LPCs, also known as oval cells in rodents, were initially identified in rat livers in 1937 [15]. In healthy adult livers, LPCs are scarce and dormant, residing in the Canal of Hering, serving as their stem cell niche. However, during severe or chronic liver injury that disrupts homeostatic hepatocyte proliferation, LPCs activate and differentiate into biliary cells and hepatocytes, contributing to liver regeneration [16]. The self-renewal capacity and bi-potentiality of LPCs make them a promising avenue for stem cell-based regenerative therapy. A notable case documented the administration of adult liver stem cells (LSCs) through two infusions to a 3-year-old girl with ornithine carbamoyltransferase (OTC) deficiency [17]. Interestingly, the recipient’s liver exhibited repopulation by the transplanted donor cells, suggesting the viability of LSC transplantation in OTC patients. Conversely, some studies contend that LPC accumulation in the ductular reaction could signal liver disease severity, as LPCs might differentiate into myofibroblasts [18]. Thus, investigating niche-specific modulators governing LPC committed differentiation into specific cell types, such as cholangiocytes or hepatocytes, is crucial. Several ongoing preclinical studies aim to achieve this [19, 20].

ESCs and iPSCs are pluripotent cells with the remarkable capacity to generate diverse body cells. ESCs are derived from the inner mass of blastocyst stage embryos, allowing spontaneous differentiation into various cell lineages, including hepatic endoderm [21]. Animal experiments have shown hepatocyte-like cells (HLCs) derived from ESCs as potential resources for tissue engineering, disease modeling, and drug metabolism, offering alternative therapeutic avenues. However, ethical concerns and the risk of tumorigenesis currently prevent clinical applications of ESCs and their derivatives [22].

IPSCs possess pluripotent properties like ESCs and hold an ethical advantage [23]. Pioneering work by Takahashi et al. [24] and Yu et al. [25] reported successful generation of iPSCs from adult human cells in 2007. iPSCs have since been widely used in disease modeling, cell therapy, and drug metabolism studies. Under specific conditions, iPSCs can differentiate into specific cell types [25]. In 2009, iPSCs were induced into hepatic cells [26], referred to as iPSC-derived hepatocyte-like cells (iPSC-HLCs). Ongoing efforts optimize reprogramming factors for high-quality iPSC-HLCs without genome modification [27, 28]. IPSCs overcome the histocompatibility issues through two known strategies: the generation of a bank comprising HLA homozygous iPSCs and their derived cells [29], and by the generation of universal donor iPSCs engineered with overexpressing CD47 gene while simultaneously suppressing the expression of HLA I/II genes [30]. All these significant advancements in reprogramming technologies present promising prospects for the application of iPSCs in the curative treatment of liver diseases.

However, it should be noted that several “bottleneck” problems hinder the clinical application of iPSCs. First, fully functional hepatocytes from iPSCs remain a challenge [31]. Second, iPSC-HLC engraftment into injured livers is limited [32]. Importantly, iPSCs’ unlimited proliferation and genomic instability pose risks of tumor and teratoma formation [33, 34]. iPSCs’ hepatic disease treatment is still in the preclinical stage.

ASCs, also termed somatic stem cells, reside in specific organs and have limited multi-differentiation capacity, generating specific mature cells for tissue homeostasis [35]. ASCs play a pivotal role in tissue repair and regeneration due to microenvironment signals [36]. Two major ASC populations are HSCs and MSCs, available from allogeneic or autologous sources [36].

HSCs can transdifferentiate into hepatocytes [37, 38] and regulate the liver microenvironment, recruiting cells to injury sites and aiding repair [39]. Currently, HSCs used for treating liver disease can originate from various sources, such as umbilical cord blood, peripheral blood, and bone marrow (BM). In 2005, Am et al. [40] made a significant discovery by demonstrating that portal infusion of BM-HSCs promoted liver regeneration. Meta-analyses and long-term follow-ups confirm autologous HSC transplantation’s efficacy in decompensated cirrhosis [41, 42]. Nevertheless, a phase II multi-arm, open-label, randomized, controlled trial (RCT) unveiled that infusions of autologous HSCs had no discernible impact on fibrosis, disease severity, or quality of life in individuals with compensated cirrhosis. Surprisingly, this treatment was linked with an increased incidence of severe side effects, including encephalopathy or ascites [43]. Hence, the effectiveness and safety of HSCs necessitate further substantiation through rigorous RCTs. Furthermore, novel approaches such as cytokine therapies utilizing bone marrow (BM) stimulation [43] and gene-modified HSCs [44] might advance the clinical applications of HSCs.

