Human Liver Mesenchymal Stem Cells: History
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Mesenchymal stem cells (MSCs) can be isolated from the majority of human tissues and easily maintained in culture. Cells derived from different sources have closely resemblant, but not identical phenotypes, gene expression patterns, and differentiation profiles. Unique features of human liver MSCs include expression of the hepatocyte-specific genes and predisposition to differentiate into the hepatocytes. This makes liver MSCs an attractive starting material for the manufacturing of human hepatocytes, which are in short supply in basic research, drug testing, and cell therapy. 

  • mesenchymal stem cells (MSCs)
  • cells

1. Mesenchymal Stem/Stromal Cell Markers

The morphology and phenotype of liver MSCs largely coincides with those of MSCs isolated from other tissue sources. These cells express mesenchymal markers such as CD29, CD44, CD73, CD90, HLA-Class I, etc. [1]. However, the expression levels of these markers vary in reports from different authors. For example, Najimi et al. [2] found that 99% of liver MSCs were positive for CD90, 92% of the cells were positive for CD73, 88% were positive for CD29, 92% for CD44, and 76% for HLA-Class I. Researchers showed by flow cytometry that only about 30% of liver MSCs isolated from the liver of patients with cirrhosis and fibrosis expressed CD90 and CD44 [3]. Moreover, a gene expression microarray confirmed that the expression level of CD90 (THY1) was low, while the expression level of CD44 was very high. Beltrami et al. [4] demonstrated that most liver MSCs (more than 90% of cells in the population), as well as MSCs isolated from the heart and bone marrow, expressed CD13, CD49b, and CD90 at a high level (high MFI values according to flow cytometry), while the main part of cells in the population (80–90%) expressed low levels of CD73, CD44, HLA-ABC, CD29, CD105, and CD49a (low MFI values according to flow cytometry). Flow cytometry analysis of liver MSCs isolated from the mononuclear fraction of the perfusate collected during liver transplantation and maintained in culture showed a profile of surface markers typical for mesenchymal stem cells: CD90+ (59% ± 18%), CD105+ (55% ± 14%), and CD166+ (44% ± 16%) between passages 4 and 9 also [5].
The Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy proposed minimal criteria to define human MSCs [6]. Among others, three markers indicating that cells in a population are mesenchymal stromal cells, namely CD44, CD90, and CD105, were suggested. While the expression of the first two markers (CD44 and CD90) by liver MSCs has been consistently demonstrated (though to varying degrees), data regarding the expression of CD105 differ greatly among the authors. Indeed, Najimi et al. in their earlier work [2] showed the absence of CD105 expression on the surface of liver MSCs. This result is consistent with flow cytometry data by Beltrami et al. [4], although, in the later work, the up-regulation of the ENG (endoglin) gene transcription at the mRNA level was demonstrated. Researchers also showed that liver MSCs do not express CD105 on their surface, although its expression at the transcriptome level is enhanced. Herrera et al. [7] demonstrated by flow cytometry that no more than 20% of liver MSCs were positively stained with anti-CD105 antibodies, and the expression of this marker varied greatly from clone to clone. Kellner et al. [8] isolated mesenchymal stromal cells from bone marrow, heart, adipose tissue, and liver and showed that 100% of the cells in these four populations expressed CD105. Comprehensive screening of surface markers of liver MSCs also showed that more than 90% of the cells express endoglin (CD105) [9], which contradicts the data reported by the same team several years earlier [2].
Liver MSCs also express intracellular mesenchymal markers such as vimentin and α-SMA (α-smooth muscle actin) [2], fibronectin [4][10], as well as the marker of resident stem/progenitor cells nestin [11].

2. Hematopoietic/Endothelial Cell Markers

As with MSCs isolated from other sources, liver MSCs do not express markers of hematopoietic and endothelial cells, such as CD11b, CD14, CD19, CD31, CD34, CD45, CD79β, CD117, CD133, CD144, and HLA-DR [2][3][9][12][13]. The lack of expression of CD34, CD45, and CD117 on the surface of liver MSCs suggests that these cells are not so-called hepatic progenitor cells (the human counterpart to rodent oval cells) which are bipotent resident hepatic cells that can differentiate into hepatocytes and cholangiocytes [11][14].

