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Open AccessArticle

Mitochondrial Transfer by Human Mesenchymal Stromal Cells Ameliorates Hepatocyte Lipid Load in a Mouse Model of NASH

1
Applied Molecular Hepatology Laboratory, Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Center, 04103 Leipzig, Germany
2
Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research (UFZ), 04318 Leipzig, Germany
3
Molecular Cell Therapy, Center for Biotechnology and Biomedicine, Leipzig University, 04103 Leipzig, Germany
4
Institute for Bioanalysis, University of Applied Sciences Coburg, 96450 Coburg, Germany
5
Department of Therapy Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
6
Institute of Biochemistry, Leipzig University, 04103 Leipzig, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Biomedicines 2020, 8(9), 350; https://doi.org/10.3390/biomedicines8090350
Received: 14 August 2020 / Revised: 2 September 2020 / Accepted: 10 September 2020 / Published: 14 September 2020
(This article belongs to the Special Issue NASH and Systemic Complications: From Basic to Clinical Research)
Mesenchymal stromal cell (MSC) transplantation ameliorated hepatic lipid load; tissue inflammation; and fibrosis in rodent animal models of non-alcoholic steatohepatitis (NASH) by as yet largely unknown mechanism(s). In a mouse model of NASH; we transplanted bone marrow-derived MSCs into the livers; which were analyzed one week thereafter. Combined metabolomic and proteomic data were applied to weighted gene correlation network analysis (WGCNA) and subsequent identification of key drivers. Livers were analyzed histologically and biochemically. The mechanisms of MSC action on hepatocyte lipid accumulation were studied in co-cultures of hepatocytes and MSCs by quantitative image analysis and immunocytochemistry. WGCNA and key driver analysis revealed that NASH caused the impairment of central carbon; amino acid; and lipid metabolism associated with mitochondrial and peroxisomal dysfunction; which was reversed by MSC treatment. MSC improved hepatic lipid metabolism and tissue homeostasis. In co-cultures of hepatocytes and MSCs; the decrease of lipid load was associated with the transfer of mitochondria from the MSCs to the hepatocytes via tunneling nanotubes (TNTs). Hence; MSCs may ameliorate lipid load and tissue perturbance by the donation of mitochondria to the hepatocytes. Thereby; they may provide oxidative capacity for lipid breakdown and thus promote recovery from NASH-induced metabolic impairment and tissue injury. View Full-Text
Keywords: non-alcoholic steatohepatitis (NASH); tunneling nanotubes (TNTs); primary hepatocytes; organelle transfer; mesenchymal stromal cells non-alcoholic steatohepatitis (NASH); tunneling nanotubes (TNTs); primary hepatocytes; organelle transfer; mesenchymal stromal cells
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MDPI and ACS Style

Hsu, M.-J.; Karkossa, I.; Schäfer, I.; Christ, M.; Kühne, H.; Schubert, K.; Rolle-Kampczyk, U.E.; Kalkhof, S.; Nickel, S.; Seibel, P.; von Bergen, M.; Christ, B. Mitochondrial Transfer by Human Mesenchymal Stromal Cells Ameliorates Hepatocyte Lipid Load in a Mouse Model of NASH. Biomedicines 2020, 8, 350. https://doi.org/10.3390/biomedicines8090350

AMA Style

Hsu M-J, Karkossa I, Schäfer I, Christ M, Kühne H, Schubert K, Rolle-Kampczyk UE, Kalkhof S, Nickel S, Seibel P, von Bergen M, Christ B. Mitochondrial Transfer by Human Mesenchymal Stromal Cells Ameliorates Hepatocyte Lipid Load in a Mouse Model of NASH. Biomedicines. 2020; 8(9):350. https://doi.org/10.3390/biomedicines8090350

Chicago/Turabian Style

Hsu, Mei-Ju; Karkossa, Isabel; Schäfer, Ingo; Christ, Madlen; Kühne, Hagen; Schubert, Kristin; Rolle-Kampczyk, Ulrike E.; Kalkhof, Stefan; Nickel, Sandra; Seibel, Peter; von Bergen, Martin; Christ, Bruno. 2020. "Mitochondrial Transfer by Human Mesenchymal Stromal Cells Ameliorates Hepatocyte Lipid Load in a Mouse Model of NASH" Biomedicines 8, no. 9: 350. https://doi.org/10.3390/biomedicines8090350

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