Liver disease accounts for approximately 2 million deaths per year worldwide with cirrhosis, viral hepatitis, and malignancy being the most common causes. Consequently, the regenerative capacity of the liver is a topic of extreme interest in the search for curative therapies to end-stage liver disease. Mesenchymal stem cells (MSCs) have emerged as a promising new therapy for hepatic regeneration. MSCs have multiple properties that make them an appropriate treatment option for liver disease including easy accessibility, targeted migration, immunomodulatory potential and antifibrotic/antioxidant effects. Additionally, MSCs have potential clinical applications in acellular therapy and tissue engineering. Liver regeneration with concurrent attenuation of liver injury makes MSCs a compelling therapeutic target in the setting of severe liver disease. This review outlines the mechanisms of MSC-driven liver regeneration and suggests potential clinical applications.

Mesenchymal stem cell, liver regeneration, end-stage liver disease

The liver is constantly subjected to noxious damage from both exogenous and endogenous toxins, thus requires a method to recover from injury. Normal liver regeneration is achieved primarily through proliferation of existing mature hepatocytes and biliary epithelial cells (BECs)[1]. Studies have demonstrated that regeneration of the liver following hepatectomies are characterized by phenotypic fidelity, meaning each cell is responsible for propagating its own cell type[2]. That is, hepatocytes make other hepatocytes, and the same applies to most other liver cell types including BECs and hepatic stellate cells (HSCs). Stem cells are not typically associated with physiologic liver proliferation, with the exception of Kupffer cells and liver sinusoidal endothelial cells (LSECs), both of which can be derived from bone marrow stem cells[3]. Of note, in the setting of impaired hepatocyte or BECs proliferation, the unaffected cell type can transdifferentiate into the impaired cell type and effectively function as facultative stem cells[4].

Despite the exceptional regenerative capacity of the liver, chronic injury can overwhelm the liver’s ability to regenerate and this leads to fibrosis. Liver fibrosis is a secondary wound healing process driven by myofibroblasts to degrade normal extracellular matrix (ECM) and accumulate excess connective tissue[5]. The majority of myofibroblasts in liver fibrosis is derived from trans-differentiation of quiescent HSCs, which lead to activation of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs)[6]. A subset of myofibroblasts are derived from portal myofibroblasts and bone marrow (BM)-derived fibrocytes[7]. Portal myofibroblasts drive fibrogenesis exclusively in the biliary system, while the BM-derived fibrocytes minimally contribute to hepatic fibrosis[7]. Interestingly, fibrocytes share many phenotypic features with MSCs. Fibrocytes are BM-derived, collagen type 1 producing cells that produce ECM components and contribute to liver fibrosis. Fibrocytes appear to have regenerative properties and express surface markers like CD11b, CD14, CD34, CD45 and α-smooth muscle antibody (SMA) that are seen in cells of hematopoietic lineage[8]. However, fibrocytes lack the heterogeneity of MSCs and have unique proteomes that suggest BM-derived fibrocytes are distinct from MSCs[9]. Regardless of the source of myofibroblasts, they all express high levels of fibrillar collagen, TIMPs, and they are dominant contributors to liver fibrosis[5].

Currently, liver transplantation is the only definitive treatment for end-stage liver disease (ESLD). Fortunately, improvements in immunosuppressive drugs and surgical methods have improved transplantation outcomes and the global organ transplantation market is projected to grow significantly through the next few years[10]. The wide range of therapeutic potential of MSCs can further improve outcomes in ESLD as adjuvant or alternative therapy to liver transplantation. First, MSCs are pluripotent stem cells capable of differentiating into hepatocyte-like cells both in vivo and in vitro[11,12]. Second, MSCs are readily accessible from multiple potential sources including adipose tissue, umbilical cord (UC), umbilical cord blood, peripheral blood, synovial membranes, muscle, dermis, and liver[13-17]. Importantly, the harvested MSCs maintain their pluripotent potential, robust proliferative ability, and capacity for ex vivo expansion[18]. Third, MSCs have the ability to migrate and engraft at sites of injured tissue[19]. Fourth, MSCs have immunosuppressive properties that allow for allogeneic transplantation. The immunosuppressive ability of MSCs also includes anti-fibrotic and antioxidant effects which can protect the liver from fibrosis and oxidative damage[20]. Lastly, MSCs produce extracellular vesicles (EV) that contain growth factors and cytokines that promote regeneration of impaired tissue such as liver parenchyma[20]. In this review, we will focus on the potential therapeutic mechanisms of MSCs and future studies that can help develop more effective treatments for ESLD [Table 1].

Categories: Stem Cells therapy


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stem cell therapy