Introduction

Hepatocellular carcinoma (HCC) accounts for 85% to 90% of primary liver cancers and generally has a poor prognosis [1]. The widely accepted hierarchical cancer stem cell (CSC) model suggests that cancer initiation begins with CSCs, with HCC originating from liver CSCs [2]. Clinically, HCC exhibits a wide range of manifestations, with varying differentiation and progression rates [3]. While some HCCs are well-differentiated and slow-growing, others are poorly differentiated and rapidly progress to extensive metastasis [3]. While the morphology and surface marker expression of HCC cells are often clearly distinct from those of cholangiocarcinoma (CC), there are cases where HCC and CC are mixed or both cell markers are expressed based on immunohistochemical staining (combined HCC-CC type) [4]. Heterogeneity in HCC forms and clinical presentations may arise from the fact that although HCC originates from liver CSCs, these CSCs may originate from different cell types [5]. For instance, HCC that arise from mature hepatocytes through dedifferentiation into liver CSCs may exhibit different marker expression and clinical features than HCC that arise from liver stem cells through oncogenic transformation into liver CSCs [5]. This review explores the normal physiology of liver regeneration, provides a comprehensive overview of hepatocarcinogenesis (including cancer initiation, isolation of liver CSCs, molecular signaling pathways, and microRNAs [miRNAs]), and then reviews the cellular origins of liver CSCs, highlighting hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs), along with well-known hepatocytes and hepatic progenitor cells (HPCs).

Liver regeneration

The normal lifespan of hepatocytes is 200 to 300 days [6]. When hepatocytes reach the end of their lifespan, they are removed and replaced with new cells derived from existing hepatocytes. Similar to the proliferation and shedding of intestinal cells, hepatocytes in the liver age near the portal vein and gradually move towards the central vein, where they are shed [7]. Various cell types contribute to hepatic regeneration in response to liver injury. In response to minimal injury, hepatocytes regenerate and maintain liver homeostasis. However, in cases of persistent liver injury, HPCs are recruited to aid hepatocyte regeneration [6,7]. In severe liver injury, bone marrow (BM) cells also participate in the regeneration process [8,9] (Fig. 1). The BM and liver are closely related because the liver is responsible for hematopoiesis during embryonic development [8]. Remarkably, after human BM hematopoietic cells are injected into fetal deer, over 10% of the deer hepatocytes are derived from the human cells [10]. In liver fibrosis or cirrhosis, the migration of HSCs from the BM to the peripheral blood increases [11]. There are several hypotheses regarding how BM cells engraft into the liver, the predominant one being cell fusion [12-14]. However, it has also been reported that stem cells can directly differentiate into hepatocytes without cell fusion due to plasticity [15-17] or undergo transdifferentiation through epithelial-mesenchymal transition (EMT) [18]. In rodents, even when two-thirds of the liver is resected, it regenerates rapidly within 10 days [6]. Both hepatocytes and HPCs, as well as MSCs and HSCs, are involved in this process [19]. Signaling molecules such as hepatocyte growth factor, interleukin (IL)-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-α, and epidermal growth factor play key roles in liver regeneration [6]. Although the exact mechanisms of the cessation of liver regeneration are not well understood, signaling molecules such as TGF-β1 are thought to be pivotal [20].

Cancer initiation

Two models have been proposed in cancer development: the stochastic model (clonal evolution), which hypothesizes that tumors arise randomly and arbitrarily through the accumulation of genetic mutations; and the hierarchical model, which hypothesizes that tumor cells form a hierarchy originating from CSCs [2]. The stochastic model is a classical concept proposing that individual cancer cells choose between self-renewal and differentiation, leading to uniform characteristics among tumor cells [2,21]. However, explaining cancer recurrence after chemotherapy is difficult with the stochastic model [2,21,22]. Currently, the hierarchical model, which suggests that cancer arises from CSCs, is widely accepted [2,21]. In the hierarchical model, CSCs are in the G0 (quiescent) phase of the cell cycle [22]. Conventional chemotherapy targets the differentiating cancer cells, but not the CSCs, which can lead to cancer recurrence. Therefore, targeting CSCs is necessary for cancer eradication [22]. To develop therapies targeting CSCs, it is essential to understand the fundamental characteristics of these cells.