MSCs are extensively examined and employed in stem cell-based therapy for addressing liver ailments. MSCs therapy demonstrates notable safety and tolerability, as indicated by numerous clinical trials targeting liver diseases, with no notable risk of adverse outcomes. Notably, MSCs possess several advantages and distinctive features [31, 45, 46, 47]. Primarily, MSCs are widely and conveniently attainable from multiple sources. Thus far, MSCs sourced from umbilical cord blood, umbilical cord, BM, and adipose tissue have been employed for treating end-stage liver diseases encompassing cirrhosis, liver transplantation-related complications, or liver failure [31]. Additionally, MSCs exhibit an exceptional ability for substantial in vitro expansion, facilitating rapid scalability to meet in vivo therapeutic requirements [45]. Thirdly, owing to their hypoimmunogenic attribute, allogeneic MSCs can be utilized without the necessity of supplementary immunosuppressant therapy [46]. Furthermore, MSCs can be cryopreserved with a low risk of viral infection [31]. Despite their notable plasticity to differentiate into hepatocyte-like cells, the therapeutic potential of MSCs primarily stems from their immunomodulatory, antioxidant, and anti-fibrotic properties [47]. Despite these merits, none of the MSC-based products has received approval for liver disease treatment primarily due to unresolved technological challenges. For instance, MSCs exhibit limited proliferative capacity, and MSCs obtained from distinct donors may exhibit variations in their attributes. Additionally, prolonged MSC culturing might lead to phenotypic changes and genetic drift [48]. Consequently, the utilization of primed or genetically-modified MSCs, or cell-free therapy, emerges as a potential strategy for therapeutic interventions [48].

Liver cirrhosis represents an advanced stage in the progression of diverse chronic liver ailments. When the liver sustains injury from factors such as hepatitis B/C infections, alcohol misuse, lipid accumulation, and exposure to noxious substances, activated hepatic stellate cells generate excessive collagen and matrix proteins, culminating in liver fibrosis [49]. While early-stage fibrosis holds potential for reversibility, cirrhosis, conversely, tends to be irreversible. Multiple prospective mechanisms of stem cell therapy have been posited for liver cirrhosis treatment. These encompass direct differentiation of stem cells into functional hepatocytes, suppression of hepatic stellate cell activation combined with induction of their apoptosis, modulation of inflammatory microenvironments via paracrine effects, and release of trophic agents to spur regeneration of existing hepatocytes [50, 51]. A meta-analysis indicated that MSCs can enhance clinical status and laboratory indicators in individuals with liver cirrhosis. This suggests that stem cell therapy could be an effective and secure choice, particularly within the initial six months of cirrhosis treatment [52]. However, prudent interpretation of current findings is essential, considering that certain studies lacked comparison groups and only conducted short-term follow-up assessments. Additionally, it must be acknowledged that stem cell applications are not devoid of risks. For instance, intraliver injection of stem cells might lead to hepatorenal syndrome, a severe and life-threatening complication [53]. Moreover, a substantial-scale RCT demonstrated that cirrhotic patients might encounter infusion-related adverse effects without significant therapeutic gains from HSCs infusion [43]. Furthermore, discerning which patients are most likely to benefit from stem cell transplantation is crucial. The efficacy of stem cell therapy is postulated to potentially vary based on the root cause of cirrhosis [54]. In accordance with this, extensive controlled trials have furnished evidence supporting the adoption of MSCs transplantation as a viable intervention to ameliorate liver function in viral-induced cirrhosis [55] and alcoholic cirrhosis [56]. Nonetheless, a pilot study excluding patients with viral-associated cirrhosis did not observe the sought-after therapeutic effect of MSCs treatment on liver cirrhosis [57]. In light of existing literature, cirrhosis cases categorized as Child-Pugh class C, aged below 60 years, and either planning liver transplantation or employing it adjunctively alongside standard medications are considered suitable candidates for stem cell therapy. Conversely, patients with advanced cirrhosis-associated complications like recurrent variceal bleeding, moderate-severe hepatic encephalopathy, bleeding tendencies, HCC, ongoing infections, or hepatic/portal/splenic thrombosis are deemed inappropriate for stem cell transplantation [58]. Nevertheless, the optimal stem cell type, ideal transplantation route, along with suitable injection frequency and cell dosage necessitate further elucidation through substantial-scale RCTs.

Liver failure is a life-threatening syndrome featuring ascites, jaundice, hemorrhagic tendency, and hepatic encephalopathy, with high mortality [59]. It is classified into acute liver failure (ALF), ACLF in chronic liver disease, and chronic liver failure (CLF). Hepatocyte loss underpins liver failure [60], making ACLF another priority area for stem cell research. MSCs’ anti-inflammatory effects make them promising for ACLF treatment [61]. RCT systematic reviews and meta-analyses demonstrate MSC therapy’s efficacy in improving liver function, albumin, coagulation, or MELD score in ACLF and cirrhosis cases [61]. Subgroup analysis shows short-term survival benefits with stem cell therapy in ACLF [62]. Most MSC clinical trials are in phase I or II [61]. Human liver organoid advancements, including integration with organs-on-a-chip perfusion, hold promise for functional liver organoids in ACLF [63].

