Mesenchymal Stem Cells as New Therapeutic Agents for the Treatment of Primary Biliary Cholangitis

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.

The role of Interleukin 1 receptor antagonist in mesenchymal stem cell‐based tissue repair and regeneration

“…MSCs alter cytokine profile in DCs resulting in decreased production of proinflammatory, Th1‐related (tumor necrosis factor alpha [TNF‐α], interferon gamma [IFN‐γ], interleukin [IL]‐12) and Th17‐related cytokines (IL‐1β, IL‐6, IL‐23, transforming growth factor beta [TGF‐β]) and increased production of anti‐inflammatory IL‐10, which results in the attenuated activation of naive T cells . Additionally, MSCs may directly suppress Th1 and Th17 cell‐driven immune response by inhibiting expression of T‐bet and RORγT transcriptional factors in CD4+ T cells and by attenuating secretion of IFN‐γ and IL‐17, which result in alleviation of Th1 and Th17 cell‐dependent chronic inflammatory diseases . Furthermore, MSC‐based suppression of acute and chronic inflammation is relied on MSC‐induced enhanced generation and expansion of CD4 + CD25 + FoxP3+ T regulatory cells (Tregs) and FoxP3 + NKTregs in injured tissues, which, in turn, create immunosuppressive microenvironment and promote tissue repair and regeneration …”

“…5 Additionally, MSCs may directly suppress Th1 and Th17 cell-driven immune response by inhibiting expression of T-bet and RORγT transcriptional factors in CD4+ T cells and by attenuating secretion of IFN-γ and IL-17, which result in alleviation of Th1 and Th17 cell-dependent chronic inflammatory diseases. 6,7 Furthermore, MSC-based suppression of acute and chronic inflammation is relied on MSC-induced enhanced generation and expansion of CD4 + CD25 + FoxP3+ T regulatory cells (Tregs) and FoxP3 + NKTregs in injured tissues, which, in turn, create immunosuppressive microenvironment and promote tissue repair and regeneration. [8][9][10] Activation of toll-like receptors (TLRs) has crucially important role for the generation of immunosuppressive phenotype in MSCs.…”

Novel Diagnostic and Therapeutic Strategies in Juvenile Autoimmune Hepatitis

“…In two separate pilot studies a total of 17 patients were treated with positive results, their quality of life substantially improved. More importantly, the safety profile was excellent (180, 181). Two studies on large cohorts of AIH patients are currently ongoing (Table 2).…”

Manipulated Mesenchymal Stem Cells Applications in Neurodegenerative Diseases

“…MSCs can significantly reduce the proliferation and activation of NK cells through direct cell contact and also soluble factors like indoleamine 2,3-dioxygenase (IDO) and PGE2 production. The secretion of sHLAG5 by MSCs lessen NK cells cytolytic activity and IFN-γ production of these cells (25,44,45). In addition, MSCs have been demonstrated to reduce the secretion of IFN-γ and TNF-α by NK cells.…”