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Cell therapy for liver diseases: current medicine and future promises Expert Rev. Gastroenterol. Hepatol. Early online, 1–14 (2015)

Meza-Rı´os Alejandra1, Armenda´riz-Borunda Juan1,2 and Sandoval-Rodrı´guez Ana*1 1 Department of Molecular Biology and Genomics, Health Sciences University Center, Institute for Molecular Biology and Gene Therapy, University of Guadalajara, Sierra Mojada 950, Colonia Independencia, Guadalajara, Jalisco 44340, Mexico 2 Innovare, Guadalajara, Jalisco, Mexico *Author for correspondence: Tel.: +52 331 058 5317 Fax: +52 331 058 5318 [email protected]

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Liver diseases are a major health problem worldwide since they usually represent the main causes of death in most countries, causing excessive costs to public health systems. Nowadays, there are no efficient current therapies for most hepatic diseases and liver transplant is infrequent due to the availability of organs, cost and risk of transplant rejection. Therefore, alternative therapies for liver diseases have been developed, including cell-based therapies. Stem cells (SCs) are characterized by their self-renewing capacity, unlimited proliferation and differentiation under certain conditions into tissue- or organ-specific cells with special functions. Cell-based therapies for liver diseases have been successful in experimental models, showing anti-inflammatory, antifibrogenic and regenerative effects. Nowadays, clinical trials using SCs for liver pathologies are increasing in number, and those that have reached publication have achieved favorable effects, encouraging us to think that SCs will have a potential clinical use in a short time. KEYWORDS: cell therapy . clinical trials . fibrosis . liver disease . progenitor cells . stem cells

Cell-based therapies are used to repair malfunctioning tissues and to regenerate tissue by replacing missing cells that no longer have functionality. Likewise, they trigger resident tissue-cells in vivo into regeneration. Nonetheless, current knowledge provides evidence that the therapeutic effect achieved by cell therapy could be a combination of both scenarios: benefits supplied by transplanted cells plus the effects on resident tissue cells by factors and cytokines secreted by transplanted cells. This article tries to update the reader in cell-based strategies to treat liver diseases, including experimental and clinical scenarios. Stem cells (SCs) are defined based on four important characteristics: SCs are unspecialized cells capable of unlimited self-renewing through cell division, even after long periods of inactivity; under certain physiological or experimental conditions, SCs can be induced to become tissue- or organ-specific cells with particular functions [1]; SCs are resistant to apoptosis and SCs are capable of residing in resting mode and trafficking [2]. As described in FIGURE 1 [1,3–6], SC can be classified as totipotent, pluripotent, multipotent, oligopotent or progenitors according to their potential for

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differentiation [4]. Furthermore, there is an additional classification of SCs according to their origin: embryonic SCs and somatic SCs. Embryonic SCs come from preimplantationstage embryos developed from eggs that have been fertilized in vitro [1]. Somatic SCs, also called adult SCs, maintain and repair the tissue in which they are found. They have been identified in brain, bone marrow (BM), peripheral blood, teeth, heart, intestines and liver. The main cell markers and characteristics of cells employed in cell-based therapies are summarized in TABLE 1 [7–18]. Cell therapy for liver cirrhosis

Advanced established fibrosis in the liver, or cirrhosis, is the common end point of chronic liver diseases. It originates from not only numerous pathologies such as alcoholic liver disease and viral or autoimmune hepatitis, but also hepatotoxic drugs and toxins. Antifibrotic strategies in the liver are most effective when they are able to cure the underlying disease. Nonetheless, the liver is the only solid organ in mammals with the capacity to regenerate. When two-thirds of the liver are removed, a complete restoration

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ISSN 1747-4124

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Zygote

Blastocist

Morula

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Somatic stem cells

Germinal stem cells Totipotent stem cells

Pluripotent stem cells

Classification

Multipotent stem cells

Definition

Totipotent stem cells

Are represented by the embryonic stem cells. They derived from a fertilized egg (zygote) and its immediate progeny. Are capable of differentiating into any cell type (embryonic or extra-embryonic tissue) and can generate a complete organism [4,5]

Pluripotent stem cells

Can be obtained after the fourth day of fertilization (blastocyst) and can differentiate into any cell type of any of the three germ cell layers: ectoderm, mesoderm or endoderm [4]

Multipotent stem cells

Multipotent stem cell can give rise broad types of cells but it is limited in its ability to differentiate; their specialization potential is limited to one or more cell lines. Mesenchymal stem cell are present in peripheral circulation of new-born and can obtained from umbilical cord blood. Multipotent stem cells are also found in the tissues of adult mammals. Some examples are HSCs, Adipose tissue-derived stem cells, Dental Pulp Stem Cells, Limbal epithelial stem cells of the cornea and Neural stem cell and another Mesenchymal stem cells [4,5]

Oligopotent stem cells

OSC are able to differentiate into a few cell types, they had a more limited linage capacity than multipotent stem cells. Examples are lymphoid stem cells, myeloid stem cells, etc. [3]

Progenitor stem cells

PSC have the capacity to differentiate into only one or two very related cell types. Examples are Epidermic stem cells that become keratin squamous cells, Precursor cells (blast) and Vascular Stem Cells which have the capacity to become both endothelial or smooth muscle cells [5]

Figure 1. Stem cell classification. Stem cells can be classified into four types according to their differentiation potential; the main characteristics of each kind are listed. HSCs: Hematopoietic stem cells; OSC: Oligopotent stem cell; PSC: Progenitor stem cell.

of the organ takes place within 1–2 weeks due to hepatocyte proliferation repopulating hepatic parenchyma. Even in normal conditions, mature hepatocytes undergo numerous cell cycles to maintain tissue density [19]. Current research in cellbased therapies for liver diseases has shown that most SCs can differentiate into hepatocytes. Nonetheless, cell therapy is not based on the differentiation of all transplanted cells, and SCs are known to have beneficial effects since they secrete cytokines, growth factors and other molecules that have demonstrated anti-inflammatory and antifibrogenic effects. Some cell-based therapies have also proven to be effective in clinical trials as described in the section ‘Clinical trials involving stem cell for hepatic diseases’ [20]. doi: 10.1586/17474124.2015.1016913

