Abstract
Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease characterized by the progressive destruction of small- and medium-sized intrahepatic bile ducts with resultant cholestasis and progressive fibrosis. Ursodeoxycholic acid and obethicholic acid are the only agents approved by the US Food and Drug Administration (FDA) for the treatment of PBC. However, for patients with advanced, end-stage PBC, liver transplantation is still the most effective treatment. Accordingly, the alternative approaches, such as mesenchymal stem cell (MSC) transplantation, have been suggested as an effective alternative therapy for these patients. Due to their immunomodulatory characteristics, MSCs are considered as promising therapeutic agents for the therapy of autoimmune liver diseases, including PBC. In this review, we have summarized the therapeutic potential of MSCs for the treatment of these diseases, emphasizing molecular and cellular mechanisms responsible for MSC-based effects in an animal model of PBC and therapeutic potential observed in recently conducted clinical trials. We have also presented several outstanding problems including safety issues regarding unwanted differentiation of transplanted MSCs which limit their therapeutic use. Efficient and safe MSC-based therapy for PBC remains a challenging issue that requires continuous cooperation between clinicians, researchers, and patients.
Highlights
Primary biliary cholangitis (PBC) is an idiopathic chronic autoimmune cholestatic liver disease characterized by the progressive granulomatous destruction of small- and medium-sized intralobular and septal intrahepatic bile ducts with resultant cholestasis and progressive fibrosis [1, 2]
Since T cells play a central role in the pathogenesis of PBC, molecular mechanisms involved in mesenchymal stem cell (MSC)-based suppression of inflammatory T cells and expansion of T regulatory cells (Tregs) were used as a starting point for a design of preclinical studies that investigated the therapeutic potential of MSCs in the treatment of PBC
Further studies are required to determine the optimal frequency of bone marrow-derived mouse MSCs (BM-MSCs) infusions and to evaluate the safety of MSC-based therapy in long-term follow-up. Because of their immunomodulatory properties, MSCs are considered as new therapeutic agents for the treatment of PBC
Summary
Primary biliary cholangitis (PBC) is an idiopathic chronic autoimmune cholestatic liver disease characterized by the progressive granulomatous destruction of small- and medium-sized intralobular and septal intrahepatic bile ducts with resultant cholestasis and progressive fibrosis [1, 2]. Serum levels of interleukin (IL)-18—which acts to release IL-12 and activate the Th1 pathway—and consequent release of IFN-γ from CD4+ T cells are elevated in PBC patients compared to healthy controls [18, 19] Immunohistochemical studies support these observations, with PBC liver samples showing strong staining for IFN-γ with a shift to increased IL-23 and IL-17 staining in the later stage of the disease, accompanied with increased Th17 : Treg ratio in peripheral blood [20, 21]. Despite the promising results of UDCA- and OCA-based therapies, liver transplantation is still the most effective treatment modality for PBC patients with end-stage liver disease [22]. Mesenchymal stem cells (MSCs) are, due to their immunomodulatory characteristics, considered as promising therapeutic agents for the therapy of PBC
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