Review
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 21, 2015; 21(43): 12334-12350
Published online Nov 21, 2015. doi: 10.3748/wjg.v21.i43.12334
Stem cell-based regenerative opportunities for the liver: State of the art and beyond
Eleftheria Tsolaki, Evangelia Yannaki
Eleftheria Tsolaki, Evangelia Yannaki, Gene and Cell Therapy Center, Hematology Department-BMT Unit, George Papanicolaou Hospital, 57010 Thessaloniki, Greece
Evangelia Yannaki, Department of Medicine, University of Washington, Seattle, WA 98195-5852, United States
Author contributions: Tsolaki E searched the literature, analyzed the data, and provided the first draft of the paper; Yannaki E designed and conceived the review; both authors critically discussed the content and approved the final version of the manuscript.
Conflict-of-interest statement: The authors declare that they do not have anything to disclose regarding financial conflict of interest with respect to this manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Evangelia Yannaki, MD, Gene and Cell Therapy Center, Hematology Department-BMT Unit, George Papanicolaou Hospital, 57010 Thessaloniki, Greece. eyannaki@u.washington.edu
Telephone: +30-231-3307518 Fax: +30-231-3307521
Received: June 3, 2015
Peer-review started: June 3, 2015
First decision: August 26, 2015
Revised: September 16, 2015
Accepted: October 17, 2015
Article in press: October 20, 2015
Published online: November 21, 2015

Abstract

The existing mismatch between the great demand for liver transplants and the number of available donor organs highlights the urgent need for alternative therapeutic strategies in patients with acute or chronic liver failure. The rapidly growing knowledge on stem cell biology and the intrinsic repair processes of the liver has opened new avenues for using stem cells as a cell therapy platform in regenerative medicine for hepatic diseases. An impressive number of cell types have been investigated as sources of liver regeneration: adult and fetal liver hepatocytes, intrahepatic stem cell populations, annex stem cells, adult bone marrow-derived hematopoietic stem cells, endothelial progenitor cells, mesenchymal stromal cells, embryonic stem cells, and induced pluripotent stem cells. All these highly different cell types, used either as cell suspensions or, in combination with biomaterials as implantable liver tissue constructs, have generated great promise for liver regeneration. However, fundamental questions still need to be addressed and critical hurdles to be overcome before liver cell therapy emerges. In this review, we summarize the state-of-the-art in the field of stem cell-based therapies for the liver along with existing challenges and future perspectives towards a successful liver cell therapy that will ultimately deliver its demanding goals.

Key Words: Stem cells, Liver regeneration, Liver cirrhosis, Acute liver injury, Stem cell based therapy

Core tip: Liver transplantation is the only effective treatment for end-stage liver diseases, but its application is limited mainly due to donor shortage. In order to fulfil the unmet medical needs in the field, alternative, cell-based therapies for the treatment of end-stage hepatic diseases are under investigation. This review aims to summarize the state of the art on stem cell-based approaches towards liver regeneration as well as to critically discuss and highlight new perspectives and challenges.



INTRODUCTION

The liver possesses a remarkable capacity to regenerate in response to injury; however, in severe cases its regenerative capacity prove insufficient and hepatic injury may progress to end-stage disease and subsequent liver failure. Orthotopic liver transplantation is currently the only effective treatment for patients with end-stage liver diseases, including acute liver failure and hepatic cirrhosis. Nevertheless, donor shortage and waiting list mortality, postoperative morbidity and mortality, high costs and long-term side effects severely limit its application[1,2]. Hepatocyte transplantation has been suggested as an alternative approach to liver transplantation because mature hepatocytes have been traditionally recognized as the major contributors to liver repair and are functionally the most robust cell type for liver cell therapy[3,4]. Indeed, many preclinical and clinical studies have been conducted using this approach to cure metabolic and end-stage liver diseases[5]. However, the widespread application of hepatocyte transplantation is limited by organ unavailability, the negative impact of cell culture on hepatocyte viability, function and engraftment[5,6], as well as hepatocyte susceptibility to cryopreservation damage inducing cell rupture, necrosis, and apoptosis after thawing[7,8]. Therefore, alternative therapies are needed to supplement organ transplantation and bridge the gap between the need for liver transplantation and the lack of a timely available cadaveric graft.