Isolation of liver cancer stem cells

Normal stem cells can self-renew indefinitely and differentiate into various cell types that are crucial for regenerating organs and tissues [22]. CSCs share these abilities but also possess the capabilities of cancer initiation, metastasis, recurrence, and therapy resistance [22]. CSCs can originate from genetic and epigenetic changes in normal stem cells or through oncogenic dedifferentiation of mature cells [2,22,23].

Since their discovery in blood cancers, researchers have also identified CSCs in various solid cancers [24]. To confirm the presence of CSCs, it is crucial to demonstrate their self-renewal, differentiation, and tumor-forming capabilities, and identify specific CSC markers [24]. Similar to those found in other solid tumors, currently known liver CSC markers include CD133 (prominin-1), CD90 (Thy-1), CD44, epithelial cell adhesion molecule (EpCAM, CD326), and CD13 [25-30]. The frequency of CD133 expression in liver cancer cell lines varies widely from 0% to 65% [25]. CD133-positive cells can form colonies in vitro, exhibit tumorigenic potential, and display resistance to radiation in vivo [25,26]. However, considering that CSCs constitute <5% of total tumor cells, the usefulness of CD133 alone may not be sufficient. For instance, Ma et al. [27] reported that cells positive for both CD133 and aldehyde dehydrogenase (ALDH) have the highest tumor-forming ability, followed by CD133⁺ALDH^– cells, and then CD133^–ALDH^– cells. Similarly, Zhu et al. [28] discovered that CD133⁺CD44⁺ cells were more tumorigenic and resistant to chemotherapy than CD133⁺CD44^– cells. CD90, which is present in approximately 0% to 2.5% of tumors, is associated with a strong tumorigenic potential [29], and its combination with CD44 further enhances both tumorigenic and metastatic capabilities [29]. EpCAM⁺ cells also show significant tumor-forming potential and CSC characteristics [30].

In a recent study, Park et al. [31] proposed that normal CD34⁺ stem cells, which are crucial for liver regeneration, can transform into CD34⁺ CSCs in liver cancer. They isolated CD34⁺ cells from a PLC/PRF/5 hepatoma cell line, injected them into immunodeficient mice, and observed tumor formation with as few as 100 cells. These CD34⁺ cells maintained their self-renewal and tumor-forming abilities over 22 serial passages [31].

Molecular signaling pathways in hepatocarcinogenesis

The signaling pathways involved in the transformation of normal stem cells into CSCs, including Wnt/β-catenin, TGF-β, Notch, and Sonic Hedgehog (SHH), are crucial for the development, growth, regeneration, and self-renewal of normal cells and stem cells [24]. However, the overactivation of these pathways triggered by various factors can lead to tumor formation [24]. The following section introduces the major signaling pathways involved in hepatocarcinogenesis.

1. Wnt/beta-catenin pathway

The Wnt/β-catenin pathway is essential for liver regeneration [32]. However, its abnormal activation is implicated in liver cancer, with over 50% of patients with HCC exhibiting aberrant expression of β-catenin [32,33]. This pathway is pivotal for HCC tumorigenesis and progression and maintains the stemness of CSCs [34]. The key event in the Wnt/β-catenin pathway is the nuclear translocation of β-catenin mediated by Wnt ligands. In the nucleus, β-catenin binds to T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors, activating the transcription of target genes [32]. The non-canonical pathway regulates various cellular functions without the involvement of β-catenin, with two representative sub-pathways: the planar cell polarity pathway and the Wnt/Ca²⁺ pathway [32]. Long noncoding RNAs (lncRNAs) activate the Wnt/β-catenin pathway to promote the self-renewal of CSCs [35]. Several miRNAs, such as miR-1246, miR-5188, miR-452, and miR-217, also contribute to the stemness of liver CSCs [36-39]. Additionally, M2 tumor-associated macrophages secrete TNF-α, inducing the Wnt/β-catenin pathway, thereby promoting EMT and CSC stemness [40].

