Exploring Mesenchymal Stem Cell Applications for Chronic Liver Diseases

1. Exploring Mesenchymal Stem Cell Applications for Chronic Liver Diseases Chronic liver diseases pose significant health challenges with substantial physical and psychosocial impact. Liver transplantation remains the only treatment at the end stage. The limited therapeutic options have urged the exploration of alternatives. A promising treatment modality for liver diseases is stem cell transplant. Stem cells, particularly mesenchymal stem cells (MSCs), with their regenerative ability, can potentially restore the hepatic structure and function. Chronic Liver Diseases Nutrient storage, detoxification, drug metabolism, clotting factor production, and bile excretion are a few of the vital tasks of the liver. A broad range of factors, including genetic inheritance, viral infections, drugs, toxins, and autoimmune disorders, can cause www.kosheeka.com

2. chronic liver diseases. They are characterized by progressive and continuous deterioration of the liver. Fibrosis, cirrhosis, and hepatic failure are clinical manifestations of such diseases. The underlying pathogenesis begins with a hepatic injury that triggers the activation of hepatic stellate cells. These cells transform into myofibroblasts, inducing inflammation and deposition of extracellular matrix (ECM). Prolonged inflammation and repetitive tissue regeneration lead to fibrosis (excessive ECM accumulation) and cirrhosis. Cirrhosis is marked by disruption of liver architecture and vascular reorganization. Current Landscape Current treatment modalities focus on eliminating the causative factor and halting the disease progression. Liver transplantation is the definitive treatment for end-stage liver diseases. However, the medications fail to restore the damaged liver. The transplant procedure requires the administration of immunosuppressants, which are associated with the risks of infections with prolonged use. Additionally, donor scarcity and the resultant long waiting times cause high mortality rates. Stem Cell Treatment Stem cells have the exceptional ability to differentiate into diverse cells. Several stem cells and progenitors have been researched for liver diseases. Transplantation of hepatic progenitors did generate functional hepatocytes, but showed limited proliferation, immunological rejection, scarring, and malignant transformation, while failing to restore the hepatic functions. The dedifferentiation of primary somatic cells into induced pluripotent stem cells (iPSCs) have www.kosheeka.com

3. piqued the interest of the scientific community. The production of iPSCs in large quantities from patients’ cells has enabled autologous transplant, tailored to the patient’s unique biological profile. iPSCs can be differentiated into hepatocytes but lack the genotype and phenotype of mature cells, thereby restricting their long-term efficacy. Mesenchymal stem cells (MSCs) demonstrate desirable self- renewal capacity, along with low immunogenicity. The Mechanisms of MSCs in Liver Treatment In addition to self-renewal and differentiation, MSCs also treat liver diseases by following mechanisms: Immune Regulation: MSCs possess immunomodulatory property. They promote the expression of anti-inflammatory cytokines, while reducing proinflammatory cytokines to suppress inflammation. MSCs also switch the immune response towards repair pathways by enhancing regulatory T cells, M2 macrophages, and myeloid-derived suppressor cells. Anti-fibrosis: MSCs inhibit the activation of hepatic stellate cells and induce apoptosis of the activated stellate cells, thereby alleviating ECM synthesis. Regeneration: MSCs differentiate into functional hepatocytes to replace the lost or damaged hepatic cells. They also mediate paracrine signaling by secreting hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and insulin-like growth factor (IGF) that promote the proliferation of hepatic progenitors and mature hepatocytes. Through a multi-faceted approach, MSCs not only restore hepatic function but also enhance the outcomes of the transplant. www.kosheeka.com

4. Clinical Studies Most clinical trials have employed MSCs derived from the umbilical cord due to their easy availability, low immunogenicity, and higher differentiation potential. Trials on patients suffering from liver cirrhosis due to alcohol or HCV-hepatitis experienced reduced hepatic fibrosis and normalized liver enzyme levels with improvements in hepatic structure and function. Acute-on-chronic liver diseases have higher mortality rates and can result in multiorgan failure. MSC administration has improved the survival rates in such patients. MSCs have demonstrated efficacy in treating non-alcoholic and alcoholic fatty liver by altering metabolic pathways and reducing inflammation. Their anti-apoptotic and antioxidant effects contribute to repairing the hepatic injury and the subsequent functional recovery. MSCs can also enhance the liver transplantation outcomes by mitigating the associated complications such as ischemia-reperfusion injury and acute graft-versus-host disease. Their immunomodulatory properties help improve graft viability and promote liver regeneration post-transplant. Advances in MSC-based Therapy MSCs have remarkable capacity in the treatment of liver diseases. Therefore, researchers have also been developing alternative therapies that integrate the potential of MSCs. MSC-Derived Exosomes: MSCs also release tiny vesicles- exosomes to establish cross-talk with the surrounding cells. These exosomes comprise diverse biomolecules that can alter the cell response. They obtain the anti-inflammatory, regenerative, and antioxidant properties of MSCs and deliver them in a cell-free manner. They can home to the hepatic injury sites and reduce fibrosis by alleviating www.kosheeka.com