ADULT LIVER STEM/PROGENITOR CELLS

When hepatocyte proliferation is impaired, deficient, or overwhelmed by severe liver injury, bipotent intrahepatic stem cell (SC) populations, known as resident liver progenitor cells (LPC) in humans or oval cells (OCs) in rodents, emerge and become activated, expand, and actively contribute to the regenerative process by giving rise to hepatocytes and biliary epithelial cells[9-12].

The term “oval” cell is used to describe small, rounded proliferating cells with a large nuclear to cytoplasmic ratio which reside in the terminal branches of the intrahepatic biliary tree, the Canals of Hering, considered along with the space of Disse as the putative hepatic SC niches. OC/LPC coexpress biliary and hepatocytic markers and also hematopoietic progenitor cell antigens[13,14].

Regarding the mechanism controlling OC fate in response to liver injury both in humans and in murine models, it has been proposed that during LPC/OC-mediated liver regeneration, an “inductive” niche is formed around OCs, constituting the ductular inflammatory reaction. This niche is populated by recruited macrophages and myofibroblasts and requires new synthesis or remodeling of extracellular matrix to facilitate appropriate OC/LPC expansion and ultimately biliary and hepatocyte regeneration[15]. The role of Wnt and Notch signaling in hepatic cell fate has been recently recognized through the proliferation and differentiation of human LPCs into hepatocytes or cholangiocytes respectively, providing potential targets for future targeted-therapies[15,16] for the liver.

The precise identification of endogenous liver SCs and of the mechanisms that govern their proliferation and differentiation into mature hepatocytes in the case of severe parenchymal extinction could facilitate their in vitro and in vivo maturation to hepatocytes and their application in clinical practice. This process was histologically identified by the description of regenerative nodules, the so called “buds” composed of small clusters of hepatocytes admixed with ductules[17]. These “buds” were suggested to be composed of new hepatocytes derived from SCs located in the small bile ducts and the canals of Hering, thus appearing to be the structures that contain SC-derived hepatocytes[18]. The progressive evolution of buds from stem/progenitor cells to integrated mature liver parenchyma was described in a recent study using various anatomic and immunohistochemical markers including epithelial cell adhesion molecule (EpCAM), K19, CD34, glutamine synthetase, and Ki-67[19].

Interestingly, hepatic stellate cells (HSTCs), considered as liver-resident mesenchymal cells[20], have recently been shown to represent a source of liver progenitor cells. Indeed, an isolated population of retinoid-storing hepatic stellate cells were able to contribute to liver regeneration through differentiation. HSTCs gave rise to parenchymal and bile duct cells and ameliorated the glucuronidation defect in GUNN rats, thus providing functional hepatocytes[21].

FETAL LIVER STEM CELLS

Fetal liver SCs appear during embryogenesis, after the establishment of the hepatic endoderm and when the liver bud is growing. Hepatoblasts, resident cells in the developing liver bud, express the signature marker α-fetoprotein and are considered bipotential, being able to give rise to both mature hepatocytes and bile duct epithelial cells (cholangiocytes)[22]. Many experimental studies have focused on the regenerative capacity of fetal hepatic progenitor cells (HPCs) as, in contrast to adult hepatocytes, fetal liver SCs can be readily isolated while they are highly proliferative, less immunogenic, and more resistant to cryopreservation[22-25], and as such, could be of clinical benefit in the treatment of liver diseases.

Indeed, their capacity to repopulate the liver upon transplantation has been demonstrated in animal models[26-28] and clinical trials (Table 1)[29,30]. In a clinical study, 25 patients with liver cirrhosis of different etiologies, were infused with human fetal liver-derived SCs. The procedure proved safe and efficient, offering a potentially supportive modality to organ transplantation in the management of liver diseases[29]. In another study, immune-sorted, human fetal biliary tree cells were safely administered to two patients with advanced liver cirrhosis who were monitored through a 12-mo follow-up period. Immunosuppressants were not required, and the patients did not experience any adverse event or immunological complications. Both patients showed biochemical and clinical improvement within the first 6 mo and one maintained the benefits for 12 mo[30].