2. Transforming growth factor-beta signaling pathway

TGF-β plays a crucial role in inhibiting hepatocyte proliferation during liver regeneration [23]. In HCC, TGF-β exhibits paradoxical roles, initially inhibiting HCC and later promoting tumor progression [41]. During HCC progression, TGF-β shifts to a protumorigenic signal, inducing aggressive phenotypes such as cancer cell proliferation, EMT, tumor microenvironment (TME) remodeling, and immune evasion [41]. Tang et al. [42] discovered that HPCs can be converted into CSCs through TGF-β and IL-6-related signaling pathways. Additionally, TGF-β signaling plays a pivotal role in the EMT process, with TGF-β1-induced EMT promoting transformation into a CSC phenotype [43].

3. Notch signaling pathway

The Notch signaling pathway is essential for stem cell renewal and differentiation and is activated in one-third of human HCCs [44,45]. In mammals, four Notch receptors (Notch 1–4) are activated by interactions with five canonical ligands (Jagged [Jag]1, Jag2, and delta-like canonical Notch ligand [Dll] 1–3) [46]. This pathway maintains CSC stemness in the liver by regulating the expression of CSC-related genes [47]. Notably, CD133⁺ liver CSCs exhibit higher Notch pathway activation than CD133^– liver CSCs [24,48]. Overexpression of hypoxia-inducible factors (HIFs) is common in HCC and contributes to angiogenesis, immune evasion, and CSC-dependent remodeling [49]. Specifically, HIF-1α activates Notch signaling and serves as a key regulator of EMT [49]. Additionally, miRNAs and Notch signaling are involved in EMT, driving HCC aggressiveness and poor survival [50]. Ren et al. [51] reported that miR-199a-3p induces Notch1 silencing, thereby reducing HCC invasiveness.

4. Sonic Hedgehog signaling

In mammals, there are three Hedgehog ligands: SHH, Indian Hedgehog, and Desert Hedgehog [52]. The SHH signaling pathway is crucial for hepatocarcinogenesis and influences tumor growth, invasion, progression, recurrence, metastasis, modulation of the TME, maintenance of CSCs, and resistance to therapy [53]. The canonical SHH signaling pathway involves the binding of SHH to patched-1, which releases smoothened (SMO) and allows glioma-associated oncogene (GLI) to translocate into the nucleus. The active form of GLI, GLIa, then promotes the expression of target genes. In contrast, the non-canonical pathway bypasses patched-1, SMO, and GLI, activating molecules such as GTPases, Rho, phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR), and protein kinase A to induce gene expression [54]. SHH ligands are present in approximately 60% of HCC liver tissues, with patched-1 and GLI-1 found in >50%, and GLI-2 in >84% [54]. Chronic hepatitis B virus (HBV) or hepatitis C virus infection and nonalcoholic fatty liver disease are associated with SHH pathway activation [54]. CD44⁺ liver CSCs, known for their resistance to sorafenib, exhibit Hedgehog signaling, which has been identified as a key mechanism [55]. Additionally, Zhang et al. [56] reported that CD90⁺ CSCs are regulated by the SHH/GLI and IL-6/Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 pathways.

5. Hippo-Yes-associated protein/transcriptional co‑activator with PDZ‑binding motif signaling pathway

The Hippo pathway plays a crucial role in cell proliferation and apoptosis [57]. The key components of the Hippo pathway are Yes-associated protein (YAP) and its corresponding transcriptional activator with a PDZ-binding motif (TAZ) protein [58]. When the Hippo pathway is activated, YAP/TAZ activity is inhibited, suppressing cell proliferation and promoting apoptosis [57]. If the Hippo pathway is disrupted, YAP/TAZ is activated and translocates into the nucleus, where it interacts with transcription factors to promote cell proliferation [57]. Dysregulation of the Hippo pathway has been reported in various cancers, including liver cancer [57]. TAZ promotes HCC cell proliferation, migration, and invasion by activating genes related to EMT and angiogenesis [57,59]. In HCC, TAZ is overexpressed and associated with tumor progression and poor survival [59]. TAZ also interacts with YAP. Tumor hypoxia activates HIFs, and YAP interacts with HIF-1α to regulate transcriptional activity [57]. In addition, YAP is associated with the stemness of liver CSCs [60]. Overall, YAP and/or TAZ play critical roles in tumor growth, metastasis, and treatment resistance. Therefore, targeting the YAP/TAZ signaling pathway could be an important approach for cancer treatment [57-60].