5. collagen levels, blocking TGFβ/Smad signaling, preventing epithelial- mesenchymal transition, and suppressing the Wnt/β-catenin pathway involved in the activation of hepatic stellate cells. Exosomes also regulate T cell differentiation, inhibit B cell proliferation, and modify inflammatory macrophages to anti-inflammatory cells. Together these effects modulate the immune system response. For enhanced therapeutic benefits, desired molecules and even drugs can be packed into exosomes. Exosomes also have the potential to ameliorate immune rejection during transplant. Bioartificial Liver: Bioartificial liver is another treatment for end- stage liver disease, which incorporates cells in a bioreactor. It is an external device that performs hepatic functions such as detoxification, metabolism, and synthesis. This device can only work for a short time period and is usually employed until a suitable donor for transplant is available. The patient’s blood is perfused or routed through the device where it interacts with bioreactor cells. These devices usually contain hepatocytes obtained from various sources. Recent studies have suggested that co-culture of MSCs with hepatocytes can enhance the effects of bioartificial liver. Currently different aspects of the device, such as bioreactor design, cellular component, and perfusion systems are being optimized for clinical use. Future Perspectives Research studies and clinical trials have demonstrated the efficacy of MSC transplant. The availability of MSCs from diverse sources and extraction in sufficient quantities have prompted their use for therapeutic treatment. Their low immunogenicity and transdifferentiating potential have established them as alternative www.kosheeka.com

6. transplant sources. They can also effectively treat liver diseases. However, challenges remain regarding their clinical application. The risk of malignancy and unwanted differentiation remains associated with MSC transplant. The efficacy of the therapy varies with the treatment procedure. Although the absence of adverse effects is evident in clinical trials, proper validation requires a larger sample size. Therefore, numerous trials are ongoing to assess the benefits of MSCs with larger populations in a plethora of liver diseases and the streamlining of the procedure to establish a clinical standard of practice. Conclusion MSC therapy has demonstrated effectiveness in the treatment of chronic liver diseases. Its diverse abilities have shown substantial improvement in the hepatic structure and function. It can be a suitable candidate for transplant for the end-stage liver diseases. However, research continues for the successful translation of the therapy in clinical settings. The source of MSCs, their dosage, administration route, and the risk of malignancies is still being investigated. Scientists are attempting to tap into the full potential of MSCs for improved outcomes with exosomes and bioartificial liver. Kosheeka supports the ongoing research by providing MSCs from diverse sources and offering the option of donor customization. Our team evaluates MSCs for their viability and purity to supply contamination-free cells with high yield to save your time in isolation and characterization. www.kosheeka.com

7. FAQs Q: What is chronic liver disease? Chronic liver disease is characterized by a progressive, continuous, and gradual decline in liver structure and function leading to liver failure. Q: What is fibrosis? Liver injury triggers the healing mechanisms that deposit extracellular matrix (ECM) on the injury along with immune cell infiltration. Repetitive injury dysregulates the repair mechanisms, causing excess ECM accumulation called fibrosis. As the ECM spreads in the tissue, the structure and subsequently the function are adversely impacted. Q: The liver has its own regenerative capacity, why don’t we use liver stem cells? Scientists have used liver progenitors for the treatment, but due to their limited ability, they failed to restore the liver structure and function. Q: How does MSC transplant aid in liver regeneration? MSCs differentiate into hepatocytes and also promote the proliferation of liver progenitors to replace damaged cells. They also reduce inflammation and ECM synthesis. STAY UPDATED! www.kosheeka.com info@kosheeka.com +91-9654321400 www.kosheeka.com