Table 1 Clinical trials using stem cells for the treatment of liver diseases.
Ref.Cell SourceNo. of patients/administration routeDisease causeNo. of cells infusedFollow-up periodOutcomes
29Fetal liver-SCs (EpCAM+)25: hepatic arteryEnd-stage liver cirrhosis80 × 1066 moImproved liver function and MELD score
30Fetal liver-SCs (EpCAM+)2: hepatic arteryAdvanced cirrhosis42 × 106 and 60 × 10612 moBiochemical and clinical improvement
133BM-MSCs4: peripheral veinDecompensated liver cirrhosis31.73 × 10612 moWell tolerated and safe procedure; improved liver function
134MSCs from iliac crest8: peripheral or portal veinEnd-stage liver disease30 × 106-50 × 10624 wkNo adverse effects; improved MELD and liver function
135BM-MSCs stimulated to hepatic lineage20: control 10: intrasplenic 10: intrahepaticpost-HCV end-stage liver disease2 × 107 in a total of 2 × 108 MNCs6 moImproved ascites, MELD and CP score; no difference between intrahepatic and intrasplenic groups
136BM-MSCs105: control 53: treated/hepatic arterypost-HBV liver failure3.4 × 108-3.8 × 108192 wkNo serious side effects or complications; improved ALB, TBIL, PT and MELD score
137Differentiated BM-MSCs vs undifferentiated10: control 15: treated/intravenouspost-HCV liver cirrhosis1 × 106/kg body weight6 moImproved MELD score, BIL, ALB and PC
138BM-MSCs20: intrasplenicpost-HCV liver cirrhosis10 × 1066 moDecreased TBIL, AST, ALT, PT; improved ALB, PC, PT, INR
139BM-MSCs11: hepatic arteryAlcoholic cirrhosis5 × 107 injected twice12 moNo significant side effects; histological improvement; improved CP score
140UC-MSC15: control 30: treated/intravenouspost-HBV decompensated liver cirrhosis0.5 × 106/kg body weight1 yrNo significant side effects; improved liver function and MELD score; reduced ascites
141UC-MSC19: control 24: treated/intravenouspost-HBV acute-on-chronic liver failure0.5 × 106/kg body weight72 wkNo significant side effects; improved liver function and MELD score; increased survival
142UC-MSC7: peripheral veinPrimary biliary cirrhosis0.5 × 106/kg48 wkNo obvious side-effects; decreased serum ALP and GGT
143Autologous MSCs12: control 15: treated/peripheral veinDecompensated cirrhosis195 × 10312 moNo beneficial effect
166BM-MNCs9: peripheral veinLiver cirrhosis5.20 +/- 0.63 × 109 MNCs24 wkNo major adverse effects; improved ALB, CP scores
175G-CSF mobilization40: controls 8: treated/subcutaneousSevere liver cirrhosisG-CSF: 5 μg/kg every 12 h for 3 d8 moNo adverse events; improved MELD score
176Autologous G-CSF mobilized CD34+ cells2: peripheral veinEnd-stage liver diseaseG-CSF :10 μg/kg per day: 4-5 d/CD34+ cells: 2.31 × 106/kg and 4 × 106/kg30 to 34 moSafe and well tolerated procedure; improved CP and MELD scores
177Autologous G-CSF-mobilized CD34+ cells3: portal vein 2: hepatic arteryLiver insufficiencyCD34+ cells: 1 × 106 to 2 × 10860 dNo complications or specific side effects; improved ALB
178G-CSF mobilization11: control 13: treated/subcutaneousAlcoholic cirrhosisG-CSF: 10 μg/kg per day 2 times daily for 5 d12 wkEffective CD34+ cells mobilization; increased HGF; induced HPC proliferation
179G-CSF mobilization24: control 23: treated/subcutaneousAcute-on-chronic liver failureG-CSF: 5 μg/kg for 12 doses60 dIncreased survival; reduced CTP, MELD and SOFA scores
180G-CSF mobilization23: control 23: treated/subcutaneousSevere alcoholic hepatitisG-CSF: 5 μg/kg every 12 h for 5 d3 moSafe and effective HSCs mobilization; improved liver function and survival
181Experimental PA-PE, combined with G-CSF1: subcutaneousAcute-on-chronic liver failure10 μg/kg per day for 5 d2 moRapid and long lasting clinical improvement; HSCs mobilization and a ductular reaction
182G-CSF mobilization24: subcutaneousAcute on chronic liver failureG-CSF: 5 and 15 μg/kg per day for 6 dSafety and feasibility of G-CSF mobilization; no clinical/biochemical improvement
183G-CSF mobilization18: subcutaneousLiver cirrhosisincreasing doses of G-CSF daily for 7 d3 wkNo severe adverse events; no liver function significant modification
184Autologous G-CSF mobilized CD34+ cells1: portal veinDrug-induced hepatitisG-CSF: 15 μg/kg/for 5 d CD34+ cells: 5 × 10630 dImproved liver function; wide areas of regeneration in liver biopsy
185Autologous G-CSF-mobilized CD34+ SCs2: hepatic artery 3: portal veinChronic liver diseaseG-CSF: 526 μg/d: 5 d, CD34+ cells: 1 × 106-2 × 1086-18 moNo side effects; improved BIL and ALB
186Autologous G-CSF-mobilized cultured CD34+ SCs9: hepatic arteryAlcoholic liver cirrhosis520 μg/d: 5 d/mean TNCC:229.7 × 10612 wkNo side effects; improved BIL, ALT, AST, CP score and ascites
187PBMCs from G-CSF mobilized PB20: control 20: treatedDecompensated liver cirrhosis5-10 μg/kg per day for 4 d. PBMC: 107-108/kg6 moNo major adverse effects; improved liver function

