Mesenchymal stem cell therapy ameliorates diabetic hepatocyte damage in mice by inhibiting infiltration of bone marrow-derived cells

Abstract

Although mesenchymal stem cells (MSCs) have been implicated in hepatic injury, the mechanism through which they contribute to diabetic liver disease has not been clarified. In this study, we investigated the effects of MSC therapy on diabetic liver damage with a focus on the role of bone-marrow-derived cells (BMDCs), which infiltrate the liver, and elucidated the mechanism mediating this process. Rat bone-marrow (BM)-derived MSCs were administered to high-fat diet (HFD)-induced type 2 diabetic mice and streptozotocin (STZ)-induced insulin-deficient diabetic mice. MSC-conditioned medium (MSC-CM) was also administered to examine the trophic effects of MSCs on liver damage. Therapeutic effects of MSCs were analyzed by assessing serum liver enzyme levels and histological findings. Kinetic and molecular profiles of BMDCs in the liver were evaluated using BM-chimeric mice. Curative effects of MSC and MSC-CM therapies were similar because both ameliorated the aggravation of aspartate aminotransferase and alanine aminotransferase at 8 weeks of treatment, despite persistent hyperlipidemia and hyperinsulinemia in HFD-diabetic mice and persistent hyperglycemia in STZ-diabetic mice. Furthermore, both therapies suppressed the abnormal infiltration of BMDCs into the liver, reversed excessive expression of proinflammatory cytokines in parenchymal cells, and regulated proliferation and survival signaling in the liver in both HFD- and STZ-diabetic mice. In addition to inducing hepatocyte regeneration in STZ-diabetic mice, both therapies also prevented excessive lipid accumulation and apoptosis of hepatocytes and reversed insulin resistance (IR) in HFD-diabetic mice. MSC therapy is a powerful tool for repairing diabetic hepatocyte damage by inhibiting inflammatory reactions induced by BMDCs and IR. These effects are likely the result of humoral factors derived from MSCs.