Mesenchymal stromal cells mitigate liver damage after extended resection in the pig by modulating thrombospondin-1/TGF-β
Open Access
- 3 December 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in npj Regenerative Medicine
- Vol. 6 (1), 1-18
- https://doi.org/10.1038/s41536-021-00194-4
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.Keywords
Funding Information
- Deutsche Forschungsgemeinschaft (CH 109/25-1, 436883643, DO 373-20/1, DO 373-19/1, TA 1583/1-1)
- Bundesministerium für Bildung und Forschung (PTJ-031L0043, PTJ-031L0043)
This publication has 71 references indexed in Scilit:
- The sva package for removing batch effects and other unwanted variation in high-throughput experimentsBioinformatics, 2012
- Highly interconnected genes in disease-specific networks are enriched for disease-associated polymorphismsGenome Biology, 2012
- Thrombospondin-1 is a novel negative regulator of liver regeneration after partial hepatectomy through transforming growth factor-beta1 activation in miceHepatology, 2011
- Network medicine: a network-based approach to human diseaseNature Reviews Genetics, 2010
- Epithelial-to-mesenchymal transitions in the liverHepatology, 2009
- Mapping identifiers for the integration of genomic datasets with the R/Bioconductor package biomaRtNature Protocols, 2009
- Adjusting batch effects in microarray expression data using empirical Bayes methodsBiostatistics, 2006
- The ???50-50 Criteria??? on Postoperative Day 5Annals of Surgery, 2005
- Propagation and functional characterization of serum-free cultured porcine hepatocytes for downstream applicationsCell and tissue research, 2005
- Shear Stress Induced Release of Von Willebrand Factor and Thrombospondin-1 in Uvec Extracellular Matrix Enhances Breast Tumour Cell AdhesionClinical & Experimental Metastasis, 2005