Liver therapy with hematopoietic SCs

Hematopoietic and hepatic systems continuously interact in the neonatal development stages. In later life, it has been suggested that hematopoietic stem cells (HSCs) are involved in immunological and pathological functions in the liver [21]. Besides, stromal cell-derived factor 1 (SDF-1) is a chemokine found in hepatic bile duct epithelium, which attracts human and murine progenitor cells as well as HSCs. SDF-1 expression is increased in damaged liver and inflammation [22,23]. HSCs can differentiate in the liver to diverse cell types such as epithelium cells, oval cells, hepatocytes and bile duct epithelial cells [24]. In mice models of liver damage, human umbilical cord blood-SC transplant after mice irradiation, generates albumin-producing hepatocytes,

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Table 1. Main cell markers and characteristics of stem cells. Stem cells

Cell markers

Sources

Lineages that generate

Advantages

Disadvantages

Ref.

ESC

SSEA3+/ SSEA4+/ TRA60+/ TRA-1-81+

Inner cell mass of blastocyst stage embryos

Any kind of cell of any of the three germ cell layers

Proliferate without differentiation

Ethical considerations Rejection response

[7–10]

iPSC

SSEA3+/ SSEA4+/ TRA60+/ TRA-1-81+

Reprogramming of somatic cells

Any kind of cell of any of the three germ cell layers

Autologous therapy

Use of viral vectors for reprogramming. Risk associated with the oncogene c-Myc

HSC

CD34+/ CD38+/ CD133+/ CD117+/ CDCP1+/ c-Kit+

Bone marrow, umbilical cord blood, peripheral blood

All the blood cell lineages

Plasticity is not limited to the tissue they derived from

Procedure for obtaining (bonemarrow aspirate)

[11,12]

MSC

CD105+/ CD73+/ CD44+/ CD71+/ CD271+/ CD90+

Bone-marrow, umbilical cord blood, amniotic liquid, placenta, adipose tissue and others

Fibroblast, adipocytes, cardiomyocyte, astrocytes, hepatocytes, chondocytes and others

Autologous therapy

Procedure for obtaining (bonemarrow aspirate to obtain BMSCs)

[13,14]

EPC

CD34+/ VEGFR2+/ vWF+/ PECAM+/ CD31+

Bone marrow

Endothelial lineage cells

Autologous therapy

Procedure for obtaining (bonemarrow aspirate)

[17]

[15,16,18]

BMSC: Bone marrow stem cell; EPC: Endothelial progenitor cell; ESC: Embryonic stem cell; HSC: Hematopoietic stem cell; iPSC: Induced pluripotent stem cell; MSC: Mesenchymal stem cell.

protein that indicates a complete differentiation to hepatocyte lineage [24]. Furthermore, Lagasse et al. showed that bone marrow stem cells (BM SCs) regenerate damaged livers in mice [25]. In this context, Camargo et al. established in a murine model that single HSC might produce, in addition to hematopoietic cells, fully functional hepatocytes and correct a given metabolic disease. One of the proposed mechanisms for BM-to-liver transdifferentiation is cellular fusion between HSC and host hepatocytes. These BM-derived hepatocytes are primarily derived from hematopoietic cells of myeloid, but not lymphoid, lineage. These authors also suggested that a myeloid cell intermediate is required or that even BM-derived differentiated macrophages are the cell entities that act as hepatic fusion partners (FIGURE 2) [26]. Besides, HSCs can be mobilized from BM with drugs to ameliorate hepatic damage. Mobilizing agents have showed similar fibrosis reduction. However in a study by Tsolaki et al.; in carbon tetrachloride (CCl4)-intoxicated mice, G-CSF treatment provided the highest antifibrotic effect induced by the proliferation of hepatic SCs and decreased hepatic inflammation [27]. Liver therapy with hepatic SCs negative for b2-microglobulin

SCs were detected in the gastrointestinal tract by Charles Le Blond 60 years ago [28]. Current studies have shown the

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presence of intrahepatic b2-microglobulin (b2m)-negative cells in the intrahepatic bile ducts (Canals of Hering) [29]. These BM-derived cells negative for b2m are believed to be undifferentiated hepatocytes or their progenitors in light of the fact that such cells express hepatic explicit genes and show specific liver functions. When these BM-derived hepatic SCs were co-cultured with differentiated hepatocytes (to simulate an environment of hepatic regeneration) and administrated via the portal vein in cirrhotic rats, liver fibrosis stage improved [30]. Avital et al. also monitored several cell markers such as b2m, hematopoietic markers (Thy-1, flt-3, CD34, c-Kit, CD38) and hepatic markers (albumin, a-FP, CK8, CK18 and CK19) in a variety of hepatic samples. All this diversity of samples such as cells derived from hepatocarcinoma, liver from patients with hepatic diseases (cirrhosis, alcoholic hepatitis and fulminant hepatic failure), fetal livers, new-born rat liver and rats subjected to bile duct ligation as well as malignant cell lines such as HepG2 and Hep3B, contained small blastocyst-like cells that lacked b2m expression, with large nuclei and few organelles in their scarce cytoplasm. Newborn and bile duct ligated rats presented a greater number of b2m(–) cells compared with healthy adult rats, suggesting that b2m(–) cells may be hepatocyte progenitors [30].

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HSC A

B

Precursor oval cell

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Hepatocyte

Fusion Oval cell

Host hepatocyte

BM-derived cells Kupffer cells ?

Bile duct epithelial cell

Figure 2. Liver cells generated by bone marrow cell mobilization due to liver damage or HSC transplantation. Some controversy about cells derived from BM-derived hematopoietic stem exists. (A) It has been shown that the following can be obtained: 1) Hepatocytes, 2) Oval cells that can generate hepatocytes or bile duct epithelial cell and 3) progenitor oval cells. On the other hand, (B) cellular fusion between BM-derived cells and host hepatocytes or even myeloid lineage derived cells such as Kupffer cells, for some authors, accounts for the principal mechanism of blood-to-liver regeneration.