The ability of fetal liver SCs to expand clonogenically in vitro, their pluripotency, and the evidence that they yield mature liver cells, encourage their clinical utility for transplantation and generation of bioartificial livers. However, ethical issues and the possibility of teratoma/teratocarcinoma formation in the recipients, justify their reserved use mainly in preclinical or pilot studies.

EXTRAHEPATIC STEM/PROGENITOR CELLS

Apart from endogenous liver SCs, several populations of exogenous stem/progenitor cells have shown potential to contribute to the liver healing process and are discussed below.

Embryonic stem cells

Human embryonic SCs (ESCs) are pluripotent cells, derived from the inner cell mass of blastocyst stage embryos, having the ability to self-renew indefinitely while maintaining the potential to give rise to all cell types in the human body when provided with the appropriate differentiation signals[31]. Because of this plasticity and the unlimited capacity for self-renewal, ESC regenerative therapies have been proposed for tissue replacement after injury or disease.

ESCs are able to differentiate efficiently into hepatocyte-like cells in vitro, producing cells which possess some of the properties of mature hepatocytes[32-34]. ESC-derived hepatocyte-like cells contribute to the recovery of injured liver tissue in mice, not only by cell replacement but also by delivering trophic factors that support endogenous liver regeneration[32,35]. In vitro ESC-derived hepatocytes, bearing the typical mature hepatocyte morphology and expressing hepatocyte-specific genes, colonized liver tissue upon transplantation and rescued liver-injured mice from death[36].

ESCs provide a valuable tool for studying the molecular basis of hepatocyte differentiation and form the basis for cell therapies. However, despite remarkable progress and the development of sophisticated differentiation protocols mimicking the normal embryonic development, ESC-derived “hepatocyte-like” cells usually fail to fully function as “true” hepatocytes. In addition, the risk for immunological rejection of the transplanted cells as well as ethical and legal concerns, hamper their use as cell replacement therapy[37,38].

Induced pluripotent stem cells

Induced pluripotent SCs (iPSCs) are embryonic-like SCs produced in vitro via reprogramming of somatic cells through the transient, forced expression, of key transcription factors such as OCT4 (O), SOX2 (S), KLF4 (K), and c-MYC (M) (so called OSKM cocktail) or O, S, NANOG (N) and LIN28 (L) (so called OSNL), traditionally by using, permanently integrated, retroviral vectors[39,40].

As factor expression is not required beyond the end of the reprogramming process and the semi-random integration of retroviral vectors has been associated with insertional mutagenesis[41], several investigators have explored techniques for iPSC generation using more clinically relevant methodologies of reprogramming, such as excisable vector systems[42], non-integrating DNA vectors[43], DNA-free methods[44,45], and small molecules[46].

iPSCs possess unique characteristics of pluripotency that render them extraordinary tools for cell and gene therapies, such as (1) unlimited self-renewal capacity in vitro, a feature that allows their indefinite maintenance in culture as cell lines; and (2) potential for directed differentiation to any cell type. In addition to their potential for regeneration, iPSCs provide a novel platform for in vitro disease-modeling[47] and drug-screening[48].

