Alcohol use disorder has significant negative health consequences on a global scale due to its effects on multiple systems. There are multiple manifestations of Alcoholic Liver Disease (ALD) among chronic alcohol users, and it can be life-threatening due to the high likelihood of developing liver cancer. This condition has both a physical and mental toll on those that suffer, due to the chronic fatigue, jaundice and hypertension of the portal system. Unfortunately, once advanced, all traditional medical treatments are ineffective against the aggressive liver fibrosis. There is a critical demand for new approaches for the treatment of advanced liver disease. Within the spectrum of advanced liver disease, one of the most innovative approaches is the use of regenerative medicine and stem cell therapy, specifically umbilical cord-derived mesenchymal stem cells (UC-MSCs). The present work will elaborate on the biological pathways of these interventions and their restorative potential.
UC-MSCs Mechanism in Alcoholic Liver Disease
To understand the potential for restorative stem cell therapy, specifically utilizing UC-MSCs, it is important to understand the pathophysiology of Alcoholic Liver Disease (ALD). The first stage begins after the hepatocytes metabolize alcohol. The remaining toxic acetaldehyde is a potent inducer of stress and damage to the hepatocyte, and a host of macrophage Kupffer cell-activating, pro-inflammatory cytokines are the result. As injury progresses, there is the rapid proliferation and transformation of quiescent Stellate cells to myofibroblasts and the excessive deposition of the extracellular matrix.
The excessive deposition of collagen in Alcoholic Liver Disease (ALD) results in distortion of hepatic sinusoids. Fibrotic septa inhibit blood flow and cause hypoxia in the hepatic parenchyma. As a result, hepatocytes continue to necrose and encourage the proliferation of hepatic fibrosis. For this hepatic cellular degeneration, the most promising approach is stem cell therapy utilizing UC-MSCs.
Lack of Effective Treatments
The primary treatment of Alcoholic Liver Disease (ALD) is abstinence and nutritional therapy. Hepatologists prescribe corticosteroids and/or pentoxifylline to control the symptoms of alcoholic hepatitis. These treatment options have numerous drawbacks and very limited efficacy. Prolonged use of corticosteroids leads to life-threatening opportunistic infections. The efficacy of pentoxifylline in the advanced stages of hepatic decompensation is almost nonexistent. When there is no other option available to cure the disease, orthotopic liver transplantation is the only avenue to take. Due to the limited availability of organ donors, the high cost of the surgery, and the high cost of the lifetime requirement of immunosuppressive therapy, it is not a viable treatment option. The absence of effective treatment options to halt the progression of the disease must direct research to advanced stem cell therapies, particularly UC-MSCs.
Why Stem cell?
The stem cell therapy of regenerative medicine hinges on the ability to modulate the immune response and the strong hepatotropic nature of UC-MSCs in treating Alcoholic Liver Disease (ALD). These cells possess more plasticity than other somatic cells. These multipotent cells have the ability to migrate to the inflamed liver tissue. After tissue inflammation and the repair process, these cells continue to increase hepatocyte proliferation and prolong the repair process by releasing cytokines and growth factors.
These secreted bioactive molecules from UC-MSCs effectively inhibit hyperactive Kupffer cell populations and mitigate occasionally destructive cytokine storms. These specialized units induce apoptosis of pathogenic activated hepatic stellate cells. This stops the ongoing collagen deposition. They also secrete matrix metalloproteinases. These enzymes disintegrate the fibrotic scar tissue and reverse the characteristic lobular dysfunction of Alcoholic Liver Disease (ALD). No other stem cell mechanism has shown this level of efficacy.
Figure 1: Limitations of Current Alcoholic Liver Disease treatment compared with UC-MSCs Therapy mechanisms
Future Trends
Regenerative medicine is rapidly changing and positions Thailand as the leading regional hub along with Southeast Asia. Thailand has a strong biomedical foundation and is home to clinical scientists who are constructing Advanced Tissue Engineering frameworks. The high incidence of serious liver conditions, including Alcoholic Liver Disease (ALD), among Southeast Asians South of China creates a strong need for therapeutically viable UC-MSCs products. Thai translational research institutes are looking to improve cryopreservation with a focus on cellular viabilities in the context of continuous cultivation. The inclusive nature of ethical clinical trial regulations in Thailand provides an avenue to utilize stem cell technologies for regenerative medicine. Thailand will be able to develop phenotypic Asian biopharmaceuticals with a decreased dependency on other nations.
Alcoholic Liver Disease (ALD) has a dire progression and impacts that warrant a complete restructuring of the treatment paradigm. There are currently no options other than the palliation of symptoms. Therapies aimed at the restoration of liver structure and function are called for. Within the context of ALD, the destruction of fibrotic tissue and the restoration of endogenous hepatocyte population can be achieved with the application of umbilical cord-derived mesenchymal stem cells (UC-MSCs) within hepatic medicine. There is a strong likelihood that the research of advanced cell-based therapies will quickly progress from early and difficult to implement phases of research to well-established clinical practices within the context of the promising biomedical research in Thailand. The effects of this advanced cell-based therapies will likely be a significant and positive global impact within the field of hepatic medicine and will likely provide a progressive and lasting solution to the problem of end-stage liver degeneration and the resulting advanced and progressive hepatic failure.