Oval cells in mice & liver precursor cells in humans

Progenitor cells exist in human and rodent livers, and were described for the first time by Farber as epithelial cells with basophilic cytoplasm, pale blue nuclei and oval form [31]. These cells have been identified in the portal and periportal hepatic zone in animals with hepatic damage. It is thought they derive from hepatic SCs of the Canals of Hering niche [29]. Oval cell proliferation is induced by hepatic damage [30] and under particular conditions, they can differentiate into hepatocytes. CD133 is a murine oval cell marker and FOXL1 is expressed during oval cell activation [28]. Petersen et al. were the first to prove that BM-derived cells transplanted into g-irradiated rats with hepatic injury migrate to the liver and differentiate into oval cells and hepatocytes [32]. Similar results were reported later in murine models and in human patients [33]. Tsao et al. used an oval cell line (WB-F344) transduced with the b-gal gene to transplant syngeneic rats. Transplanted cells increase hepatic regeneration and when integrated into the liver, changed their morphology, resembling a mature hepatocyte and expressed hepato-specific genes [19]. Isolated oval cells from rats by Yasui et al. with the phenotype: g-glutamyl transpeptidase+/a-fetoprotein+/CK18+/CK19+/albumin–, were transplanted into the livers of analbuminemic rats. These cells differentiated into functional hepatocytes producing albumin, demonstrating in vivo differentiation of oval cells [34]. In addition, other oval lineage cells have shown in vitro capacity to differentiate into adult hepatocytes and biliary ducts cells, depending on culture conditions [19]. In order to improve liver cell engraftment and to reduce cell dispersal to ectopic sites and emboli formation, human fetal hepatic SCs were embedded into a mix of extracellular matrix biomaterials doi: 10.1586/17474124.2015.1016913

(hyaluronans, type III collagen, laminin) that resemble SC liver niches. This strategy demonstrated that transplanted cells to immunocompromised murine remained localized to the liver in a larger bolus, under quiescent conditions and with a more rapid expansion under injured liver conditions [35]. Human adult liver SCs have also demonstrated to protect from death in model of fulminant liver failure induced by D-galactosamine and lipopolysaccharide in SCID mice. Liver apoptosis showed reduction and liver regeneration was enhanced [36]. Liver therapy using human mesenchymal SCs

Mesenchymal stem cells (MSCs) reside in various tissues such as BM, umbilical cord blood, placenta, liver, adipose tissue and others. MSCs can differentiate into multiple cell lineages, and have demonstrated immunomodulation, inflammation suppression and antifibrogenic effects [37]. Preclinical and clinical trials highlight the ability of MSCs to prevent fibrosis through immunosuppression, inhibition of the TGF-b1 pathway, reduction of hypoxia and oxidative stress and restoration of ECM degradation [38]. Human MSCs has the capacity to differentiate into functional hepatocytes according to the surrounding microenvironment, as shown by Lee et al. [39]. Umbilical cord blood or BM-derived mononuclear cells (CD13–/CD34–/CD45–/CD133–/CD29+/ CD44+/CD73+/CD90+/CD105+) from healthy donors were cultured in media enriched with HGF, FGF and Oncostatin M. After 4 weeks, cells developed a cubic morphology, expressed cytochrome P450 and specific hepatocyte genes and produced albumin [39]. On the other hand, Cho et al. evaluated the participation of different SC lineages in hepatic regeneration. BM-derived cells, mononuclear cells, HSCs and MSCs labeled with green fluorescent protein were injected into a mouse tail vein. MSCs showed a greater liver engraftment than any of the other cells tested. Also, MSC co-cultured with cells from injured liver differentiated into hepatocytes suggested that MSC had a greater regenerative potential than the other cell types [40]. Other studies have described that MSC in vitro can differentiate into hepatocytes [20]. Aurich et al. isolated MSCs from human adipose tissue and observed that engraftment and hepatocyte restoration in damaged liver was superior when transplanted cells were in vitro-differentiated hepatocytes rather than undifferentiated MSCs [41]. Kuo et al. proved that MSC differentiates 100% into hepatocytes when culture conditions are optimal. Besides, hepatocyte repopulation in damaged liver was faster and oxidative stress decreased in host mice [42]. It has been demonstrated that MSCs treatment indirectly corrected Expert Rev. Gastroenterol. Hepatol.

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Table 2. Beneficial characteristics of mesenchymal stem cells in liver diseases. Effect

Molecule involved

Action

Type of study

Antiinflammatory

Secrete IL1RN (antagonist receptor)

Suppression of proinflammatory cytokine TNF-a and IL-1a

In vitro/ in vivo

[53]

Reparation

VEGF-a, EGF, keratinocytes growth factor, SDF-1, IGF-1, Angiopoietin-1

Recruitment of macrophage, keratinocytes and endothelial cells to injured tissues

In vitro/ in vivo

[52]

Secrete HGF, EGF

Stimulates proliferation of hepatocytes and apoptosis of hepatic stellate cells

In vitro

[37,48]

Secrete IL-10 and TNF-a

Promotes inhibition of proliferation of hepatic stellate cells and decreased collagen synthesis

In vitro

[48]

High expression of MMP-9 and IL-10

Extracellular matrix degradation

In vitro

[48]

MSCs engrafted in liver

Cells can differentiate into hepatocytes

In vivo

[51]

Limitation of oxidative stress

Increase gene expression of Nrf2, GSH and SOD

Reduce ROS production in the injured liver

In vivo

[45,54]

Angiogenesis

Paracrine mechanism, expression of VEGF and FGF

BM-MSCs were transformed in vitro into vascular endothelial-like cells and promote angiogenesis

In vitro, in vivo

[49,55]

Tissue regeneration

Ref.