6. B-lymphoma Moloney murine leukemia virus insertion region 1

B-lymphoma Moloney murine leukemia virus insertion region 1 (BMI-1) is a key proto-oncogene involved in the initiation and progression of various cancers and is upregulated in HCC [61]. As an epigenetic regulator, BMI-1 is crucial for stem cell self-renewal and differentiation [61]. In many cancers, including HCC, BMI-1 is overexpressed, promoting EMT and accelerating tumor growth [62]. High levels of BMI-1 are correlated with poor prognosis in patients with HCC [63].

7. Janus kinase/signal transducer and activator of transcription pathway

The JAK/STAT pathway involves the kinase activity of JAK, which activates STAT transcription factors [64]. This pathway is triggered by various cytokines and growth factors, which play crucial roles in cell proliferation and differentiation [64]. The pathway includes four JAK proteins (JAK1–3 and tyrosine kinase 2) and seven STAT proteins (STAT1–4, 5A, 5B, and 6) [64]. When activated, JAKs induce the expression of suppressors of cytokine signaling (SOCS) proteins, which provide negative feedback to inhibit the pathway [65]. Decreased levels of SOCS-1 have been observed in HCC [66]. STAT3 is notably activated in human HCC and is associated with aggressive tumor behavior [64]. Inflammatory cytokines, such as IL-6, IL-10, IL-17, and IL-23, are believed to drive JAK/STAT signaling, promoting hepatocarcinogenesis and tumor progression [64].

8. Phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway

The PI3K/AKT/mTOR pathway is crucial for tumorigenesis and progression of HCC [67]. Receptor tyrosine kinases activate PI3K, which subsequently activates AKT. Activated AKT regulates downstream effectors including mTOR [67]. The tumor suppressor gene phosphatase and tensin homolog (PTEN) negatively regulates this pathway by dephosphorylating PI3K [67]. Mutations in PTEN lead to overactivation of the PI3K/AKT/mTOR pathway, thereby promoting tumor growth [68]. This pathway is overexpressed in nearly 50% of patients with HCC and affects processes such as tumor cell proliferation and EMT [67]. Additionally, the loss of PTEN and increased levels of phosphorylated AKT and phosphorylated mTOR are associated with a higher tumor grade, vascular invasion, and intrahepatic metastasis [68].

MicroRNAs in hepatocarcinogenesis

Noncoding RNAs are categorized according to their length and structure into miRNAs, lncRNAs, and circular RNAs [69]. miRNAs are single-stranded RNAs of 19–25 nucleotides that regulate gene expression by binding to the 3′ untranslated region of target messenger RNAs [69]. Dysregulation of miRNA expression can lead to various diseases, including cancer [70]. From a cancer perspective, miRNAs can function as oncogenes or tumor suppressors [70]. Aberrant miRNA expression and interactions with signaling pathways contribute to hepatocarcinogenesis by influencing tumor cell proliferation, invasion, and metastasis [70]. Tables 1 to 3 summarize key oncogenic and tumor-suppressive miRNAs, and those that have contradictory roles [71-130].

miRNAs directly or indirectly target genes involved in key pathways such as Wnt/β-catenin, TGF-β, JAK/STAT signaling, and EMT [131]. EMT is a process in which epithelial cells lose their adhesion and become MSCs with invasive characteristics [132]. For example, miR-155 promotes EMT and drives HCC metastasis [108]. MiR-122, a liver-specific tumor suppressor, accounts for 70% of hepatic miRNAs in humans and plays a critical role in inhibiting EMT and the Wnt/β-catenin pathway, thereby reducing HCC invasion and metastasis [75,76]. Oncogenic miR-181 is overexpressed in EpCAM-positive HCC, and its inhibition significantly reduces liver CSC tumorigenesis, suggesting that it is a potential therapeutic target [109]. Interestingly, some miRNAs act as both oncogenes and tumor suppressors. For instance, miR-589-5p reduces CD90⁺ CSC stemness by silencing mitogen-activated protein kinase kinase kinase 8, while simultaneously activating STAT3 signaling, which is associated with chemoresistance and poor survival [127,128]. Thus, miRNAs play a crucial role in hepatocarcinogenesis by interacting with various signaling pathways. Understanding these interactions could aid in the use of miRNAs as biomarkers and therapeutic targets.