It has been shown that iPSCs can be efficiently induced to differentiate into hepatocyte-like cells (HLCs)[49-52], whereas transplantation of iPSC-derived HLCs reversed lethal fulminant hepatic failure, enhanced liver regeneration, and improved the performance status of NOD-SCID[52], fumarylacetoacetate hydrolase-deficient[53], or CCl4-injured[54] mice. In an acute hepatic failure model, iPSCs were reprogrammed from human dental pulp-derived fibroblasts into iPSCs (DP-iPSCs) capable of differentiating into HLCs (iPSC-HLCs). An injectable carboxymethyl-hexanoyl chitosan hydrogel (CHC) with sustained hepatocyte growth factor (HGF) release (HGF-CHC) was developed to improve iPSC-HLC engraftment. Intrahepatic delivery of HGF-CHC-iPSC-HLCs rescued liver function and the recipients through high anti-oxidant and anti-apoptotic activity that shrinked hepatic necrotic areas[55]. Engineered donor grafts derived from iPSCs, including re-cellularized biomatrix[56], and liver buds produced from iPSCs[57] may someday provide “autologous” organs for liver transplantation, thus highlighting their enormous potential for treating liver failure.

In addition to acquired liver diseases, HLC differentiation from iPSCs isolated from patient somatic tissues could provide patient-specific hepatocyte sources for treatment of inherited liver diseases, combining ex vivo gene correction and cell transplantation[58].

iPSCs have renewed hopes for regenerative medicine because they could deliver personalized therapies, and their production from somatic, patient-specific cells, without the use of embryonic tissues or oocytes, may overcome ethical concerns and the risk of rejection. Despite these hopes for iPSCs, the issues that still need to be addressed before moving this exciting new technology from proof of concept to the clinic are: (1) the optimal reprograming method, using clinically relevant methodologies; (2) the avoidance of teratoma formation and tumorigenicity; (3) the development of novel and rapid differentiation protocols for the generation of mature cell types from iPSCs by cost-efficient manufacturing procedures; and (4) the long-term safety, tolerability, and efficacy of the iPSC-based treatments.

Annex stem cells

Annex SCs derived from umbilical cord, umbilical cord blood, placenta, and amniotic fluid (AF) are an easily accessible source of pluripotent SCs capable of giving rise to hematopoietic, epithelial, endothelial, and neural cells both in vitro and in vivo[59], thus constituting an attractive target for cell-based therapy. Human umbilical cord blood SCs, when infused into NOD-SCID mice with induced liver damage, can differentiate into HLCs in the absence of fusion events[60], boost regeneration and reduce mortality[61]. In vitro expanded and differentiated umbilical cord SCs exhibited hepatocyte-like morphology, expressed upregulated levels of markers of hepatic lineage, and were capable of in vivo liver repopulation and expression of hepatic markers upon transplantation into mice[62,63].

Placenta-derived multipotent cells have also been shown to differentiate into multilineage cells including HLCs. These cells not only expressed characteristics of human liver cells, but also demonstrated several functions of typical hepatocytes[64,65].

EXTRAHEPATIC ADULT BONE MARROW STEM CELLS

As already mentioned, liver regeneration is mainly an endogenous process, driven by mature hepatocytes[3,4] and resident intrahepatic SC populations[9,10]. Bone marrow (BM) is the largest reservoir of pluripotent SCs in adults and traditionally considered as giving rise to only hematopoietic cell lineages. This concept was challenged by reports demonstrating that BM-derived SCs (hematopoietic, mesenchymal and endothelial cells) can generate a variety of adult cell types that express non-hematopoietic cell markers and contribute to the liver healing process after tissue injury[66-72].