BM-MSC: Bone marrow-derived mesenchymal stem cell; GSH: Glutathione; HGF: Hepatocyte growth factor; IL-1RN: IL-1 receptor antagonist; MMP-9: Matrix metalloproteinase 9; MSCs: Mesenchymal stem cells; Nrf2: Nuclear factor erythroid 2-related factor; ROS: Reactive oxygen species; SDF-1: Stromal cell-derived factor 1; SOD: Superoxide dismutase.

liver dysfunction. The role of cytokines and growth factors produced by MSCs that are homing to other organs induced distant hepatic protection without engraftment of MSC in the liver [43]. Also, MSCs ability to relieve oxidative stress has already been shown in several works. MSCs increase expression and concentration of enzymes responsible for scavenging free radicals [44]. MSC treatment correlates with an increase in nuclear factor erythroid 2-related factor and superoxide dismutase, which might reduce reactive oxygen species accumulation, thus decreasing oxidative stress [45]. The mechanisms of MSCs to restore liver include a secretome of multiple growth factors, like VGF, HGF, GM-CSF, bGFG, IGF-1 and cytokines such as IL-6, IL-7, IL-8, IL-11, IL-10, TNF-a [46,47]. MSC-derived IL-10 and TNF-a inhibit the proliferation of hepatic stellate cells, and MSC-derived HGF was shown to induce the apoptosis of hepatic stellate cells in a co-culture system [48]. Also, BM-derived MSCs transplantation reduces apoptosis of liver cells in animals with acute liver failure. Yuan et al. administrated autologous 1.4  107 cells/kg through the tail vein. Expression of caspase-I and IL-18 that regulate hepatocyte apoptosis was lower in MSC-treated group [49]. In a study by Meier et al., alginate-poly(ethylene glycol) hydrogel was used to encapsulate human MSCs. This gel is permissive for soluble factors (e.g., O2, glucose, cytokines) but not for immune cells or antibodies, and thus protects MSCs from immune rejection. Intraperitoneal transplanted microencapsulated MSCs decreased liver fibrosis, inflammation and transaminases, in mouse models of chronic liver injury. These effects can be attributed solely to factors secreted by MSCs like IGFBP-1 and -2, IL-6, monocyte chemotactic protein-1 and informahealthcare.com

IL-1Ra [50]. These results suggest that MSC therapy can be a useful tool in the treatment of hepatic illness. TABLE 2 shows the beneficial characteristics of MSC in liver diseases [37,45,48,49,51–55]. Some of the concerns that have to be addressed when MSCs are used to treat liver diseases include the profibrogenic potential that MSCs may display in chronically injured liver by differentiating into profibrogenic myofibroblast-like cells as reported by Li et al. [56]. Besides, some studies suggest that MSCs might promote tumor growth via transformation, suppression of the antitumor immune response and direct trophic action on tumor cells [57,58]. Furthermore, MSCs secrete angiogenic growth factors like VEGF, FGF that could promote cancer growth and PDGF and SDF-1 that could increase invasion of tumor cells or metastasis [59]. However, long-term studies must be done to have an insight into the molecular mechanisms controlling the hepatic engraftment and tumor potential of MSCs, as well as, the occurrence of differentiation of MSCs to myofibroblast. Liver therapy with adult hepatocytes

Hepatocytes have a high cell division rate, although evidence obtained from injured livers points out the fact that hepatocytes may generate hepatic epithelial cells. Studies using mature hepatocyte transplantation in knockout mice for the fumarylacetoacetate hydrolase gene (FAH–/–), which is a model of hepatic damage by massive apoptosis, showed that transplanted hepatocytes repopulate 90% of the liver and expand preferentially over FAH–/– hepatocytes [20]. Also, progress has been made in the source of hepatocytes to achieve the quality required for cell transplantation, trying to obtain them from either live or dead human donors, or from hepatocyte doi: 10.1586/17474124.2015.1016913

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expansion in cell cultures. Hepatocyte transplantation has recently shown remarkable results in treating acute hepatic failure. For instance, 20% of patients transplanted with allogenic hepatocytes using portal vein or intrasplenic administration improved hepatic function, thus eliminating the need of a liver transplant. Furthermore, 30% of the patients needing liver transplant use hepatocyte transplantation as support therapy while waiting for a donor [20]. On the other hand, administration route and the precise quantity of hepatocytes to transplant are still challenges to overcome since only 30% of the hepatocytes administrated via portal vein survive. Thus, it seems that direct liver administration could be suitable, notwithstanding the existence of portal hypertension. However, studies have revealed that ectopic transplantation (renal capsule, subcutaneous via and peritoneal cavity administration) is also useful and less invasive than hepatic administration [20,60]. Hepatocyte preservation is another obstacle to overcome. Due to cryopreservation, hepatocytes decrease their viability by 30% and lose adhesion molecules that play a key role in extravasation and coupling of transplanted hepatocytes with hepatic receptors [20]. Also, Kobayashi et al. have evaluated intrasplenic and intraperitoneal administration in rats with hepatic damage. Hepatocyte intrasplenic transplantation was superior in generating body weight and improving albumin serum level [61]. Liver therapy using embryonic SCs

