzed data.
Supported by National Research Foundation of Korea, No. NRF-2015R1C1A1A02036931
Institutional animal care and use committee statement: Approved by the Animal Care Committee of the Catholic University of Korea, No. CMCDJ-AP-2016-001.
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, Division of Hepato-biliary Pancreatic 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
Received: April 12, 2019
Peer-review started: April 14, 2019
First decision: May 16, 2019
Revised: August 16, 2019
Accepted: September 26, 2019
Article in press: September 26, 2019
Published online: January 26, 2020
Abstract
BACKGROUND

Recently, the exclusive use of mesenchymal stem cell (MSC)-secreted molecules, named as the secretome, have been evaluated for overcoming the limitations of cell-based therapy while maintaining its advantages.

AIM

To improve cell-free therapy by adding disease-specificity through stimulation of MSCs using disease-causing materials.

METHODS

We collected the secretory materials (named as inducers) released from AML12 hepatocytes that had been pretreated with thioacetamide (TAA) and generated the TAA-induced secretome (TAA-isecretome) after stimulating adipose-derived stem cells with the inducers. The TAA-isecretome was intravenously administered to mice with TAA-induced hepatic failure and those with partial hepatectomy.

RESULTS

TAA-isecretome infusion showed higher therapeutic potential in terms of (1) restoring disorganized hepatic tissue to normal tissue; (2) inhibiting proinflammatory cytokines (interleukin-6 and tumor necrosis factor-α); and (3) reducing abnormally elevated liver enzymes (aspartate aminotransferase and alanine aminotransferase) compared to the naïve secretome infusion in mice with TAA-induced hepatic failure. However, the TAA-isecretome showed inferior therapeutic potential for restoring hepatic function in partially hepatectomized mice. Proteomic analysis of TAA-isecretome identified that antioxidant processes were the most predominant enriched biological networks of the proteins exclusively identified in the TAA-isecretome. In addition, peroxiredoxin-1, a potent antioxidant protein, was found to be one of representative components of TAA-isecretome and played a central role in the protection of TAA-induced hepatic injury.

CONCLUSION

Appropriate stimulation of adipose-derived stem cells with TAA led to the production of a secretome enriched with proteins, especially peroxiredoxin-1, with higher antioxidant activity. Our results suggest that appropriate stimulation of MSCs with pathogenic agents can lead to the production of a secretome specialized for protecting against the pathogen. This approach is expected to open a new way of developing various specific therapeutics based on the high plasticity and responsiveness of MSCs.

Keywords: Adipose-derived stem cells, Disease-specificity, Mesenchymal stem cells, Secretome, Peroxiredoxin-1, Thioacetamide, Toxic hepatic failure

Core tip: Appropriate stimulation of adipose-derived stem cells with thioacetamide (TAA) led to the production of a secretome enriched with proteins, especially peroxiredoxin-1, with higher antioxidant activity. Free radicals are principal pathogenic agents in the pathogenesis of TAA-induced hepatic injury. The TAA-induced secretome was superior to the naïve secretome in restoring hepatic function while minimizing inflammatory processes in mice with TAA-induced hepatic failure. However, it was less effective in the mice with partial hepatectomy, suggestive of disease-specificity. Our results suggest that appropriate stimulation of adipose-derived stem cells with pathogenic agents can lead to the production of a secretome specialized for protecting against the pathogen.