Fibrogenic Potential of Human Multipotent Mesenchymal Stromal Cells in Injured Liver

Abstract

Multipotent mesenchymal stromal cells (MSC) are currently investigated clinically as cellular therapy for a variety of diseases. Differentiation of MSC toward endodermal lineages, including hepatocytes and their therapeutic effect on fibrosis has been described but remains controversial. Recent evidence attributed a fibrotic potential to MSC. As differentiation potential might be dependent of donor age, we studied MSC derived from adult and pediatric human bone marrow and their potential to differentiate into hepatocytes or myofibroblasts in vitro and in vivo. Following characterization, expanded adult and pediatric MSC were co-cultured with a human hepatoma cell line, Huh-7, in a hepatogenic differentiation medium containing Hepatocyte growth factor, Fibroblast growth factor 4 and oncostatin M. In vivo, MSC were transplanted into spleen or liver of NOD/SCID mice undergoing partial hepatectomy and retrorsine treatment. Expression of mesenchymal and hepatic markers was analyzed by RT-PCR, Western blot and immunohistochemistry. In vitro, adult and pediatric MSC expressed characteristic surface antigens of MSC. Expansion capacity of pediatric MSC was significantly higher when compared to adult MSC. In co-culture with Huh-7 cells in hepatogenic differentiation medium, albumin expression was more frequently detected in pediatric MSC (5/8 experiments) when compared to adult MSC (2/10 experiments). However, in such condition pediatric MSC expressed alpha smooth muscle more strongly than adult MSC. Stable engraftment in the liver was not achieved after intrasplenic injection of pediatric or adult MSC. After intrahepatic injection, MSC permanently remained in liver tissue, kept a mesenchymal morphology and expressed vimentin and alpha smooth muscle actin, but no hepatic markers. Further, MSC localization merges with collagen deposition in transplanted liver and no difference was observed using adult or pediatric MSC. In conclusion, when transplanted into an injured or regenerating liver, MSC differentiated into myofibroblasts with development of fibrous tissue, regardless of donor age. These results indicate that MSC in certain circumstances might be harmful due to their fibrogenic potential and this should be considered before potential use of MSC for cell therapy.

Impact of Mesenchymal Stem Cell secreted PAI-1 on colon cancer cell migration and proliferation

“…Messenger RNA for PAI-1 has been localised by in situ hybridization to endothelial cells within colon tumours [24]. It is interesting to note that MSCs have been reported to differentiate into endothelial cells and myofibroblasts [25,26].…”

Prognostic Value of PLCE1 Expression in Upper Gastrointestinal Cancer: a Systematic Review and Meta-analysis

“…Luo et al (2014) determined that PLCE1 is a suppressor of P53 in NSCLC, which was inconsistent with the results of Wang. Thereafter, a different pattern of PLCE1 expression is said to exist in different types of cancer, including cancers of the intestine, skin, colon, and rectum (Gonzalez-Garcia et al, 2005;Bourguignon, 2006;Wang et al, 2007;Baertschiger et al, 2009;Ou et al, 2010).…”

Allogeneic Murine Mesenchymal Stem Cells: Migration to Inflamed Joints In Vivo and Amelioration of Collagen Induced Arthritis When Transduced to Express CTLA4Ig

“…We identified eGFP DNA in the lungs and liver after systemic infusion of FVB-GFP MSCs to mice with and without arthritis. MSCs have been shown to engraft to lung and liver and this is to be expected due to the high circulating blood volume in these organs [48][49][50]. During active inflammation, hepatocytes become upregulated and increase production of acute phase proteins [51] leading to the hypothesis that the increased hepatocyte activity may generate chemoattractants for MSCs.…”