Embryonic stem cells (ESCs) can differentiate into cells with morphological, biological and functional hepatic characteristics as shown by Yamamoto et al. in CCl4-chronic intoxicated rodents where hepatic damage improved and organ function was restored after transplanting ESC-derived hepatocytes [2,62]. ESCs have been transplanted into adult mice liver, showing integration in the tissue and morphological and functional characteristics of hepatocytes. Kuai et al. examined the potential of ESC to generate hepatocytes when cultured with retinoic acid, HGF and NGF-b. Characterization showed morphology, biochemical markers and gene expression usually found in hepatocytes [63]. Teratani et al. refers that ESC can differentiate into functional hepatocytes without embryonic body formation, even if they are recently isolated, which facilitates their use for cirrhosis treatment. DNA-chip analysis showed that these cells express HGF, FGF1 and FGF4. Then, by using these genes, ESCs were differentiated in vitro into hepatocytes expressing specific hepatic genes and adult hepatocyte biochemical markers. Transplantation of these hepatocytes in cirrhotic mice improves hepatic function and increases their survival rate [64]. Hamazaki et al. reported the generation of embryoid bodies using ESC cell lines R1, W9.5 and SEK1 null. Embryoid bodies were cultured in collagen-I-coated culture plates to induce hepatocyte differentiation in a media enriched with FGF, HGF, Oncostatin M, dexamethasone, insulin, transferrin and selenous acid. On day 18 of culture, mature hepatocytes expressed specific hepatocyte genes and produced albumin and urea [65]. These hepatocytes were transplanted into mice concomitantly with 2-acetylaminofluorene administration to doi: 10.1586/17474124.2015.1016913

prevent proliferation of endogenous hepatocytes. Four weeks later, albumin-producer cells were identified in the liver [65,66]. In the study by Yamada et al., indocyanine green was used as a marker of in vitro differentiated hepatocytes derived from ESC. Indocyanine-positive cells were isolated from the culture and characterized. Cells presented hepatocyte characteristics and when transplanted in mice, albumin-producer cells were detected [66]. However, ESCs are not suitable for clinical applications due to the risk of teratoma formation and other ethical issues. Liver treatment using endothelial progenitor cells

Taniguchi et al. mentioned intrasplenic transplanted human and murine endothelial progenitor cells (EPC) in mice with hepatic damage induced by CCl4. Early on after transplantation, EPCs were localized in necrotic areas around the central vein. Later on, EPCs formed tubular structures and some engrafted in hepatic sinusoids. Survival rate in treated mice increased from 28.6 to 85.7% and transplanted EPCs produced HGF, TGF-a and VEGF, growth factors known as hepatic regeneration promoters. Several studies have proven that growth factors presence, exogenous or endogenous, after EPC transplant improve impaired liver regeneration. Thus, EPCs could represent a new therapeutic strategy to promote liver regeneration [67]. Another study by Nakamura et al. using EPCs transplanted in CCl4-cirrhosis model in rats, indicates that EPC engrafted in portal regions and fibrotic septums resulted in reduced fibrosis and diminished mRNA levels of collagen, fibronectin, TGF-b and a-SMA, while increasing matrix metalloproteinase (MMP)-2, MMP-9 and MMP-13 gene expression at the same time. Also, HGF, TGF-a, EGF and VEGF levels increased and hepatic stellate cells diminished [68]. In conclusion, therapeutic strategy using EPCs for cirrhosis treatment seems promising in the clinical scenario as described in the section ‘Safety of cell-based therapies for liver’. Cell therapy for livers using induced pluripotent stem cells

The potential of murine induced pluripotent stem cells (iPSCs) to differentiate in hepatocyte-like cells is not completely elucidated [69]. However, Li et al. successfully differentiated iPSCs to functional hepatocytes in 2009, employing a sequential addition of dimethyl sulfoxide and sodium butyrate to the medium. Hepatocytes showed CK7, CK8, CK18, CK19, a-fetoprotein and albumin, but differentiation achieved with iPSCs was lower when compared with ESC differentiation efficacy into hepatocytes [70]. Song et al. generated iPSC cell lines 3U1 and 3U2 from human fibroblast transduced with Oct-4, Sox2, Klf4 and Utfl [71,72]. Four stages were achieved to induce hepatocyte differentiation: endoderm induction using activin A, hepatic specificity adding FGF4 and BMP2, hepatoblast expansion using HGF and KGF and hepatic maturation with dexamethasone and Oncostatin M [71]. Advances in the iPSCs field include the transplantation of human iPSCs in vitro differentiated to hepatocytes, which failed to proliferate after transplantation which is needed to establish Expert Rev. Gastroenterol. Hepatol.

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Cell therapy for liver diseases

and sustain a therapeutically beneficial cell mass in patients [73]. Then, some scientific groups induced human fibroblasts to a multipotent progenitor cell state (iMPC), from which hepatocytes (iMPC-Heps) not compromised by growth arrest could be differentiated. iMPC-Heps expressed alpha-fetoprotein (AFP), ALB and alpha-1 antitrypsin (AAT), were polygonal, occasionally binucleate and expressed HNF4a and cytokeratin 18. Hepatocyte functions such as glycogen storage, lipid uptake and storage and urea production were present. iMPC-Heps did not form tumors because of avoidance of a pluripotent state [74]. Clinical trials involving SCs for hepatic diseases

SC clinical trials for hepatic diseases have increased over the past few years according to official government sources. TABLE 3 lists the clinical trials using SCs registered in the ClinicalTrials. gov web site (January 2015) for liver diseases. The search was made using the words: stem cells, liver and EPCs. Improvement in survival along with a decrease in fibrosis and increase in serum albumin in cirrhotic animals treated with BM-derived SCs suggest that this approach might become a potentially effective treatment for humans with liver failure [75]. SC transplantation induces hepatic regeneration

Patients subjected to peripheral blood SC transplantation showed liver regeneration and 0.7% of the new hepatocytes contained the Y chromosome indicating they derived from transplanted cells [76]. Human HSCs also seem to have potential for hepatic reconstruction. Clinical trials employing CD34+ autologous cells or monocyte transplantation have improved hepatic biochemical markers and hepatic regeneration [20,77]. In 2005, am Esch et al. published a study of patients with hepatic neoplasia treated with partial hepatectomy and cell therapy as co-adjuvant treatment (using BMSCs CD133+) via the portal vein. When compared with control subjects (no cell therapy), computerized tomography showed that patients administered BMSCs had 2.5-fold more tissular growth, suggesting an increase in hepatic regeneration [78]. In this context, Terai et al. transplanted BM-derived mononuclear cells systemically to nine patients with liver cirrhosis and followed them for 24 weeks, observing increased serum albumin and total proteins, improved Child-Pugh score as well as decreased ascities [75]. Also, 13 patients with generalized hepatic neoplasm were treated by Fu¨rst et al., with portal vein embolization (PVE) for the purpose of stimulating hepatic regeneration before performing extended hepatectomy. Patients were then divided in two groups: seven patients treated only with PVE and six patients with PVE plus administration of autologous BMSC CD133+ cells via the portal vein. A significant increase in hepatic regeneration was noted in this latter group when compared with the first group [79]. Levicar et al. followed 5 patients during 12–18 months with chronic hepatic disease who were transplanted via portal vein/ hepatic artery with autologous peripheral blood CD34+ (1  106 – 2  108) cells mobilized from BM with G-CSF. No post-transplant adverse events were noticed; four patients informahealthcare.com

