Chronic liver diseases (CLDs) are the leading cause of liver-related fatalities, accounting for 2 million deaths yearly (Devarbhavi et al., 2023). According to Moon et al., approximately 1.5 billion people suffer from CLDs (Moon, Singal, & Tapper, 2020). CLDs, such as hepatitis, fibrosis, cirrhosis, and liver cancer develop over time due to long-term exposure to various risk factors. The most common causes of CLDs include extreme consumption of alcohol, viral hepatitis (e.g., hepatitis B and C), and non-alcoholic fatty liver disease (NAFLD) (Khurana et al., 2022; Khurana, Sayed, Allawadhi, & Weiskirchen, 2021). Until 2019, 43% of individuals consumed alcohol worldwide, which has significantly risen since the COVID-19 pandemic. Alcohol-related deaths increased by 25% in 2020 compared to 2019 (Meza et al., 2022; Pollard, Tucker, & Green Jr., 2020; White, Castle, Powell, Hingson, & Koob, 2022). The number of cases of cirrhosis, hepatitis, and fibrosis caused by alcohol is increasing day by day (Stein et al., 2016). In 2019, it was estimated that alcohol contributed to one-fifth of deaths from liver cancer and one-quarter of deaths from cirrhosis worldwide. From 2010 to 2019, alcohol misuse was the second-fastest growing factor contributing to mortality due to liver cancer (Huang et al., 2023, Huang et al., 2023). Likewise, the prevalence of NAFLD has also increased globally from 25% to 30%. (Younossi et al., 2016; Younossi et al., 2023). Moreover, the WHO’s global report shows 354 million people are infected with hepatitis B or C (https://www.who.int). These data underpin the growing burden of CLDs.

CLDs such as alcohol-related liver disease (ALD), NAFLD, and viral hepatitis cause the liver to lose its functionality and experience cell destruction. At the end of these processes, the only therapeutic option is liver transplantation. The assessment of liver transplantation statistics worldwide showed that the number of transplants has increased significantly since 2015 (Terrault, Francoz, Berenguer, Charlton, & Heimbach, 2023). In particular, NAFLD is a leading cause of liver transplantation among all CLDs. However, there are possibilities of numerous complications following liver transplantation, such as hepatic artery and portal vein-related complications (Hakoda et al., 2023; Pamecha et al., 2023; Terrault et al., 2023). Nevertheless, end-stage CLD requires transplantation. Over the recent years, novel therapeutic options have emerged by harnessing the natural regeneration capacity of liver using tissue engineering methods.

Tissue engineering and regenerative medicine are effective approaches to improve tissue damage. Therefore, respective techniques are central to many clinical trials, research programs, and translational initiatives (Han et al., 2020). Tissue engineering is mainly based on three components: (i) stem cells (SCs), (ii) important growth factors (i.e., chemokines and cytokines), and (iii) scaffolds to repair damaged tissue or replace and regenerate organs (Kwon, Kwon, Lee, Park, & Kim, 2018; Ude, Miskon, Idrus, & Abu Bakar, 2018). In chronic tissue injury, SCs play a significant role in the direct differentiation or regeneration of damaged tissue and the regulation of immune microenvironment (Li et al., 2019). Thus, SC therapy is further useful for stimulating the body’s pool of SCs. This can be accomplished by delivering growth factors like hepatocyte growth factor (HGF), which can stimulate the proliferation and differentiation of SCs already present in the liver (Fuchs et al., 2021; Yu et al., 2021). According to the definition, SCs are undifferentiated cells that have the potential to differentiate into multiple types of cells and participate in the development of many tissues and organs. These cells are found in the embryonic, neonatal, and adult stages. On the basis of their differentiation potential, SCs can be classified into unipotent, oligopotent, multipotent, pluripotent, and totipotent types (Kolios & Moodley, 2013). The remarkable advancements in SC research have paved the way for cell-based therapeutics for diseases that cannot be treated with traditional medications (Mahla, 2016).

In liver research, SC-derived cells have potential applications in treating fibrosis, cirrhosis, and hepatic cellular carcinoma (HCC) (El Agha et al., 2017; Hassan et al., 2023). In particular, therapy for liver fibrosis has received vigorous attention due to its progression to end-stage liver disorders such as cirrhosis and HCC. To develop novel therapies for targeting fibrosis, it is necessary to understand how the cells interact with the extracellular matrix (ECM) and sense and convey mechanical stimuli triggering the accumulation of ECM, which is the hallmark of fibrosis development (Long, Niu, Liang, & Du, 2022). On the background of donor organ shortage, alternative therapies like cell therapy may be able to postpone or even eliminate the need for organ transplantation. Thus, there is hope that SC-based therapeutics offer new therapeutic avenues to healthcare that can significantly reduce the burden of disease (Srivastava & Bulte, 2014).

Numerous preclinical studies using SCs for liver regeneration have already yielded promising results. In particular, some studies demonstrate that transplantation of SCs can significantly improve liver function. However, more research is indispensable to fully comprehend the mechanisms underlying SC-mediated liver regeneration and optimize the use of SCs in clinical settings. Besides, there are many ethical concerns surrounding the use of SCs which must be first addressed before using SC-based treatments (Li, Li, & Hui, 2020; Michalopoulos & Bhushan, 2021).

In the present review, we discuss SC-based therapy in CLDs by focusing on common stages of CLD (inflammation, fibrosis, and cirrhosis) and different pathways that can be modulated by SCs. We further highlight clinical studies in which SCs have been used in the management of CLDs. We conclude by formulating a professional judgment regarding the ongoing difficulties and potential future directions of SC-based therapy for CLDs.