Endothelial progenitor cells

Endothelial progenitor cells (EPCs) may contribute to the repair and regeneration of the damaged liver mainly by promoting the secretion of factors supportive of the host’s endogenous repair mechanisms. EPC transplantation halted established liver fibrosis in rats by suppressing activated hepatic stellate cells, increasing matrix metalloproteinase activity, and regulating hepatocyte proliferation[73]. BM-derived liver sinusoidal EPCs recruited to the injured rat liver, promoted hepatocyte proliferation and contributed to organ recovery[74]. Antifibrogenic and regenerative effects of engrafted EPCs, in transplanted rats, were mediated by increased expression of endogenous and exogenous growth factors, such as HGF, transforming growth factor (TGF)-α, epidermal growth factor, and vascular endothelial growth factor which triggered the generation of a new vascular network and promoted hepatocyte proliferation, ultimately resulting in liver regeneration[75-77].

Mesenchymal stromal cells

Bone marrow stroma contains a subset of mesodermal progenitor cells, named mesenchymal stromal cells (MSCs) which are fibroblast-like, plastic-adherent, multipotent cells rapidly expanding in vitro under standard culture conditions. MSCs are most frequently isolated from bone marrow (BM-MSCs)[78], but can also be obtained from a variety of tissues including umbilical cord blood (UC-MSCs)[79], trabecular bone[80], synovial membrane[81], adipose tissue (AT-MSCs)[82], placenta[83], AF-MSCs[84], fetal lung (FL-MSCs), and blood[85]. MSCs have the capacity to differentiate into tissues of mesodermal origin (bone, cartilage, fat) but also to give rise to cells from unrelated embryonic layers such as nerve cells and hepatocytes. In addition, they have low immunogenicity and possess immunomodulatory properties which allow them to evade the host immune surveillance[86]. Because of these features, MSCs have been proposed as a cell therapy source with increased therapeutic potential for a wide range of diseases[87-91], including acute and chronic liver diseases. Studies conducted both in rodents[92-94] and humans[95-100] have shown that MSCs derived from BM, AT, AF, dental pulp, UC, and FL under specific culture conditions, are able to transdifferentiate in vitro into HLCs which express genes and fulfill some metabolic functions typical of hepatocytes.

BM-MSCs, the first and the best characterized source reported to contain MSCs, AT-MSCs, an abundant and easily accessible source of MSCs, and UC-MSCs, obtainable by the least invasive method, have been tested comparatively in terms of morphology, enrichment in MSCs following isolation and expansion, colony formation, multilineage differentiation capacity, and immune phenotype. While there were no distinct morphological or immune phenotypic features among the three sources of MSCs, AT provided a 100% success rate in MSC isolation and the highest colony frequency, while UC-derived MSCs had the highest rates of proliferation in culture, suggesting UC and AT as attractive alternatives to BM for obtaining MSCs[101].

MSCs and acute liver failure

The therapeutic effect of MSCs in models of acute liver failure has been elucidated in various studies. MSCs derived from BM, placenta, and AT showed potential for differentiation into hepatocytes in vitro and in vivo, ameliorated liver damage, reduced mortality, and exerted immunoregulation by suppressing intrahepatic natural killer T cells and inhibiting inflammatory signaling, in animal models of induced acute liver failure[102-106].

When AT-, UC blood-, and human BM-derived MSCs, either as undifferentiated MSCs or as MSC-derived HLCs (DHLCs), were compared for their capacity to reverse acute fulminant hepatitis in an animal model, it was demonstrated that undifferentiated MSCs and DHLCs from AT and BM sources equivalently regenerated the damaged liver, suggesting that hematopoietic pre-differentiation of MSCs may not be necessary for liver repopulation. In addition, because of the abundance and accessibility of AT-MSCs as well as their consistent hepatocyte expression profile upon differentiation, AT may be an excellent SC source for liver-regenerative procedures[107].

The conversion of MSCs into HLCs has been repeatedly demonstrated[108,109], and effort has been made to characterize hBMSC-derived hepatocytes in vitro and in vivo. Towards this end, tissue inhibitor of metalloproteinases 4 and follistatin expression have been associated with transdifferentiation events and suggested as two potential novel biomarkers for the characterization of hBMSC-derived hepatocytes[110]. However, accumulating evidence supports the notion that the therapeutic effects of MSCs in acute liver injury are mediated to a large degree via paracrine mechanisms releasing trophic and immunomodulatory factors, rather than true transdifferentiating events. This is reinforced from experiments with MSC-conditioned medium where soluble factors contained in MSC-conditioned medium (interleukin-6, VEGF, HGF, and insulin-like growth factor binding proteins) seem responsible for reduced hepatocyte apoptosis[111], downregulation of proinflammatory cytokines, increased hepatocyte proliferation[112] and decreased mononuclear cell infiltration in the liver[113]. Indeed, secreted molecules in culture supernatant from both hFL-MSCs and hepatocyte progenitor-like cells derived from hFL-MSCs had a therapeutic effect in a CCl4-induced acute liver injury model[114]. In addittion, transplantation of different origin MSCs rescued acute liver failure and repopulated mouse liver through paracrine effects that reduced the inflammatory response, inhibited apoptosis in the liver, and stimulated endogenous regeneration mechanisms[115,116].

