![]() Tissue injury releases stress signals that attract MSCs to the site of damage. MSCs homing involves initial tethering by selectins, activation by cytokines, arrest by integrins, and extravascular migration towards chemokine gradients. The regenerative potential of MSCs in ESLD is largely reliant on the MSCs’ ability to migrate to the liver following administration. HOMING AND MIGRATION OF MSCS IN LIVER REGENERATIONĪ major criterion for effective stem cell therapy is the induction and engraftment of cells into the region of damage. 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. Lastly, MSCs produce extracellular vesicles (EV) that contain growth factors and cytokines that promote regeneration of impaired tissue such as liver parenchyma. The immunosuppressive ability of MSCs also includes anti-fibrotic and antioxidant effects which can protect the liver from fibrosis and oxidative damage. Fourth, MSCs have immunosuppressive properties that allow for allogeneic transplantation. Third, MSCs have the ability to migrate and engraft at sites of injured tissue. Importantly, the harvested MSCs maintain their pluripotent potential, robust proliferative ability, and capacity for ex vivo expansion. 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. First, MSCs are pluripotent stem cells capable of differentiating into hepatocyte-like cells both in vivo and in vitro. The wide range of therapeutic potential of MSCs can further improve outcomes in ESLD as adjuvant or alternative therapy to liver transplantation. 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. Ĭurrently, liver transplantation is the only definitive treatment for end-stage liver disease (ESLD). Regardless of the source of myofibroblasts, they all express high levels of fibrillar collagen, TIMPs, and they are dominant contributors to liver fibrosis. However, fibrocytes lack the heterogeneity of MSCs and have unique proteomes that suggest BM-derived fibrocytes are distinct from MSCs. 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. Fibrocytes are BM-derived, collagen type 1 producing cells that produce ECM components and contribute to liver fibrosis. Interestingly, fibrocytes share many phenotypic features with MSCs. Portal myofibroblasts drive fibrogenesis exclusively in the biliary system, while the BM-derived fibrocytes minimally contribute to hepatic fibrosis. A subset of myofibroblasts are derived from portal myofibroblasts and bone marrow (BM)-derived fibrocytes. 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). Liver fibrosis is a secondary wound healing process driven by myofibroblasts to degrade normal extracellular matrix (ECM) and accumulate excess connective tissue. ĭespite the exceptional regenerative capacity of the liver, chronic injury can overwhelm the liver’s ability to regenerate and this leads to fibrosis. 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. 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. That is, hepatocytes make other hepatocytes, and the same applies to most other liver cell types including BECs and hepatic stellate cells (HSCs). 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. Normal liver regeneration is achieved primarily through proliferation of existing mature hepatocytes and biliary epithelial cells (BECs). The liver is constantly subjected to noxious damage from both exogenous and endogenous toxins, thus requires a method to recover from injury.
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