Effetto delle cellule staminali mesenchimali nella rigenerazione del fegato e applicazioni cliniche

Astratto
Le malattie del fegato rappresentano circa 2 milioni di morti all’anno in tutto il mondo per cirrosi, epatite virale, e la malignità sono le cause più comuni. Di conseguenza, la capacità rigenerativa del fegato è un argomento di estremo interesse nella ricerca di terapie curative per le malattie epatiche allo stadio terminale. Cellule staminali mesenchimali (MSC) sono emersi come una nuova promettente terapia per la rigenerazione epatica. Le MSC hanno molteplici proprietà che le rendono un’opzione terapeutica appropriata per le malattie del fegato, compresa la facile accessibilità, migrazione mirata, potenziale immunomodulatore ed effetti antifibrotici/antiossidanti. Inoltre, Le MSC hanno potenziali applicazioni cliniche nella terapia acellulare e nell'ingegneria dei tessuti. 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.

Parole chiave
Cellula staminale mesenchimale, rigenerazione del fegato, end-stage liver disease

INTRODUCTION
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]. Questo è, hepatocytes make other hepatocytes, and the same applies to most other liver cell types including BECs and hepatic stellate cells (HSC). 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 (MMP) 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]. È interessante notare, 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]. Tuttavia, 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].

Attualmente, liver transplantation is the only definitive treatment for end-stage liver disease (ESLD). Fortunatamente, 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. Primo, MSCs are pluripotent stem cells capable of differentiating into hepatocyte-like cells both in vivo and in vitro[11,12]. Secondo, MSCs are readily accessible from multiple potential sources including adipose tissue, cordone ombelicale (UC), sangue del cordone ombelicale, sangue periferico, synovial membranes, muscolo, dermis, and liver[13-17]. È importante sottolineare che, 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].