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showed initial improvement in serum bilirubin, holding those levels for 6 months, serum AFP and CAT scan analyses proved the absence of local lesions, indicating that the use of SCs is safe in the short and long term with the absence of tumor formation [80]. Lorenzini et al. published their results on mobilization of BMSC CD34+ and CD133+ cells to peripheral blood induced by G-CSF in 18 patients with hepatic cirrhosis. They found 15 g/kg/day of G-CSF as the optimal dose. None of the patients showed significant modification in hepatic function [81]. Eighty patients with liver decompensation were transplanted with 1.13 – 2.45  106 CD34+ HSC cells/kg via hepatic artery (n = 44) or portal vein (n = 36) by Huang et al. Knodell score, ALT and total bilirubin serum levels decreased and albumin levels increased in both groups at 6 and 12 months after transplantation. The 1-year survival rate was 100% [82]. Safety of cell-based therapies for liver

BM-derived MSCs improve liver function in patients with liver cirrhosis as evidenced by Phase I clinical trials, along with demonstrating safety and efficacy of these therapies. Kharaziha et al. published results on the administration of autologous MSC induce to hepatic differentiation prior to injection to eight cirrhotic patients and followed them for 24 weeks. Administration of 30–50 million MSCs via either the portal vein or peripheral administration resulted in an improvement of hepatic function as verified by the end-stage liver disease model, which dropped significantly. Serum creatinine and others fibrosis markers also decreased. Treatment was well tolerated and no adverse events were noticed [83]. Later on, Couto et al. tried to evaluate safety, kinetics and feasibility of autologous BM mononuclear cells and performed transplants of 2 – 1.5  108 cells into eight cirrhotic patients through hepatic artery and followed-up on them for a year. One patient displayed a dissection of the hepatic artery, and another had the Tako-Tsubo syndrome as early complications. One year later, another patient underwent immunologic skin alteration and one more patient suffered hepatocarcinoma. On the other hand, bilirubin levels dropped in 1 week and albumin increased significantly 1 month posttreatment [84]. By 2011, Nikeghbalian et al. published the results of transplanting autologous BM mononuclear CD133+ cells into six patients with decompensated cirrhosis, and followed-up on them for 24 months. No short- or long-term adverse events were noticed. Furthermore, no significant alterations in hepatic function parameters, hepatic enzymes, creatinine and cell volume after the transplant were observed, which suggests safety and the possibility of implementing these types of strategies [85]. Finally, in 2012 Mohamadnejad et al. transplanted BMSC into patients with decompensated liver fibrosis cirrhotic patients to evaluate potential hepatocellular carcinoma development. Thirty-two patients enrolled between 2005 and 2011 were systemically infused with BMSC either by the peripheral veins, portal vein or hepatic artery. Forty-seven percent of the patients received MSCs, 28% BM-derived mononuclear cell, 16% BM CD133+ cells and 3% BM CD34+ cells. The goal was to doi: 10.1586/17474124.2015.1016913

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Table 3. Clinical trials using stem cells for liver diseases. Author

Start year

Phase

Characteristics

Status

Nagy Habib et al.

2005

I

Each patient with liver insufficiency will receive autologous bone marrow stem cells via the hepatic artery or portal vein under image guided scanning

Completed

Guilherme FM Rezende et al.

2005

I/II

Autologous bone marrow derived mononuclear cells in liver cirrhosis of any origin, cell were delivered in the common hepatic artery by celiac trunk catheterism

Terminated

Richard Burt et al.

2006

I

Allogenic hematopoietic stem cell transplantation in patients with primary biliary cirrhosis

Withdrawn

Mohammad Reza Zali et al.

2006

I/II

Autograft MSCs from end stage liver disease differentiated into progenitor of hepatocytes for the salvage treatment of patients with end-stage liver disease, inyected in portal vein under ultrasound guide

Completed

Reza Malekzadeh et al.

2007

II

Autologous bone marrow MSCs were administered via periopheral vein in patients with descompensated cirrhosis

Active, not recruiting

Bruno Gridelli et al.

2007

I/II

Human fetal liver cell transplantation for treatment of chronic liver failure

Recruiting

Zhu k shun et al.

2008

II

Autologous bone marrow MSCs transplantation via hepatic artery in patients with liver cirrhosis

Unknown

Hamid Gorabi et al.

2008

I/II

Autologous transplantation of bone marrow derived CD133+ stem cells and mononuclear cell transplantation in patients with descompensate cirrhosis form autoimmune hepatitis

Completed

Guilherme FM Rezende et al.

2009

I

Autologous bone marrow mononuclear cells infusion in peripheral vein in liver cirrhosis due to hepatitis C virus

Unknown

Lin B liang et al.

2009

II

Autologous bone marrow MSCs transplantation in patients with early or middle stage liver cirrhosis

Active, not recruiting

Shuichi Kaneko et al.

2009

I

Liver regeneration therapy using autologous adipose tissue derived stromal cells

Terminated

Roberto M Lemoli et al.

2009

I

Intrahepatic reinfusion of highly purified CD133+ stem cells in patients with end-stage liver disease

Recruiting

Ho-Seong Han et al.

2009

N/A

Liver regeneration with autologous peripheral stem cells transplantation in patients that need extensive hepatectomy

Recruiting

Fu-Sheng Wang et al.

