Mesenchymal stromal cells mitigate liver damage after extended resection in the pig by modulating thrombospondin-1/TGF-β
Abstract Post-surgery liver failure is a serious complication for patients after extended partial hepatectomies (ePHx). Previously, we demonstrated in the pig model that transplantation of mesenchymal stromal cells (MSC) improved circulatory maintenance and supported multi-organ functions after 70%...
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Nature Portfolio
2021
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oai:doaj.org-article:d8c5dc1a3f2a4ecc8f2999b0b4e1c1852021-12-05T12:24:37ZMesenchymal stromal cells mitigate liver damage after extended resection in the pig by modulating thrombospondin-1/TGF-β10.1038/s41536-021-00194-42057-3995https://doaj.org/article/d8c5dc1a3f2a4ecc8f2999b0b4e1c1852021-12-01T00:00:00Zhttps://doi.org/10.1038/s41536-021-00194-4https://doaj.org/toc/2057-3995Abstract Post-surgery liver failure is a serious complication for patients after extended partial hepatectomies (ePHx). Previously, we demonstrated in the pig model that transplantation of mesenchymal stromal cells (MSC) improved circulatory maintenance and supported multi-organ functions after 70% liver resection. Mechanisms behind the beneficial MSC effects remained unknown. Here we performed 70% liver resection in pigs with and without MSC treatment, and animals were monitored for 24 h post surgery. Gene expression profiles were determined in the lung and liver. Bioinformatics analysis predicted organ-independent MSC targets, importantly a role for thrombospondin-1 linked to transforming growth factor-β (TGF-β) and downstream signaling towards providing epithelial plasticity and epithelial-mesenchymal transition (EMT). This prediction was supported histologically and mechanistically, the latter with primary hepatocyte cell cultures. MSC attenuated the surgery-induced increase of tissue damage, of thrombospondin-1 and TGF-β, as well as of epithelial plasticity in both the liver and lung. This suggests that MSC ameliorated surgery-induced hepatocellular stress and EMT, thus supporting epithelial integrity and facilitating regeneration. MSC-derived soluble factor(s) did not directly interfere with intracellular TGF-β signaling, but inhibited thrombospondin-1 secretion from thrombocytes and non-parenchymal liver cells, therewith obviously reducing the availability of active TGF-β.Sandra NickelSebastian VlaicMadlen ChristKristin SchubertReinhard HenschlerFranziska TautenhahnCaroline BurgerHagen KühneSilvio ErlerAndreas RothChristiane WildJanine BrachSeddik HammadClaudia GittelManja BaunackUndine LangeJohannes BroschewitzPeggy StockIsabella MetelmannMichael BartelsUta-Carolin PietschSebastian KrämerUwe EichfeldMartin von BergenSteven DooleyHans-Michael TautenhahnBruno ChristNature PortfolioarticleMedicineRENnpj Regenerative Medicine, Vol 6, Iss 1, Pp 1-18 (2021) |
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Medicine R Sandra Nickel Sebastian Vlaic Madlen Christ Kristin Schubert Reinhard Henschler Franziska Tautenhahn Caroline Burger Hagen Kühne Silvio Erler Andreas Roth Christiane Wild Janine Brach Seddik Hammad Claudia Gittel Manja Baunack Undine Lange Johannes Broschewitz Peggy Stock Isabella Metelmann Michael Bartels Uta-Carolin Pietsch Sebastian Krämer Uwe Eichfeld Martin von Bergen Steven Dooley Hans-Michael Tautenhahn Bruno Christ Mesenchymal stromal cells mitigate liver damage after extended resection in the pig by modulating thrombospondin-1/TGF-β |
| description |
Abstract Post-surgery liver failure is a serious complication for patients after extended partial hepatectomies (ePHx). Previously, we demonstrated in the pig model that transplantation of mesenchymal stromal cells (MSC) improved circulatory maintenance and supported multi-organ functions after 70% liver resection. Mechanisms behind the beneficial MSC effects remained unknown. Here we performed 70% liver resection in pigs with and without MSC treatment, and animals were monitored for 24 h post surgery. Gene expression profiles were determined in the lung and liver. Bioinformatics analysis predicted organ-independent MSC targets, importantly a role for thrombospondin-1 linked to transforming growth factor-β (TGF-β) and downstream signaling towards providing epithelial plasticity and epithelial-mesenchymal transition (EMT). This prediction was supported histologically and mechanistically, the latter with primary hepatocyte cell cultures. MSC attenuated the surgery-induced increase of tissue damage, of thrombospondin-1 and TGF-β, as well as of epithelial plasticity in both the liver and lung. This suggests that MSC ameliorated surgery-induced hepatocellular stress and EMT, thus supporting epithelial integrity and facilitating regeneration. MSC-derived soluble factor(s) did not directly interfere with intracellular TGF-β signaling, but inhibited thrombospondin-1 secretion from thrombocytes and non-parenchymal liver cells, therewith obviously reducing the availability of active TGF-β. |
| format |
article |
| author |
Sandra Nickel Sebastian Vlaic Madlen Christ Kristin Schubert Reinhard Henschler Franziska Tautenhahn Caroline Burger Hagen Kühne Silvio Erler Andreas Roth Christiane Wild Janine Brach Seddik Hammad Claudia Gittel Manja Baunack Undine Lange Johannes Broschewitz Peggy Stock Isabella Metelmann Michael Bartels Uta-Carolin Pietsch Sebastian Krämer Uwe Eichfeld Martin von Bergen Steven Dooley Hans-Michael Tautenhahn Bruno Christ |
| author_facet |
Sandra Nickel Sebastian Vlaic Madlen Christ Kristin Schubert Reinhard Henschler Franziska Tautenhahn Caroline Burger Hagen Kühne Silvio Erler Andreas Roth Christiane Wild Janine Brach Seddik Hammad Claudia Gittel Manja Baunack Undine Lange Johannes Broschewitz Peggy Stock Isabella Metelmann Michael Bartels Uta-Carolin Pietsch Sebastian Krämer Uwe Eichfeld Martin von Bergen Steven Dooley Hans-Michael Tautenhahn Bruno Christ |
| author_sort |
Sandra Nickel |
| title |
Mesenchymal stromal cells mitigate liver damage after extended resection in the pig by modulating thrombospondin-1/TGF-β |
| title_short |
Mesenchymal stromal cells mitigate liver damage after extended resection in the pig by modulating thrombospondin-1/TGF-β |
| title_full |
Mesenchymal stromal cells mitigate liver damage after extended resection in the pig by modulating thrombospondin-1/TGF-β |
| title_fullStr |
Mesenchymal stromal cells mitigate liver damage after extended resection in the pig by modulating thrombospondin-1/TGF-β |
| title_full_unstemmed |
Mesenchymal stromal cells mitigate liver damage after extended resection in the pig by modulating thrombospondin-1/TGF-β |
| title_sort |
mesenchymal stromal cells mitigate liver damage after extended resection in the pig by modulating thrombospondin-1/tgf-β |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/d8c5dc1a3f2a4ecc8f2999b0b4e1c185 |
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