AILD encompasses a range of chronic liver diseases marked by immune dysfunction, including primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), and autoimmune hepatitis (AIH) [64]. AILD patients often have limited treatment options and a poor prognosis, particularly those who inadequately respond to initial medical treatment. In such cases, stem cell therapy stands as a potentially effective alternative treatment for AILD [65].

Currently, clinical studies primarily target PBC. An initial study enrolled seven PBC cases with incomplete response to ursodeoxycholic acid (UDCA). These patients received monthly infusions of cultured umbilical cord-derived MSCs (0.5 $\times$ 10${}^6$ cells/kg) three times. Throughout a 48-week follow-up, all patients tolerated treatment well with no noticeable side effects, and most experienced remission. Additionally, serum $\gamma$-glutamyl transferase (GGT) and alkaline phosphatase (ALP) levels significantly decreased. Subsequently, another study included ten UDCA-resistant PBC cases. These patients received intravenous infusions of allogeneic BM-MSCs at 3–5 $\times$ 10${}^5$ cells/kg [66]. Unlike the prior study, this investigation administered a single dose of BM-MSCs, with follow-ups at 1, 3, 6, and 12 months. Substantial improvements in quality of life and serological biochemical indicators were observed, with no transplant-related complications. However, both studies suffered from small sample sizes. The impact of continuous UDCA therapy, natural PBC progression, and potential UDCA-MSC interaction when combined could not be fully ruled out. Addressing critical issues, including determining minimal effective MSC dosage, optimal administration route, repeated therapy timing, and understanding infused MSC fate, is crucial.

For AIH and PSC, stem cell therapy’s application is limited to animal models and case reports, underscoring the need for further experimental and clinical studies to ascertain efficacy and safety [3, 67].

WD is an autosomal recessive genetic disorder marked by ATP7B deficiency, a copper (Cu)-transporting ATPase mainly expressed in liver cells. This deficiency leads to Cu accumulation, causing hepatic, neurologic, and psychiatric symptoms of varying severity. Lifelong treatment usually maintains copper balance in WD patients. However, current pharmacotherapy is not curative and has severe side effects. Liver transplantation also faces donor shortages and challenges in neurologically uncontrolled patients. Therefore, stem cell therapy explores potential treatment to restore hepatobiliary copper excretion and alter WD progression [68].

Currently, only one RCT compared BM-MSC transplantation plus penicillamine with penicillamine alone in 60 WD patients [4, 68]. Penicillamine, a chelator balancing copper intake and excretion, has serious side effects and cannot cure WD [68]. Interestingly, the study showed BM-MSCs combined with penicillamine positively affected WD-related liver fibrosis, with few adverse reactions from MSC treatment. Yet, the study did not measure serum copper and ceruloplasmin level changes, important indicators of MSC efficacy in copper removal. Additionally, developing an integrated cell/gene therapy to restore ATP7B levels without extra genetic modification and optimizing protocols for stem cell delivery and liver-specific targeting for proliferation and differentiation remain in preclinical stages [4].

Stem cell therapy holds promise as a treatment option for liver-based metabolic disorders. Studies have indicated that transplanting a hepatocyte mass equivalent to around 1/10 of the patient’s liver is sufficient to normalize enzyme deficiencies [4].

Inborn errors of liver metabolism encompass a group of disorders marked by a deficiency in a single enzyme involved in various metabolic pathways. These deficiencies lead to impaired liver function and dysfunction in distant organs. These conditions typically manifest during the neonatal period. The two most notable disorders within inborn errors of liver metabolism are Crigler-Najjar (CN) syndrome and urea cycle defects (UCD). Presently, no effective treatment is available for these disorders, resulting in approximately 10–50% of affected children requiring liver transplantation. Stem cells have the potential to restore liver enzyme activities in affected individuals. In line with this, the safety and efficacy of heterologous human adult LPCs (HHALPCs) were preliminarily confirmed in a phase I/II, multi-arm, open-label, prospective study involving 14 UCD and 6 CN pediatric patients [69]. A subsequent phase II clinical study is underway to further explore the use of HHALPCs. Notably, HHALPCs were administered via intraportal infusion; however, clinicians need to be vigilant about the possible risk of portal vein thrombus formation. Another partially randomized phase I/II study involving 6 CNs and 5 UCDs revealed that the combination of heparin and bivalirudin exhibited high safety and could limit thrombogenesis caused by MSCs infusion to subclinical signs. This approach indicates significant progress in inhibiting the procoagulant activity of MSCs during transplantation [70].