3. Pluripotency Markers

Regarding the expression of pluripotent stem cell markers, the results obtained by different authors are very contradictory. A large-scale screening of the surface markers of liver MSCs showed that these cells do not express such pluripotent stem cell markers as SSEA-3 and -4, Tra1-60, and Tra1-81 [9]. The only putative pluripotent cell marker found to be highly expressed was CD13 (membrane alanyl aminopeptidase). However, though once CD13 was assumed to be a pluripotency marker [15], later it was detected on many cell types, not just on adult stem/progenitor cells [16], but also on various types of mature fully differentiated cells, such as endothelial cells [17], dendritic cells [18], and others. Moreover, CD13 has been listed as a major marker of mesenchymal stem/stromal cells, but not embryonic stem cells or induced pluripotent stem cells [19][20]. It was demonstrated high CD13 expression on the surface of liver MSCs, along with MSCs derived from bone marrow and umbilical cord. The function of CD13 on the surface of MSCs is to regulate the activation of FAK (focal adhesion kinase) and, therefore, to improve cell adhesion to the extracellular matrix and enhance cell migration; CD13 is also an important angiogenic regulator [21][22]. On the other hand, Herrera et al. [7] revealed that liver MSCs express embryonic stem cell markers NANOG, Oct-4, SOX2, and SSEA4. Beltrami et al. [4] also showed that adult human liver contains mesenchymal stem cells similar to bone marrow and cardiac MSCs, which show a low level of tissue commitment, express specific pluripotency markers on the mRNA level, such as Oct-4, REX1, and NANOG, and exhibit telomerase activity. Our gene expression microarray data show that liver MSCs isolated from liver biopsies of patients with cirrhosis and fibrosis do not express NANOG, REX-1 (ZFP42), and SOX2. The expression of Oct3/4 (POU5F1) varied in different patients, and was in general low.

4. Integrins and Adhesion Molecules

Since MSCs of different origin possess high migration ability and can undergo homing in various tissues and organs [23][24], expression of adhesion molecules on the cell surface represents an important phenotypic characteristic of these cells. To reach the parenchyma of the organ after systemic administration, MSCs should behave like leukocytes do during inflammation. Specifically, the cells first need to slow down inside the vascular endothelium by means of selectin ligands, followed by firm adhesion to endothelial proteins, such as ICAM and VCAM-1, through integrin heterodimers, VLA-1 (consists of alpha chain α1 (CD49a) and beta chain β1 (CD29)) and VLA-4 (consists of alpha chain α4 (CD49d) and beta chain β1 (CD29)), respectively. Like most MSCs, liver MSCs do not express CD162 (PSGL-1), the high-affinity receptor for P-selectin, and also do not express sialyl-Lewis X (CD15s or SSEA-1), which is required for E-selectin binding [9]. Thus, as with other mesenchymal cells, liver MSCs probably employ an alternative mechanism of adhesion and rolling along the vascular endothelium. In particular, it is supposed that liver MSCs can use the hyaluronic acid receptor CD44 highly expressed on the cell surface [25]. A similar adhesion/rolling mechanism has been shown for neutrophils—their adhesion to the sinusoidal endothelium in the event of an inflammatory process in the liver depends on the direct binding of CD44 on the surface of neutrophils to hyaluronan expressed by endothelial cells [26]. As with MSCs obtained from other sources, liver MSCs manifest a high expression of the integrin subunit beta 1 (or CD29) [2][7][13][27]; however, reports on the expression of integrin α-chains, which are part of the VLA-1 and VLA-4 heterodimers responsible for the interaction with ICAM and VCAM-1 on the vascular endothelium, vary. Dollet et al. [9] did not detect VLA-1 expression by liver MSCs at either the protein or the mRNA level; VLA-4 was expressed on the cell surface at a low level, although constitutive high expression was manifested at the mRNA level. Our gene expression microarray data show that liver MSCs obtained from the liver of patients with fibrosis and cirrhosis express medium levels of VLA-1 (CD49a; ITGA1) and low levels of VLA-4 (CD49d; ITGA4). Beltrami et al. [4] showed by flow cytometry that approx. 