2009

I/II

Study of umbilical cord-derived MSCs treatment in patients with liver cirrhosis

Recruiting

Yufang Shi et al.

2009

I/II

Umbilical cord MSCs transfusion in patients with severe liver cirrhosis

Recruiting

Soon Koo Baik et al.

2009

II

Therapy with bone marrow derived autologous MSCs for hepatic failure caused by alcoholic liver cirrhosis

Recruiting

Hamid Gourabi et al.

2010

I/II

Comparison of therapeutic outcome of transplantation of CD133+ and mononuclear cells bone marrow-derived stem cells in cirrhotic patients

Recruiting

Chengwei Chen et al.

2010

I/II

Human umbilical cord MSCs transplantation for patients with descompensated liver cirrhosis

Completed

Hamid Gourabi et al.

2010

I

Combined pioglitazone plus autologous bone marrow MSCs transplantation in patients with compensated cirrhosis

Completed

Qiyu zhang et al.

2010

II/III

Autologous bone marrow stem cells infusion via hepatic artery in open abdominal portal hypertension surgery for the treatment of liver cirrhosis

Unknown

Lin B Liang et al.

2010

II

Allogenic bone marrow stem cells transplantation in patients with cirrhosis resulting from chronic hepatitis B

Unknown

ADSC: Adipose tissue-derived stem cell; BM-MSC: Bone marrow-derived mesenchymal stem cell; CD133: Prominin 1; HBV: Hepatitis B virus; MSC: Mesenchymal stem cells.

doi: 10.1586/17474124.2015.1016913

Expert Rev. Gastroenterol. Hepatol.

Cell therapy for liver diseases

Review

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Table 3. Clinical trials using stem cells for liver diseases (cont.). Author

Start year

Phase

Characteristics

Status

Zibin Tian et al.

2010

I/II

Umbilical cord MSCs infusion via hepatic artery in cirrhosis patients

Not yet recruiting

Charlie Xiang et al.

2010

I/II

Human menstrual blood-derived MSCs transplantation in patients with liver cirrhosis

Enrolling by invitation

Murat Kantarcioglu et al.

2011

N/A

In vitro expanded bone marrow derived allogenic MSCs transplantation via portal vein or hepatic artery in patients with Wilson cirrhosis

Recruiting

Yihua An et al.

2011

II/III

Umbilical cord MSCs transplantation in liver cirrhosis patients

Recruiting

Fu-sheng Wang et al.

2011

I/II

Umbilical cord derived MSCs treatment for patients with primary biliary cirrhosis

Recruiting

Ayman Abdo et al.

2011

I/II

Intra-hepatic artery infusion of bone marrow-derived stem cells for the treatment of advanced liver cirrhosis

Not yet recruiting

Shinichi Oka et al.

2011

N/A

Autologous bone marrow cell infusion therapy in HIV-infected patients with advanced liver cirrhosis

Enrolling by invitation

Fengchun Zhang et al.

2011

I

Therapy with allogenic MSCs from bone marrow for patients with refractory primary biliary cirrhosis

Unknown

Daiming Fan et al.

2012

I/II

Human autologous bone marrow stem cells for treatment of HBV-related liver cirrhosis

Recruiting

Yihua An et al.

2012

I/II

Difference between umbilical cord MSCs transplantation and classical therapy in liver cirrhosis patients

Unknown

Xuetao Pei et al.

2012

I/II

Umbilical MSCs transplantation for liver cirrhosis

Not yet recruiting

BV Tantry et al.

2012

II

Intra-arterial (hepatic) ex vivo cultured adult allogenic MSCs in patients with alcoholic liver cirrhosis

Recruiting

Quiroga Jorge et al.

2012

I/II

Intra-arterial (hepatic artery) administration of autologous bone marrowderived endothelial progenitor cells in patients with advanced liver cirrhosis

Active, not recruiting

Shuichi Kaneko et al.

2012

N/A

Intrahepatic arterial administration of autologous adipose tissue derived stromal cell in patients with liver cirrhosis

Enrroling by invitation

Soon Koo Baik et al.

2012

ll

Randomized, exploratory clinical trial to evaluate the safety and effectiveness of autologous BM-MSCs in patients with alcoholic liver cirrhosis using a hepatic artery catheterization through the right aorta femoralis

Recruiting participants

Zhi-Liang Gao

2012

I/II

Safety and efficacy of human UC-MSCs transplantation combined with plasma exchange for patients with liver failure

Recruiting participants

Anant E Bagul et al.

2013

I/II

Study to evaluate the safety and efficacy of autologous BM-MSCs and UC-MSCs administrated sistemically in liver cirrhosis

Not yet open for recruitment

N/A

2015

I

Study using autologous human ADSC trought intrahepatic administration for liver cirrhosis

Not yet open for recruitment

ADSC: Adipose tissue-derived stem cell; BM-MSC: Bone marrow-derived mesenchymal stem cell; CD133: Prominin 1; HBV: Hepatitis B virus; MSC: Mesenchymal stem cells.

follow them for 20.5 months measuring AFP levels and using ultrasound. Only one of the patients developed carcinoma 3 months after the BM-derived mononuclear cell transplant. The authors reached the conclusion that infusion of autologous BMSC apparently does not increase the risk of developing hepatocellular carcinoma and significantly improved quality of life [86]. An open-label, paired, controlled study by Wang and collaborators examined the safety and efficacy of umbilical cord-derived MSCs in patients with decompensated liver informahealthcare.com

cirrhosis due to chronic hepatitis B infection. Thirty patients received umbilical cord-derived MSC (UC-MSC) transfusion and 15 patients received saline and followed-up for 40 weeks. UC-MSC therapy demonstrated no significant side effects or complications; and in patients treated with UC-MSC a significant reduction in the volume of ascites, increase in serum HGF – an antifibrotic growth factor – and albumin levels, decrease in total serum bilirubin levels and in the sodium Model for End-stage Liver Disease score were observed [87]. doi: 10.1586/17474124.2015.1016913

Review

Alejandra, Juan & Ana

Table 4. Sources of stem cells for human liver applications. Cell type

Safety

Effectiveness

BM-derived CD133 cells (autologous)

Proved

Patients exhibited improvement (proliferation)

[78,79,85,93]

Mobilized peripheral blood HSC (autologous)

Proved

Improvement in clinical course of the disease

[77]

Autologous BM-derived CD34+ cells

Proved

Improvement in clinical parameters

Autologous BM-MSCs

Proved

Improvement in liver function, quality of life and MELD score

Autologous BM mononuclear cells

Proved

Improved liver function

UC-MSCs

Proved

Improvement of clinical symptoms and liver function

[87,94]

Human fetal liver cells

Proving

Not available information (study group of Gridelli B)

[96]

Autologous ADSCs

Proving

No publication provided (study group of Kaneko S)

[88]

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+

Ref.

