We investigated the effect of human umbilical mesenchymal stem cells (HUMSCs) from Wharton's jelly on carbon tetrachloride (CCl 4 )-induced liver fibrosis in rats. Rats were treated with CCl 4 for 4 weeks, and this was followed by a direct injection of HUMSCs into their livers. After 4 more weeks of CCl 4 treatment (8 weeks in all), rats with HUMSC transplants [CCl 4 (8W)ϩHUMSC liver] exhibited a significant reduction in liver fibrosis, as evidenced by Sirius red staining and a collagen content assay, in comparison with rats treated with CCl 4 for 8 weeks without HUMSC transplants [CCl 4 (8W)]. Moreover, rats in the CCl 4 (8W)ϩHUMSC (liver) group had significantly lower levels of serum glutamic oxaloacetic transaminase, glutamic pyruvate transaminase, ␣-smooth muscle actin, and transforming growth factor-␤1 in the liver, whereas the expression of hepatic mesenchymal epithelial transition factor-phosphorylated type (Met-P) and hepatocyte growth factor was up-regulated, in comparison with the CCl 4 (8W) group. Notably, engrafted HUMSCs scattered mostly in the hepatic connective tissue but did not differentiate into hepatocytes expressing human albumin or ␣-fetoprotein. Instead, these engrafted, undifferentiated HUMSCs secreted a variety of bioactive cytokines that may restore liver function and promote regeneration. Human cytokine assay revealed that the amounts of human cutaneous T cell-attracting chemokine, leukemia inhibitory factor, and prolactin were substantially greater in the livers of the CCl 4 (8W)ϩHUMSC (liver) group, with considerably reduced hepatic inflammation manifested by a micro positron emission tomography scan. Our findings suggest that xenogeneic transplantation of HUMSCs is a novel approach for treating liver fibrosis and may be a promising therapeutic intervention in the future. Liver Transpl 15: 484-495, 2009.

Biochemical tests, especially gamma glutamyl transferase with 97.9% negative predictive value, are ideal noninvasive predictors for the absence of common bile duct stones in patients undergoing laparoscopic cholecystectomy. We suggest that unnecessary, costly, or risky procedures such as endoscopic retrograde cholangiopancreatography can be omitted prior to laparoscopic cholecystectomy in patients without abnormal elevation of these biochemical values.

Pulmonary fibrosis (PF) is a progressive and irreversible condition with various causes, and no effective treatment has been found to rescue fibrotic lungs. Successful recovery from PF requires inhibiting inflammation, promoting collagen degradation and stimulating alveolar regeneration. Human umbilical mesenchymal stem cells (HUMSCs) not only regulate immune responses but also synthesize and release hyaluronan to improve lung regeneration. This study investigated the feasibility of HUMSC engraftment into rats with bleomycin (BLM)-induced PF to explore HUMSC therapeutic effects/outcomes.Methods: A unique BLM-induced left-lung-dominated PF animal model was established. Rats were transplanted with low-dose (5×106) or high-dose (2.5×107) HUMSCs on Day 21 after BLM injection. Combinations in co-culture of pulmonary macrophages, fibroblasts, HUMSCs treated with BLM and the same conditions on alveolar epithelia versus HUMSCs were evaluated.Results: Rats with high-dose HUMSC engraftment displayed significant recovery, including improved blood oxygen saturation levels and respiratory rates. High-dose HUMSC transplantation reversed alveolar injury, reduced cell infiltration and ameliorated collagen deposition. One month posttransplantation, HUMSCs in the rats' lungs remained viable and secreted cytokines without differentiating into alveolar or vascular epithelial cells. Moreover, HUMSCs decreased epithelial-mesenchymal transition in pulmonary inflammation, enhanced macrophage matrix-metallopeptidase-9 (MMP-9) expression for collagen degradation, and promoted toll-like receptor-4 (TLR-4) expression in the lung for alveolar regeneration. In coculture studies, HUMSCs elevated the MMP-9 level in pulmonary macrophages, released hyaluronan into the medium and stimulated the TLR-4 quantity in the alveolar epithelium.Principal Conclusions: Transplanted HUMSCs exhibit long-term viability in rat lungs and can effectively reverse rat PF.

Diabetes mellitus can be treated with islet transplantation, although there is a scarcity of donors. This study investigated whether human mesenchymal stem cells (MSCs) from umbilical cord stroma could be induced to differentiate into insulin-producing cells and the effects of retro-orbital injection of human insulin-producing cells for the treatment of nonobese diabetic (NOD) mice. MSCs were isolated from human umbilical cord stroma and induced to differentiate into insulin-producing cells using differentiation medium. Differentiated cells were evaluated by immunocytochemistry, RT-PCR, and real-time PCR. C-peptide release, both spontaneous and after glucose challenge, was measured by ELISA. Insulin-producing cells were then transplanted into NOD mice. Blood glucose levels and body weights were monitored weekly. Human nuclei and C-peptide were detected in mouse livers by immunohistochemistry. Pancreatic β-cell development-related genes were expressed in the differentiated insulin-producing cells. Differentiated cells' C-peptide release in vitro increased after glucose challenge. Further, in vivo glucose tolerance tests showed that blood sugar levels decreased after the cells' transplantation into NOD mice. After transplantation, insulin-producing cells containing human C-peptide and human nuclei were located in the liver. Thus, we demonstrated that differentiated insulin-producing cells from human umbilical cord stromal MSCs transplanted into NOD mice could alleviate hyperglycemia in diabetic mice.