MSC-based therapy for liver cirrhosis

The beneficial effect of MSCs in liver cirrhosis has been extensively demonstrated both in animal and clinical studies. Infused BM-MSCs have been shown to engraft into host liver and ameliorate fibrosis in a time-dependent manner by decreasing α-smooth muscle actin expression, reducing collagen deposition, and improving recovery of damaged hepatocytes in animal models of experimental liver fibrosis[117-119]. Recently, AT-MSCs have attracted much interest as liver repopulating cells in different models of cirrhosis. AT-MSCs, transplanted intraportally, rather than through the tail vein, inhibited the proliferation and activation of hepatic stellate cells in vitro and ameliorated liver fibrosis in CCl4-treated rats by improving the microcirculation of the fibrotic liver[120,121]. In a murine steatohepatitis cirrhosis model, injected AT-MSCs resided in the liver and expressed albumin, ultimately restoring albumin expression in hepatic parenchymal cells. Gene expression profiling of AT-MSCs revealed that the amelioration of hepatic fibrosis in this model correlated with induction of anti-inflammatory and regeneration/repair pathways as well as suppression of pathogenic helper T-cell activation[122].

In contrast to the similar hepatic integration between undifferentiated AT-MSCs and AT-MSCs pre-differentiated to HLCs shown in acute liver injury models[107], other liver injury models suggest that pre-differentiation of AT-MSCs to HLCs may facilitate liver engraftment. In a xenogenic transplantation model of liver regeneration, long-term engraftment of human AT-MSC-derived HLCs was demonstrated and was significantly improved when in vitro pre-differentiated AT-MSCs, instead of undifferentiated MSCs were used, reaching repopulation rates of more than 10% along with functional hepatic regeneration[123].

Fibroblast growth factor (FGF)-pretreatment of AT-MSCs facilitated their transdifferentiation towards hepatic lineage in vitro, and the infused FGF-pretreated AT-MSCs reduced hepatic fibrosis in mice[124]. In chronic liver injury models, FGF-treated AT-MSCs led to enhanced hepatocyte proliferation and induction of hepatic stellate cell apoptosis through activation of JNK-p53 signaling in hepatic stellate cells[125], while BM-MSCs pretreated with hepatocyte growth factor (HGF) and FGF4 or with injured liver tissue showed increased homing and hepatic differentiation ability providing therapeutic benefit in injured mice[126,127].

It seems that MSCs exert their therapeutic effects predominantly by releasing trophic and immunomodulatory factors rather than trans-differentiating into parenchymal hepatocytes. MSCs modulate the function of activated stellate cells via paracrine secretion of IL-10, HGF and Nerve Growth Factor, providing a plausible explanation for the protective role of MSCs in liver inflammation and fibrosis[128-130]. Additionally, MSCs may alleviate hepatic cirrhosis through the expression of matrix metalloproteinases (MMP-9, MMP-13), enzymes capable of degrading the extracellular matrix, thus exerting a direct antifibrotic effect in the injured liver[131,132].