Cellular origins of liver cancer stem cells

There are two types of hepatoma cell lines: well-differentiated and poorly differentiated [133]. Six well-differentiated HCC cell lines (Huh-6, Huh-7, PLC/PRF/5, Hep G2, Hep 3B, and Tong) exhibit epithelioid morphology, lack myeloid antigens and do not produce granulocyte-macrophage colony-stimulating factor (GM-CSF). In contrast, poorly differentiated HCC cell lines (HA22T/VGH and SK-HEP-1) produce GM-CSF, display macrophage-like morphology, and express CD14, CD68, and human leukocyte antigen (HLA)-DR [133]. These observations suggest that well-differentiated HCCs originate from mature hepatocytes, whereas poorly differentiated HCCs derive from BM stem cells [133]. Although hepatocytes and HPCs are the currently accepted origins of liver CSCs [2], this discussion emphasizes the roles of HSCs and MSCs, along with hepatocytes and HPCs.

1. Hepatocytes

It has been reported that 18.3% of regenerative hepatocytes originate from mature hepatocytes after partial hepatectomy [133,134]. Surprisingly, 17.7% of HCC cases have also been reported to have originated from mature hepatocytes [133,134]. HCC typically develops because of chronic inflammation or cirrhosis. This leads to extracellular matrix (ECM) remodeling, and changes in the ECM can cause genetic mutations by altering liver-specific transcription factors such as hepatocyte nuclear factor (HNF)-1 and HNF-4 [135]. Additionally, chemical and structural changes in the ECM result in modifications to the intermediate filaments of hepatocytes, which is a critical process in dedifferentiation [136]. Recently, it has been reported that inflammatory cytokines such as TNF-α, IL-6, and TGF-β are involved in hepatocyte dedifferentiation [137]. Notably, IL-6 activates STAT3, a key transcription factor involved in HCC development, and high levels of IL-6 are associated with a poor prognosis [137].

2. Hepatic progenitor cells

HPCs, commonly known as oval cells in rodents, are the most well-known liver stem cells [138]. In humans, they reside in the canals of Hering, the junction between bile canaliculi and interlobular bile ducts, providing a niche for liver stem cells [139]. HPCs express markers similar to HSCs, such as CD34 and c-kit, suggesting a potential origin from BM-HSCs [140]. HPCs also express alpha-fetoprotein (AFP), a hepatocyte marker, as well as the cholangiocyte markers cytokeratin (CK) 7 and CK19 [138-140]. HPCs can self-renew and differentiate into both hepatocytes and cholangiocytes. Some liver cancer cells exhibit a mixture of hepatocytes and cholangiocytes, suggesting that the combined HCC-CC type originates from HPCs [141]. Theise et al. [139] identified HPCs in human liver cancer, indicating that some liver cancers may originate from these cells. Durnez et al. [141] reported that 28% of HCCs expressed CK7 and/or CK19. Hepatocyte proliferation is initially active during the progression from chronic hepatitis to cirrhosis. However, at a certain point of severe damage in cirrhosis, hepatocyte proliferation sharply decreases and HPCs become activated, a process known as the ductular reaction [142]. This reaction is directly related to the severity of the underlying premalignant liver disease and indicates a higher risk of malignant transformation [142]. The origin of liver cancer derived from HPCs can be determined by identifying markers such as OV-6, CK7, CK19, and chromogranin-A [138]. HCC expressing CK19 is associated with a poor prognosis [141,142].

3. Hematopoietic stem cells

HSCs and MSCs are the main components of the BM. HSCs are responsible for generating blood cells, including white blood cells, red blood cells, and platelets, whereas MSCs can differentiate into osteoblasts, chondrocytes, myocytes, and adipocytes [143]. In addition, both HSCs and MSCs can differentiate into hepatocytes, cholangiocytes, and oval cells [143]. CD34⁺ HSCs are pivotal in liver development and regeneration and migrate to the liver to aid in tissue repair [11,12]. Petersen et al. [144] initially documented the conversion of rodent BM cells into oval cells and hepatocytes following their transplantation into lethally irradiated rats. Similarly, donor-derived hepatic regeneration was observed when adult BM cells were intravenously injected into fumarylacetoacetate hydrolase(–/–) mice, an animal model of tyrosinemia type I [18]. Human studies have corroborated these findings with donor-derived hepatocytes emerging after post-HSC transplantation [145].