70–80% of liver MSCs express CD49a at a low level. Weak positivity for CD49a in MSCs isolated from the liver was also shown [9]. Most studies showed that the expression levels of integrins on liver MSCs responsible for interaction with the extracellular matrix are rather high. Specifically, liver MSCs express VLA-2 (CD49b; integrin subunit alpha 2; ITGA2) that binds collagen, VLA-3 (CD49c; integrin subunit alpha 3; ITGA3) that binds laminin, and VLA-5 (CD49e; integrin subunit alpha 5; ITGA5) that binds fibronectin [4][9][11]. According to our gene expression microarray results (see Table 1), in addition to the above-mentioned integrins, liver MSCs also express integrin subunit alpha 11 (ITGA11) which interacts with collagen, integrin alpha-V beta 3 (CD51; ITGAV)—interacts with extracellular matrix proteins (e.g., vitronectin, fibronectin, fibrinogen, and thrombospondin), integrin subunit alpha 7 (ITGA7) which is a laminin receptor, and integrin subunit alpha E (CD103; ITGAE) which interacts with E-cadherin and several other integrins [28][29].
In the tissues, cell-cell adhesion is mediated through the interaction of various cell adhesion molecules (CAMs), including cadherins, integrins, selectins, and immunoglobulin-like CAMs. In addition to adhesion, these molecules also regulate a wide range of cellular processes, such as proliferation, differentiation, apoptosis, and self-renewal of pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells [30][31]. Cadherins, transmembrane glycoproteins that mediate Ca2+-dependent homophilic interactions between the cells, represent one of the classes of CAMs. Different types of cadherins are expressed by different types of cells. For example, E-cadherin (or cadherin-1) is mainly expressed on epithelial cells, and N-cadherin (or cadherin-2) is highly expressed on neurons and mesenchymal cells. Liver MSCs also express several cadherins. In particular, at the transcriptome level, MSCs isolated from the liver of patients with fibrosis and cirrhosis express cadherins-2, -4, -6, -11, -22, and -24 (see Table 1).
Cadherins are the major proteins involved in the formation of adherens junctions. Adherens junctions formed by N-cadherin (or cadherin-2) are important for regulating wound healing [32], cell attachment and migration [33], embryogenesis [34][35], metastasis [36], and also play a key role in cell differentiation and formation of specialized tissues, such as fibrous connective tissues [37][38]. Cadherin-2 is also required for long-term engraftment of hematopoietic stem cells and the restoration of hematopoiesis after bone marrow transplantation [39]. Another important cadherin expressed, among others, in liver MSCs is cadherin-11. It was first identified in mouse osteoblasts, and later its expression was shown on many types of human cells, including mesenchymal stem/stromal cells. The functions of cadherin-11 are diverse. Similar to cadherin-2, this molecule is involved in the formation of adherens junctions and mediates metastasis of tumor cells [40] and synthesis of collagen and elastin, thereby regulating the mechanical properties and contractile function of tissues [41], as well as cell adhesion and proliferation [42]. Both cadherin-11 and cadherin-2 mediate the transformation of fibroblasts into myofibroblasts during the granulation phase of the wound healing process [43]. Cadherins play an important role in the differentiation of MSCs. Accordingly, both cadherin-2 and, most importantly, cadherin-11 are necessary for osteogenesis [44]; cadherin-11 regulates the differentiation of MSCs into smooth muscle cells [45]. Importantly, both cadherins (-2 and -11) are involved in the epithelial-to-mesenchymal transition [46]. During the epithelial-to-mesenchymal transition taking place during fibrosis and carcinogenesis E-cadherin expression is reduced, while cadherin-2 and -11 expression is up-regulated [47].

