Experimental and clinical proof-of-concept to establish stem cell treatment of post-hepatectomy liver failure
Final Report Abstract
Thrombospondin-1 (THBS1) was identified a negative predictor of liver regeneration after partial hepatectomy (PHx). Yet, the cellular and molecular actions of THBS1 remained largely unknown. We have shown in various mouse and rat models of acute and chronic liver dysfunction that mesenchymal stromal cells (MSC) improved liver function and supported regeneration after PHx. We hypothesized that MSC might interfere with THBS1 and its downstream actions. Therefore, it was the goal to substantiate this interference and unravel cellular and molecular mechanisms involved. In a mouse model of 2/3 PHx, transfusion of MSC ameliorated circulatory and hepatic THBS1. In the liver, MSC lowered the THBS1-mediated increase in TGF-β, an activator of parenchymal plasticity, thereby supporting epithelial integrity and liver regeneration. Mechanistically, MSC attenuated the secretion of THBS1 from thrombocytes and non-parenchymal cells of the liver. MSC reduced the number of thrombocytes in the liver, and simultaneously stimulated their activation. In addition, they attenuated the hepatic recruitment of other inflammatory cells, thus supporting regeneration after PHx. In patients undergoing the ALPPS procedure or partial liver resections, we found, as in mice, the coincidence of high THBS1/TGF-β and the loss of tissue and function homeostasis indicating a causal relationship. This analogy may hence open the clinical perspective to establish MSC therapy to support tissue and functional homeostasis after complex liver surgery. This, however, needs further clinical proof.
Publications
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Mitochondrial Transfer by Human Mesenchymal Stromal Cells Ameliorates Hepatocyte Lipid Load in a Mouse Model of NASH. Biomedicines, 8(9), 350.
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
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Co-Culture of Human Mesenchymal Stromal Cells and Primary Mouse Hepatocytes. Methods in Molecular Biology, 151-165. Springer US.
Hsu, Mei-Ju; Christ, Madlen & Christ, Bruno
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Greasy hair against obesity. Signal Transduction and Targeted Therapy, 6(1).
Nickel, Sandra & Christ, Bruno
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Hepatectomy-Induced Alterations in Hepatic Perfusion and Function - Toward Multi-Scale Computational Modeling for a Better Prediction of Post-hepatectomy Liver Function. Frontiers in Physiology, 12.
Christ, Bruno; Collatz, Maximilian; Dahmen, Uta; Herrmann, Karl-Heinz; Höpfl, Sebastian; König, Matthias; Lambers, Lena; Marz, Manja; Meyer, Daria; Radde, Nicole; Reichenbach, Jürgen R.; Ricken, Tim & Tautenhahn, Hans-Michael
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Mesenchymal Stromal Cells Inhibit Thrombocyte Secretion to Protect Liver Damage after Partial Hepatectomy in the Pig. Eur Surg Res 2021:62:166–220.
Nickel S., Christ M., Henschler R. et al.
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Mesenchymal stromal cells mitigate liver damage after extended resection in the pig by modulating thrombospondin-1/TGF-β. npj Regenerative Medicine, 6(1).
Nickel, Sandra; Vlaic, Sebastian; Christ, Madlen; Schubert, Kristin; Henschler, Reinhard; Tautenhahn, Franziska; Burger, Caroline; Kühne, Hagen; Erler, Silvio; Roth, Andreas; Wild, Christiane; Brach, Janine; Hammad, Seddik; Gittel, Claudia; Baunack, Manja; Lange, Undine; Broschewitz, Johannes; Stock, Peggy; Metelmann, Isabella ... & Christ, Bruno
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Mesenchymal stromal cells provide hepatic support after extended hepatectomy by modulating thrombospondin-1/TGF-β. Zeitschrift für Gastroenterologie. Georg Thieme Verlag KG.
Nickel, S.; Tautenhahn, HM; Vlaic, S.; Christ, M.; Henschler, R.; Tautenhahn, F.; Burger, C.; Kühne, H.; Erler, S.; Roth, A.; Wild, C.; Brach, J.; Hamad, S.; Gittel, C.; Baunack, M.; Lange, U.; Broschewitz, J.; Stock, P.; Metelmann, I. ... & Christ, B.
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Multimodale Therapie bei Lebermetastasen kolorektaler Karzinome in kurativer Intention. Die Chirurgie, 93(7), 652-658.
Tautenhahn, Hans-Michael; Nickel, Sandra; Kindler, Eva Maria & Settmacher, Utz
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Approaching Thrombospondin-1 as a Potential Target for Mesenchymal Stromal Cells to Support Liver Regeneration after Partial Hepatectomy in Mouse and Humans. Cells, 13(6), 529.
Tietze, Lysann; Christ, Madlen; Yu, Jiyeon; Stock, Peggy; Nickel, Sandra; Schulze, Annelie; Bartels, Michael; Tautenhahn, Hans-Michael & Christ, Bruno
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Building up a model family for inflammations. Journal of Mathematical Biology, 89(3).
Reisch, Cordula; Nickel, Sandra & Tautenhahn, Hans-Michael
