Mesenchymal stromal cells provide hepatic support after extended hepatectomy by modulating thrombospondin-1/TGF-β

Question Extended partial hepatectomiy carries a high risk of post-surgery liver failure (ePHx), a serious complication for the patient. The pig liver features high anatomical and physiological similarity to the human liver. In a pig model of ePHx, systemic delivery of mesenchymal stromal cells (MSC) supported blood circulation and prevented multiorgan failure. The mechanisms mediating the beneficial MSC effects are largely unknown.

Methods Partial liver resection (70 %) was performed in pigs with and without MSC treatment. Animals were monitored for 24 h post-surgery. Gene expression profiles of lung and liver were obtained by gene array analysis. Subsequent combined bioinformatics analysis predicted organ-independent common molecular targets of MSC action. Predictions were verified in the pig livers and lung, and mechanisms investigated in vitro using cell culture systems.

Results Bioinformatics analysis predicted a novel role for thrombospondin-1 (THBS1) linked to transforming growth factor-beta (TGF-β) and downstream signaling towards providing epithelial plasticity and epithelial-mesenchymal transition (EMT). This was confirmed by the increase in THBS1 and TGF-β in serum and liver associated with impairment of liver function and tissue integrity. MSC attenuated the surgery-induced damage, and decreased THBS1 and TGF-β, as well as epithelial plasticity in both liver and lung. Hence, MSC ameliorated surgery-induced hepatocellular stress and EMT, thus supporting epithelial integrity and facilitating post-resection function and regeneration. Mechanistically, MSC-derived soluble factor(s) inhibited THBS1 secretion from thrombocytes, therewith obviously reducing the availability of active TGF-β and its downstream actions.

Conclusions MSC provide functional support for lung and liver after ePHx, likely by modulation of the thrombospondin-1/TGF-β axis. This might open perspectives to treat multiorgan dysfunction after ePHx by pharmacological interference with thrombospondin-1 secretion and/or action.

Work was supported by funding through the DFG by grants to H-MT and BC (TA 1583/1-1 and CH 109/25-1).

Publication History

Article published online:
04 January 2021