Park et al. [31] hypothesized that the oncogenic transformation of CD34⁺ HSCs could give rise to CD34⁺ CSCs. Isolation of CD34⁺ cells from the PLC/PRF/5 cell line, which was derived from a patient with HCC and long-term chronic HBV infection, and expansion in culture revealed that these cells retained CSC properties and clonogenic proliferative capacity [31]. The CD34⁺ PLC/PRF/5 cells exhibited significant tumorigenicity and chemotherapy resistance in xenograft models, expressing CSC markers (CD44, CD133, EpCAM, and CD90) and liver stem cell markers (AFP, CK19, CK18, and OV-6), along with the stem cell transcription factor SRY-box transcription factor 2 (SOX2), which is known to regulate self-renewal [31]. Research demonstrated that CD34⁺ liver CSCs can induce various liver cancers, including HCC, CC, and combined HCC-CC [146]. The co-expression of markers such as CD31, CD133, CD90, CD44, OV-6, and EpCAM is associated with the development of combined HCC-CC, whereas CD34⁺ alone is associated with HCC [146]. These CSCs likely originate from the fusion of CD34⁺ hematopoietic precursor-derived myeloid intermediates and HPCs [147]. Surface marker analysis helps identify the origin of the cells. For instance, CD34⁺OV-6⁺ cells or their derivatives may originate from HPCs [147]. The co-expression of myelomonocytic markers (CD68, CD14, and CD31) in CD34⁺ liver CSCs suggests a fusion between HPCs and myelomonocytic cells. Cytogenetic analysis revealed that 82% of CD34⁺ liver CSCs exhibited a mean modal chromosome number of 50 to 60 [147].

In summary, PLC/PRF/5 cells derived from a patient with HCC and long-term HBV infection highlight how persistent liver injury can drive the differentiation of BM-HSCs into myeloid intermediates that migrate to the liver. During fusion with HPCs, these intermediates may undergo oncogenic transformation, leading to the formation of liver CSCs [147].

4. Mesenchymal stem cells

1) Do mesenchymal stem cells exist in the liver?

MSCs are non-HSCs primarily found in the BM but are also present in various organs, including the liver [143]. Pericytes, or perivascular cells, morphologically support endothelial cells in the capillary walls and play an essential role in angiogenesis and in maintaining the structure and function of blood vessels [148]. Pericytes express MSC markers such as CD146, neuron-glial antigen 2 (NG2), and CD140b on their surface but do not express endothelial or hematopoietic cell markers such as CD34, CD31, and CD45 [148]. Similar to other organs, the liver contains pericytes. Crisan et al. [148] provided a detailed analysis of pericyte characteristics. Pericytes were isolated by fluorescence-activated cell sorting as CD146^high, CD45^–, CD56^–, and CD34^– cells. The cells also tested negative for CD144, von Willebrand factor, CD31, and paired box 7 (Pax7). The frequency of pericytes varied between 0.29% and 1.79% depending on the organ, with the highest frequency (14.6%) in adipose tissue [148,149]. Although the cited study included most organs, the liver was excluded. Gerlach et al. [149] confirmed the presence of pericytes in the liver, similar to other organs. Defined as CD146⁺CD45^–CD56^–CD34^– cells, liver pericytes accounted for 0.56%±0.81% in adult livers and 0.45%±0.39% in fetal livers [149]. When cultured for extended periods, these pericytes exhibited MSC-like morphology and characteristics, demonstrating their ability to differentiate into adipocytes, osteocytes, and chondrocytes. Therefore, liver pericytes are considered a source of MSCs [149].

2) Are hepatic stellate cells and pericytes, which are considered a source of mesenchymal stem cells, the same cell population?

