Bone marrow endothelial progenitor cells activate hepatic stellate cells and aggravate carbon tetrachloride induced liver fibrosis in mice via paracrine factors

• Published in: Cell proliferation 2017-08, Vol.50 (4), p.n/a
• Main Authors: Garg, Manali, Kaur, Savneet, Banik, Arpita, Kumar, Vikash, Rastogi, Archana, Sarin, Shiv K., Mukhopadhyay, Asok, Trehanpati, Nirupma
• Format: Article
• Language: English
• Subjects: Animals; Blood; Bone marrow; Bone Marrow Cells - cytology; Bone marrow transplantation; Carbon tetrachloride; Carbon Tetrachloride - toxicity; Cells (biology); Cells, Cultured; Coculture Techniques; Collagen; Conditioning; Culture Media, Conditioned - pharmacology; Cytometry; Disease Models, Animal; Dosage; Endothelial Cells - cytology; Endothelial Cells - metabolism; Femur; Fibrosis; Flow cytometry; Hepatic Stellate Cells - cytology; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - metabolism; Immunofluorescence; Irradiation; Liver; Liver Cirrhosis - chemically induced; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver diseases; Liver transplantation; Male; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Original; Osteoprogenitor cells; Paracrine Communication - drug effects; Paracrine Communication - physiology; Paracrine signalling; Regeneration; Rodents; Stellate cells; Transforming Growth Factor beta - analysis; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - analysis
• ISSN: 0960-7722; 1365-2184
• DOI: 10.1111/cpr.12355

Objectives Bone marrow derived endothelial progenitor cells (BM‐EPCs) are increased in chronic liver disease (CLD). Their role in hepatic fibrosis and regeneration remains an area of intense studies. We investigated the migration and secretory functions of BM‐EPCs in fibrotic mice liver. Materials and methods Bone marrow cells from C57BL6‐GFP mice were transplanted into the femur of irradiated C57BL6 mice, followed by CCl4 doses for 8 weeks, to develop hepatic fibrosis (n = 36). Transplanted C57BL6 mice without CCl4 treatment were used as controls. EPCs were analyzed in BM, blood and liver by flow cytometry and immunofluorescence. VEGF and TGF‐β were analysed in the hepatic stellate cells (HSCs) and BM‐EPCs co‐cultures using ELISAs. Results There was a significant migration of EPCs from BM to blood and to the liver (P ≤ 0.01). Percentage of GFP+CD31+ EPCs and collagen proportionate area was substantially increased in the liver at 4th week of CCl4 dosage compared to the controls (19.8% vs 1.9%, P ≤ 0.05). Levels of VEGF (533.6 pg/ml) and TGF‐β (327.44 pg/ml) also increased significantly, when HSCs were treated with the EPC conditioned medium, as compared to controls (25.66 pg/ml and 5.87 pg/ml, respectively; P ≤ 0.001). Conclusions Present findings suggest that BM‐EPCs migrate to the liver during CCl4‐induced liver injury and contribute to fibrosis.