5. Cytokeratins and Hepatic Markers

In most studies, it was shown that liver MSCs, in addition to classical mesenchymal markers, also express several hepatic markers, indicating their hepatic commitment. A comparative RT-PCR analysis of primary human hepatocytes, human hepatic stellate cells, HepG2 cell line, and human liver MSCs showed that liver MSCs express mRNA of specific hepatic markers such as albumin and α-fetoprotein [2]. At the protein level, liver MSCs expressed albumin, whereas α-fetoprotein expression was low. At the mRNA level, these cells also expressed other liver-specific markers, such as glucose 6-phopshatase, α-antitrypsin, glutamine synthase, γ-glutamyl transpeptidase, MRP2 transporter, hepatocyte nuclear factor-4, CYP3A4, and CYP1B1, but not CYP2B6, tyrosine aminotransferase (TAT), or tryptophan 2,3-dioxygenase (TDO). The authors believe that the expression of such liver-specific markers is the ultimate proof the hepatic origin of these MSCs [2]. Herrera et al. [7] also showed that liver MSCs were positive for albumin and α-fetoprotein. However, there are differences in the expression of cytokeratins in liver MSCs obtained by different research groups. Najimi et al. [2] showed lack of expression of both cytokeratins 8 and 18, and cytokeratins 7 and 19. At the same time, Herrera et al. [7][48] found that in the absence of expression of cytokeratin 19, liver MSCs express cytokeratins 8 and 18 at a significant level. Other authors observed alternative signs of hepatic commitment of MSCs obtained from human liver: (1) high expression of cytokeratin 19 and hepatocyte growth factor (HGF), low expression of cytokeratin 18, c-Met, and Lgr5, and also lack of albumin expression at the mRNA level [5]; (2) expression of CD26 and cytokeratin 18 by a small subpopulation of cells in the general population of liver MSCs [49].
Our gene expression microarray data show that MSCs isolated from the liver of patients with fibrosis or cirrhosis express several liver-specific genes: ribonuclease RNase A family 4 (RNASE4), CYP1A2, γ-glutamyl transpeptidase (GGT1), and glutamine synthase (GLUL)—at a low level; CYP1B1—at a relatively high level; a very high level of expression was observed only for the NNMT gene encoding the nicotinamide N-methyltransferase. Albumin, α-phetoprotein (AFP), and hepatocyte nuclear factor-4 (HNF4A) were not expressed in our liver MSCs both at the protein level [50] and at the mRNA level. At the same time, expression of the c-Met hepatocyte growth factor receptor was detected by researchers in 60% of cells in the liver MSC population by flow cytometry [50] as well as at the transcriptome level.
Although the aforementioned markers are considered relatively liver-specific, they can also be expressed in non-liver cells and tissues. For example, proteomic analysis showed the expression of CYP1B1 in bone marrow MSCs [51]. Also, human umbilical cord MSCs constitutively express a whole spectrum of liver markers, such as albumin, α-fetoprotein, cytokeratin-19, connexin-32, dipeptidyl peptidase IV, glucose-6-phosphatase, and claudin [52][53]. The NNMT gene is strongly expressed in the human liver [54], and its low level expression is also detected in adipose tissue (subcutaneous and visceral) [55], arteries, muscles, and in various types of mesenchymal cells, in particular, in fibroblasts. Moreover, NNMT is expressed at a very low level in the central nervous system and in hematopoietic cells [56]. Several studies have also demonstrated aberrant expression of NNMT in several tumors, namely renal cell carcinoma [57], colorectal cancer [58], and gastric cancer [59].
Thus, while MSCs isolated from the human liver by different research groups do differ in individual phenotypic features, they have several common characteristics. In particular, these cells simultaneously express both mesenchymal and hepatic markers, which may indicate their partial hepatic commitment.
At the same time, these cells are different from bipotent hepatic progenitor cells which are human counterparts of rodent oval cells due to the lack of expression of specific markers such as CD34, CD45, and CD117. Also, these liver MSCs are not classic liver mesenchymal cells, i.e., hepatic stellate cells (HSCs). Despite the common phenotypic and morphological characteristics [10], liver MSCs differ from HSCs in the lack of expression of neuronal markers, such as glial fibrillary acidic protein (GFAP), neural cell adhesion molecule (NCAM), neurotrophin-3 (NT-3), CD271 (nerve growth factor receptor or NGFR), etc., which are expressed in HSCs at a high level [60], but are not expressed in liver MSCs [10][61]. Moreover, in several studies, it has been shown that HSCs express CD133 and HLA-DR [62][63], whereas liver MSCs do not express these surface markers. The differences in the expression of markers in liver MSCs obtained by different research groups that were shown in this section can be associated with many factors, including the initial donor material (healthy liver, diseased liver, cadaveric liver, etc.) or details of the method of cell isolation and cultivation.
In general, liver MSCs have much in common with MSCs isolated from other sources. However, careful consideration of data derived by comprehensive screening of cell surface markers expressed by liver MSCs [9] and bone marrow MSCs [64] reveal different levels of the expression of some of them. Liver MSCs exhibit higher expression of such adhesion and cell motility markers as CD49c, CD49e, CD49b, CD63, and CD9, as well as CD46 and CD55 receptors participating in the complement regulation. On the other hand, liver MSCs do not express CD91, CD97, CD130, and epidermal growth factor receptor (EGFR), while bone marrow MSCs do, though at a low level. Considering the level of the uniqueness of liver MSCs, it is necessary to remember that in culture, as with other MSCs, liver MSCs most probably form heterogenous populations, consisting of cells with varying phenotypes. Phenotypic and functional cell variability is typical for the majority of MSC cultures, though its degree may be different [65][66]. For example, single-cell microarray analysis demonstrated high level of variability of the properties of cultured human bone marrow MSCs [67], while umbilical cord [68] or adipose tissue [69] MSCs showed limited variability. This dissimilarity is probably associated with differences in the cell cycle trajectories. The variability of liver MSCs is still difficult to evaluate, because, to our knowledge, no single-cell microarray data are available for them.

This entry is adapted from the peer-reviewed paper 10.3390/cells8101127


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