Hepatic stellate (HS) cells represent 1.4% of the total liver area and comprise 5% to 8% of all liver cells [150]. HS cells are located in the space of Disse, a region between the basal surface of hepatocytes and sinusoidal endothelial cells [150]. Historically referred to as perisinusoidal cells, lipocytes, fat-storing cells, Ito cells, or pericytes, they were designated as HS cells in 1996 [151]. HS cells play crucial roles in liver fibrosis and regeneration [152]. In the early stages following partial hepatectomy, they secrete matrix metalloproteases and proteoglycans to regulate matrix degradation and hepatocyte growth factor to promote hepatocyte proliferation. In the later stages, they secrete TGF-β to halt hepatocyte proliferation [152].

HS cells are believed to originate from the septum transversum mesenchyme during development [153]. However, other studies have suggested a neuroectodermal and endodermal origin because fetal liver HS cells express neural markers such as nestin and glial fibrillary acidic protein (GFAP), and endodermal markers such as CK8 and CK18 [150]. HS cells may also originate from HSCs or induced pluripotent stem cells, and in the injured adult liver, they can be generated through EMT of hepatocytes [150]. Therefore, HS cells have diverse origins [150]. In the damaged liver, HS cells transform into myofibroblasts in a process known as activation, which is crucial in the response to liver injury [150]. Key signals that activate HS cells include platelet-derived growth factor, TGF-β, and the Fas cell surface death receptor [152]. These signals originate from various cells including sinusoidal endothelial cells, Kupffer cells, damaged hepatocytes, and HS cells themselves [152]. Although HS cells have historically been referred to as pericytes, there is an ongoing debate about whether they are the same cell population as MSC-sourced pericytes. Häussinger and Kordes [154] described HS cells as pericytes and resident MSCs in the liver. They noted that quiescent HS cells express GFAP and embryonic stem cell-derived RAS (ERAS) and retain retinoids, distinguishing them from pericytes or MSCs [154]. However, activated HSCs exhibit reduced expression of GFAP and ERAS, lose retinoid storage, and express typical markers, such as NG2, CD44, and nestin, suggesting that HS cells are quiescent MSCs [154]. Conversely, Gerlach et al. [149] identified liver pericytes as CD146⁺CD45^–CD56^–CD34^– cells that are distinct from HS cells and account for approximately 0.5% of cells in the liver. When cultured for extended periods, these cells exhibit typical MSC morphology and characteristics but do not express α-smooth muscle actin or GFAP, making them easily distinguishable from HS cells [149]. Additionally, Castilho-Fernandes et al. [155] showed that the LX-2 cell line, derived from HS cells, expresses classical mesenchymal markers (CD105, CD44, CD29, CD13, CD90, HLA class I, CD73, CD49e, CD166, and CD146) but is negative for endothelial markers (CD31), endothelial progenitor cell markers (CD133), and hematopoietic markers (CD45 and CD34). This suggests that HS cells are unrelated to hematopoietic or endothelial lineages and are derived from BM-MSCs.

3) Mesenchymal stem cells as cellular origin of liver cancer stem cells

As mentioned earlier, MSCs are found not only in the BM but also in various solid organs, including the liver. In the liver, pericytes account for approximately 0.5% of the cell population and are considered precursors of MSCs [149]. Eun et al. [156] observed that the hepatoma cell line SK-HEP-1 cells (SK cells) exhibited an MSC-like morphology (Fig. 2). They hypothesized that liver cancer might arise from the oncogenic transformation of MSCs into liver CSCs, although it is unclear whether these MSCs originate from liver pericytes or BM-MSCs. SK cells express MSC markers and can differentiate into osteocytes, chondrocytes, and adipocytes, which are typical characteristics of MSCs. Notably, a single SK cell was sufficient to induce tumors in immunocompromised mice and exhibited a strong metastatic potential [156]. This highlights the powerful tumor-forming capability of liver CSCs, suggesting that aggressive forms of liver cancer, such as HCC with extensive metastasis, may originate from MSCs. Co-culturing HCC cells with MSCs further enhances the aggressive phenotype, promoting CSC characteristics and tumor metastasis [156].

