We describe a novel therapeutic approach for cirrhosis using mesenchymal stem cells (MSCs) and colony‐stimulating factor‐1‐induced bone marrow‐derived macrophages (id‐BMMs) and analyze the mechanisms underlying fibrosis improvement and regeneration. Mouse MSCs and id‐BMMs were cultured from mouse bone marrow and their interactions analyzed in vitro. MSCs, id‐BMMs, and a combination therapy using MSCs and id‐BMMs were administered to mice with CCl4‐induced cirrhosis. Fibrosis regression, liver regeneration, and liver‐migrating host cells were evaluated. Administered cell behavior was also tracked by intravital imaging. In coculture, MSCs induced switching of id‐BMMs toward the M2 phenotype with high phagocytic activity. In vivo, the combination therapy reduced liver fibrosis (associated with increased matrix metalloproteinases expression), increased hepatocyte proliferation (associated with increased hepatocyte growth factor, vascular endothelial growth factor, and oncostatin M in the liver), and reduced blood levels of liver enzymes, more effectively than MSCs or id‐BMMs monotherapy. Intravital imaging showed that after combination cell administration, a large number of id‐BMMs, which phagocytosed hepatocyte debris and were retained in the liver for more than 7 days, along with a few MSCs, the majority of which were trapped in the lung, migrated to the fibrotic area in the liver. Host macrophages and neutrophils infiltrated after combination therapy and contributed to liver fibrosis regression and promoted regeneration along with administered cells. Indirect effector MSCs and direct effector id‐BMMs synergistically improved cirrhosis along with host cells in mice. These studies pave the way for new treatments for cirrhosis. Stem Cells Translational Medicine 2019;8:271&284

Mesenchymal stem cell (MSC) therapies have been used in clinical trials in various fields. These cells are easily expanded, show low immunogenicity, can be acquired from medical waste, and have multiple functions, suggesting their potential applications in a variety of diseases, including liver disease and inflammatory bowel disease. MSCs help prepare the microenvironment, in response to inflammatory cytokines, by producing immunoregulatory factors that modulate the progression of inflammation by affecting dendritic cells, B cells, T cells, and macrophages. MSCs also produce a large amount of cytokines, chemokines, and growth factors, including exosomes that stimulate angiogenesis, prevent apoptosis, block oxidation reactions, promote remodeling of the extracellular matrix, and induce differentiation of tissue stem cells. According to ClinicalTrials.gov, more than 680 clinical trials using MSCs are registered for cell therapy of many fields including liver diseases (more than 40 trials) and inflammatory bowel diseases (more than 20 trials). In this report, we introduce background and clinical studies of MSCs in liver disease and inflammatory bowel diseases.

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The high heterogeneity of hepatocellular carcinomas (HCCs) complicates stratification of HCC patients for treatment. Therefore, it is necessary to establish a comprehensive panel of HCC biomarkers related to tumour behaviour and cancer prognosis. Resected HCCs from 251 patients were stained for hepatic progenitor cell (HPC) markers epithelial cell adhesion molecule (EpCAM), neural cell adhesion molecule (NCAM), delta-like 1 homolog (DLK1), and cytokeratin 19 (CK19). Staining patterns were analysed for their prognostic association with relapse-free survival and overall survival. α-Fetoprotein (AFP), lectin-reactive α-fetoprotein (AFP-L3), and des-γ-carboxy prothrombin (DCP) were assessed as indicators of HPC protein expression. Expression pattern of HPC markers correlated with tumour malignancy indicated by high AFP/AFP-L3 serum levels, more frequent vascular invasion, and poorer tumour differentiation. EpCAM expression, DCP ≥300 mAU/ml, age ≥60, and Child-Pugh score grade B or C were independent prognostic factors of poor outcome and were used in a new scoring system for HCC prognosis after operation. Expression of two or more HPC markers was a significant predictor of poor HCC outcome and serum levels of AFP/AFP-L3 correlated with the expression of HPC proteins. Our study paved the way for further elucidation of the association among HPC markers, serum tumour markers, and HCC clinical outcome for precision medicine.

Mesenchymal stem cells (MSCs) can be acquired from medical waste. MSCs are easily expanded and have multiple functions, including anti-inflammatory effects. We evaluated the effects of human adipose tissue-derived MSCs (AD-MSCs) and umbilical cord tissue-derived MSCs (UC-MSCs) in a dextran sulfate sodium (DSS)-induced mouse model. Human AD-MSCs and UC-MSCs (1 • 10 6 cells) were injected intravenously into a 7-day DSS-induced colitis model. The therapeutic effects of cell origin, injection timing, and supernatants obtained from MSC cultures were evaluated. We also analyzed messenger RNA (mRNA) expression in MSCs, tissues, and intestinal flora. AD-MSCs and UC-MSCs were found to show strong anti-inflammatory effects when injected on day 3 in a mouse model. On day 11, the mRNA levels of inflammatory factors in colon tissues were significantly decreased after injection of MSCs on day 3. Supernatants from MSCs culture decreased mRNA levels of tumor necrosis factor (Tnf)-a, but had reduced therapeutic effects compared with MSC cell injection. RNA sequencing using colon tissues obtained the day after cell injection revealed changes in the TNF-a/nuclear factor-jB and T cell receptor signaling pathways. Additional analyses showed that several factors, including chromosome 10 open reading frame 54, stanniocalcin-1, and TNF receptor superfamily member 11b were increased in MSCs after adding serum from DSS colitis mice. Furthermore, both AD-MSCs and UC-MSCs maintained the balance of intestinal flora. In conclusion, AD-MSCs and UC-MSCs showed therapeutic effects against inflammation after early cell injection while maintaining the intestinal flora. Although supernatants showed therapeutic effects, cell injection was more effective against inflammation.