npj Regenerative Medicine (Dec 2021)

Mesenchymal stromal cells mitigate liver damage after extended resection in the pig by modulating thrombospondin-1/TGF-β

  • 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

DOI
https://doi.org/10.1038/s41536-021-00194-4
Journal volume & issue
Vol. 6, no. 1
pp. 1 – 18

Abstract

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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.