[77,82,90,91,93] [83,95]

[92]

ADSC: Adipose tissue-derived stem cell; BM: Bone marrow; CD133: Prominin 1; CD34: Hematopoietic progenitor cell antigen CD34; HSC: Hematopoietic stem cells; MELD: Model for end-stage liver disease; MSC: Mesenchymal stem cells; UC: Umbilical cord.

Based on these clinical trials, it appears that human MSCs may exert an antifibrotic effect on liver cirrhosis. Still running is the study by Quiroga-Vila et al. at the University of Navarra Clinic. This Phase I–II clinical trial for liver cirrhosis by different etiologies using autologous BM-derived EPCs transplanted by hepatic artery, will evaluate besides safety, hepatic function efficacy and portal hypertension. There will be no report of results until publication [88]. Together, these data emphasize that Phase I clinical trials using cell-based therapies in end-stage liver disease patients have demonstrated that SCs can be feasible and safely systemically infused. All patients have tolerated the treatment and any sign of hypersensitivity reaction, fever and other possible side effects due to SC transplantation were noted. Ultrasound revealed that no SC-derived liver tumor and serum levels of AFP changed. However, disadvantages for cell therapy in liver diseases refers to the use of autologous sources of SCs that in decompensated patients could be an issue to stabilize them in order to carry on the surgical procedure. Until this moment, heterologous or xenogenic cell sources does not seem viable for clinical scenarios. Also, it has been preferred to infuse cells through portal vein or hepatic artery [89], but this is not always possible due to patient’s condition. Nevertheless, other peripheral vessels seem adequate like administration via. Furthermore, long-term studies and large number of patients are needed to evaluate clinical application of human SCs in the treatment of liver disease. TABLE 4 summarizes the SC sources tested for human clinical applications [75,77–79,82,83,85,87,90–96]. Conclusions

The discovery of SCs in adult tissues, cell plasticity and the isolation of embryonic SCs have expanded cell therapy applications for liver diseases [97]. The combination of cell therapy with genetic reprogramming generates numerous therapeutic options, thus permitting treatment of illnesses that till today

doi: 10.1586/17474124.2015.1016913

have not been able to be cured, including hepatic diseases. Experiments with animals using genetically engineered ESCs have proven to be a valid hopeful strategy for treating genetic disorders [28]; however, the future of cell therapy are clinical trials. At this time, most studies, regardless of the disease, have been made in animal models to evaluate safety and efficiency of specific cell therapies. In the near future, it will be necessary to test these cell-based therapies in clinical scenarios, particularly for currently untreatable pathologies such as liver cirrhosis. Cell therapy represents a great possibility for the treatment of many diseases. Thanks to SC research, there are cell-type options for treating cirrhosis, such as EPCs or MSCs. These cells have had outstanding results in experimental and clinical trials, clearing the way for cell therapy in humans with liver diseases and other pathologies. Expert commentary

Liver diseases such as cirrhosis still represent a medical challenge due to the lack of effective therapy. Liver transplantation is still considered the sole therapy and is not available for all patients, especially those infected with HCV or hepatitis B virus. Current standard treatment for liver fibrosis, then, focuses on prophylactic management or clearance of the etiologic agent (alcohol, HCV, hepatitis B virus, etc.). Therefore, research efforts should underscore the development of therapies to heal fibrotic tissue. In recent years, cell-based therapies have been used to treat this pathology. Studies have shown that MSCs can differentiate in vitro and in vivo into hepatocyte-like cells. A regenerative activity in hepatocytes and a decrease in fibrotic tissue have been reported in animal models after SC administration. Patients subject to cell therapy showed improved liver function when compared with controls in available clinic trials. Cellbased therapies for liver diseases using MSCs present advantages such as immunomodulation activity, xenographic or allogenic transplant and a variety of sources for cell isolation as well as the need of relative low doses to achieve therapeutic effects.

Expert Rev. Gastroenterol. Hepatol.

Cell therapy for liver diseases

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Five-year view

The encouraging results obtained in clinical trials using cellbased therapies will lead to an increase in the number of studies in patients, alone or as an adjuvant therapy along with a major diversity in the type of diseases to be treated. Accelerated progress in the cell therapy field together with tissue engineering and biomaterial development is inevitable. These strategies, combined with and accompanied by gene therapy improvement, will continue benefiting scientific knowledge and

Review

patients’ health. The use of SCs represents the future of medicine. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

Key issues .

Different types of cell-base therapies have been used in liver disease, including hematopoietic stem cells, mesenchymal stem cells from different sources, adult hepatocytes, embryonic stem cells, endothelial progenitor cells and induced pluripotent stem cells.

.

Stem cells can differentiate in vitro and in vivo into hepatocyte-like cells.

.

Stem cells have shown anti-inflammatory, antifibrogenic and regenerative effects in vitro and in vivo.

.

Cell-based therapies have reduced fibrotic tissue in animal models and patients with liver cirrhosis.

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Cell therapy for liver diseases: current medicine and future promises.

Liver diseases are a major health problem worldwide since they usually represent the main causes of death in most countries, causing excessive costs t...
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