Conclusion

A summary of hepatocarcinogenesis, which focuses on cellular origins, is summarized in Fig. 3. Similar to other types of cancers, HCC arises from liver CSCs. Liver CSCs can originate from the oncogenic dedifferentiation of mature hepatocytes or the malignant transformation of HPCs. This process involves interactions between various molecular signaling pathways, inflammatory cytokines, and miRNAs. An imbalance between oncogenic and tumor-suppressor miRNAs, along with the aberrant activation of the Wnt/β-catenin, Notch, SHH, BMI-1, JAK/STAT, and TGF-β signaling pathways, plays a crucial role in hepatocarcinogenesis. Therefore, these signaling pathways and miRNAs may be critical therapeutic targets.

HCCs arise in the context of chronic hepatitis or cirrhosis, in which ECM remodeling and genetic mutations occur. This process is accompanied by the release of inflammatory cytokines and aberrant activation of signaling pathways, ultimately resulting in oncogenic dedifferentiation of hepatocytes. During the progression from chronic hepatitis to cirrhosis, hepatocyte proliferation is initially active, but sharply declines at a certain point, leading to the activation of HPCs in a process known as the ductular reaction. If an oncogenic hit occurs during this process, HPCs can transform into liver CSCs.

During persistent liver damage, BM cells, such as hematopoietic cells or MSCs, which are mobilized for liver regeneration, can fuse with resident liver parenchymal cells. This fusion, coupled with an oncogenic hit, can transform these cells into liver CSCs. Thus, HCC is likely to exhibit different clinical manifestations depending on its cellular origin. Specifically, if HCC originates from MSCs, it is likely to present a very aggressive phenotype with significant metastasis. Therefore, identifying the cellular origin of liver CSCs is crucial for the development of therapeutic strategies targeting liver CSCs in HCC.

Article information

Conflicts of interest

Jong Ryeol Eun has been an editorial board member of the Journal of Yeungnam Medical Science since 2015. He was not involved in the review process of this manuscript. There are no other conflicts of interest to declare.

Acknowledgment

The author thanks the Yeungnam University College of Medicine research support team (design director: Hyun Yoon Choi) for providing the illustrations used in this study.

Funding

None.

Fig. 1.

Liver homeostasis. Mature hepatocytes primarily contribute to the repair of minor liver injuries. During ongoing liver injury, hepatic progenitor cells (HPCs) are recruited to aid in liver regeneration. In cases of severe liver injury, bone marrow (BM) stem cells mobilize into the circulation and engraft in the liver. Illustrated by the Yeungnam University College of Medicine research support team.

Fig. 2.

Morphology of SK-HEP-1 cells and MSC-L. Both cell types appear similar. SK-HEP-1 cells represent an oncogenic mesenchymal stem cell line with significant metastatic capacity. MSC-L refers to mesenchymal stem cells derived from the liver. MSC-L, mesenchymal stem cells derived from the liver.

Fig. 3.

Cellular origins of liver CSCs. Liver CSCs can arise from the oncogenic dedifferentiation of mature hepatocytes or the oncogenic transformation of HPCs. BM-HSCs can differentiate into hepatocytes or HPCs to support liver repair. Fusion of BM-derived cells with hepatocytes or HPCs, coupled with oncogenic transformation may lead to the formation of liver CSCs. The development of cancer stemness involves interactions between miRNAs, inflammatory cytokines, and various molecular signaling pathways. Representative liver CSC markers include CD133, CD90, EpCAM, CD44, CD13, and CD34. Depending on the cellular origins, primary liver cancers can exhibit diverse pathological and clinical features, as well as variations in marker expression. CSCs, cancer stem cells; BM-HSCs, bone marrow-derived hematopoietic stem cells; CD, cluster of differentiation; EpCAM, epithelial cell adhesion molecule; HPC, hepatic progenitor cell; HCC, hepatocellular carcinoma; miRNA, microRNA; TGF-β, transforming growth factor beta; SHH, Sonic Hedgehog; BMI-1, B-lymphoma Moloney murine leukemia virus insertion region 1; JAK, Janus kinase; STAT, signal transducer and activator of transcription; PI3K, phosphatidylinositol 3-kinase; ECM, extracellular matrix; MSC, mesenchymal stem cell.

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