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Article

A Novel Hepatic Anti-Fibrotic Strategy Utilizing the Secretome Released from Etanercept-Synthesizing Adipose-Derived Stem Cells

by
Jae Hyun Han
1,
Ok-Hee Kim
2,3,
Sang Chul Lee
4,
Kee-Hwan Kim
3,5,
Jung Hyun Park
6,
Jae Im Lee
5,
Kyung Hee Lee
2,3,
Ha-Eun Hong
2,3,
Haeyeon Seo
2,3,
Ho Joong Choi
2,
Ji Hyeon Ju
7 and
Say-June Kim
2,3,*
1
Department of Surgery, St. Vincent Hospital, College of Medicine, The Catholic University of Korea, Seoul 16247, Korea
2
Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
3
Catholic Central Laboratory of Surgery, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
4
Department of Surgery, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 34943, Korea
5
Department of Surgery, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 11765, Korea
6
Department of Surgery, Eunpeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Korea
7
Division of Rheumatology, Department of internal medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(24), 6302; https://doi.org/10.3390/ijms20246302
Submission received: 6 November 2019 / Revised: 11 December 2019 / Accepted: 11 December 2019 / Published: 13 December 2019
(This article belongs to the Section Molecular Biology)
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Abstract

Tumor necrosis factor-α (TNF-α)-driven inflammatory reaction plays a crucial role in the initiation of liver fibrosis. We herein attempted to design genetically engineered adipose-derived stem cells (ASCs) producing etanercept (a potent TNF-α inhibitor), and to determine the anti-fibrotic potential of the secretome released from the etanercept-synthesizing ASCs (etanercept-secretome). First, we generated the etanercept-synthesizing ASCs by transfecting the ASCs with mini-circle plasmids containing the gene insert encoding for etanercept. We subsequently collected the secretory material released from the etanercept-synthesizing ASCs and determined its anti-fibrotic effects both in vitro (in thioacetamide [TAA]-treated AML12 and LX2 cells) and in vivo (in TAA-treated mice) models of liver fibrosis. We observed that while etanercept-secretome increased the viability of the TAA-treated AML12 hepatocytes (p = 0.021), it significantly decreased the viability of the TAA-treated LX2 HSCs (p = 0.021). In the liver of mice with liver fibrosis, intravenous administration of the etanercept-secretome induced significant reduction in the expression of both fibrosis-related and inflammation-related markers compared to the control group (all Ps < 0.05). The etanercept-secretome group also showed significantly lower serum levels of liver enzymes as well as pro-inflammatory cytokines, such as TNF-α (p = 0.020) and IL-6 (p = 0.021). Histological examination of the liver showed the highest reduction in the degree of fibrosis in the entanercept-secretome group (p = 0.006). Our results suggest that the administration of etanercept-secretome improves liver fibrosis by inhibiting TNF-α-driven inflammation in the mice with liver fibrosis. Thus, blocking TNF-α-driven inflammation at the appropriate stage of liver fibrosis could be an efficient strategy to prevent fibrosis.
Keywords: adipose-derived stem cells; etanercept; liver fibrosis; secretome; tumor necrosis factor-α (TNF-α) adipose-derived stem cells; etanercept; liver fibrosis; secretome; tumor necrosis factor-α (TNF-α)

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MDPI and ACS Style

Han, J.H.; Kim, O.-H.; Lee, S.C.; Kim, K.-H.; Park, J.H.; Lee, J.I.; Lee, K.H.; Hong, H.-E.; Seo, H.; Choi, H.J.; et al. A Novel Hepatic Anti-Fibrotic Strategy Utilizing the Secretome Released from Etanercept-Synthesizing Adipose-Derived Stem Cells. Int. J. Mol. Sci. 2019, 20, 6302. https://doi.org/10.3390/ijms20246302

AMA Style

Han JH, Kim O-H, Lee SC, Kim K-H, Park JH, Lee JI, Lee KH, Hong H-E, Seo H, Choi HJ, et al. A Novel Hepatic Anti-Fibrotic Strategy Utilizing the Secretome Released from Etanercept-Synthesizing Adipose-Derived Stem Cells. International Journal of Molecular Sciences. 2019; 20(24):6302. https://doi.org/10.3390/ijms20246302

Chicago/Turabian Style

Han, Jae Hyun, Ok-Hee Kim, Sang Chul Lee, Kee-Hwan Kim, Jung Hyun Park, Jae Im Lee, Kyung Hee Lee, Ha-Eun Hong, Haeyeon Seo, Ho Joong Choi, and et al. 2019. "A Novel Hepatic Anti-Fibrotic Strategy Utilizing the Secretome Released from Etanercept-Synthesizing Adipose-Derived Stem Cells" International Journal of Molecular Sciences 20, no. 24: 6302. https://doi.org/10.3390/ijms20246302

APA Style

Han, J. H., Kim, O.-H., Lee, S. C., Kim, K.-H., Park, J. H., Lee, J. I., Lee, K. H., Hong, H.-E., Seo, H., Choi, H. J., Ju, J. H., & Kim, S.-J. (2019). A Novel Hepatic Anti-Fibrotic Strategy Utilizing the Secretome Released from Etanercept-Synthesizing Adipose-Derived Stem Cells. International Journal of Molecular Sciences, 20(24), 6302. https://doi.org/10.3390/ijms20246302

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