Several clinical trials (Table 1) have investigated the therapeutic potential of MSCs derived from BM or UC blood in liver cirrhosis, providing however, conflicting results. In two pilot, phase I and I-II, studies, autologous BM-MSCs were injected into peripheral or portal vein of a small number of patients with end-stage liver disease. Liver function and clinical features were improved while the procedure was safe and well tolerated[133,134]. Safety and short-term efficacy of autologous BM-MSCs stimulated towards hepatic lineage and injected via intrasplenic or intrahepatic route was evidenced in two groups of 20 patients with post-HCV end-stage liver cell failure. Patients significantly improved their Child and MELD score, fatigue scale and performance status over the control group who received conventional supportive treatment[135]. In 53 patients with post-HBV liver failure, autologous transplantation of BM-MSCs through the hepatic artery provided short-term efficacy in respect to several clinical and biochemical parameters, but long-term outcomes were not markedly improved[136]. Similarly, in a phase II trial with autologous transplantation of BM-derived, undifferentiated and differentiated, MSCs in 15 post-HCV cirrhotic patients, follow up at 3 and 6 mo postinfusion, revealed partial improvement of liver function tests and decline of elevated bilirubin and MELD score[137]. Another study in post-HCV cirrhotic patients, suggested the safety, feasibility, and efficacy of intrasplenically administered autologous BM-MSCs in improving liver function[138]. Eleven patients with alcoholic cirrhosis safely received autologous BM-MSCs through the hepatic artery in a phase II clinical trial; histological and clinical (by Child-Pugh score) improvement was observed in 54.5% and 90.9% of patients respectively, while the levels of TGF-b1, type 1 collagen, and a-smooth muscle actin were significantly decreased[139]. Similarly, UC-MSC infusion was well tolerated in patients with decompensated cirrhosis, acute in chronic liver failure and in patients with primary biliary cirrhosis, resulting in significant improvement of liver function and increased survival rates[140-142].

In contrast to the above mentioned studies, a randomized, placebo-controlled trial using peripheral administration of autologous MSCs to cirrhotic patients, failed to show a beneficial effect of MSCs in cirrhotic patients. Indeed, 3 of 15 patients who received MSCs died in the first 5 mo following cell administration while the absolute changes in Child and MELD scores, serum albumin, INR, serum transaminases and liver volumes did not differ significantly between the MSC and placebo group at 12 mo-follow-up, indicating that further studies with higher number of patients are warranted to clarify the true impact of systematic or liver-directed MSC infusion in cirrhosis[143].

Considerations on the clinical application of MSCs

The unique properties of MSCs including easy access and expansion, engraftment capacity, paracrine secretion, trans-differentiation and immunomodulation render them ideally suited for cell therapies. Importantly, compared to embryonic SCs, MSCs do not raise ethical issues and presumably have a safer profile in terms of tumorigenesis. Up to date, a considerable amount of preclinical and clinical evidence is currently available as regards the promise of MSCs as a relatively safe and effective approach in improving liver disease. However, several issues still need to be addressed before MSCs-based liver therapy passes to the clinical practice and these are discussed below.

There is a lack of uniformity in the design of clinical trials, characterized by different MSC sources, doses and routes of administration, all of which may influence the outcome of MSC infusion on the basis also of the underlying disease; MSCs engrafted into injured or regenerating livers only after intrahepatic but not intrasplenic injection[144] whereas intravenously injected BM-MSCs migrated and engrafted into normal and injured liver parenchyma, under conditions of chronic but not acute injury[145]. On the contrary, the systematic administration of MSCs in a randomized trial with cirrhotic patients failed to provide efficacy over placebo[143].

In terms of safety, and despite the absence of severe adverse events in the clinical trials conducted thus far, a pro-fibrogenic potential of MSCs and unwanted differentiation into myofibroblasts has been described in several studies[144-146]. To avoid this unwanted differentiation, some groups have suggested that BM-MSCs should be induced to differentiate into HLCs before their infusion[123] Alternatively, others have proposed the microencapsulation of MSCs in alginate-polyethylene glycol microspheres as a means to prevent scar formation through the artificial interruption of the cell-to-cell interactions but still the enablement of release of soluble molecules[147].

Although MSCs are at low risk of malignant transformation, concern exists on their potential to promote tumor growth in vivo[148-150]. Thus, screening of MSCs for a gene expression signature before administration, could serve as a safety measure[151]. In vitro, the spontaneous transformation of MSCs resulting in tumorigenesis was a rather rare event and occurred only after extended (beyond five weeks) culture. On the contrary, because of their immunomodulatory properties, MSCs may exert an antitumor effect by modulating the inflammatory environment that characterizes many tumors and by inhibiting signaling pathways associated with tumor growth and cell division[152-156].

Hematopoietic stem cells

Bone marrow has been considered as a source of liver-repopulating cells that contributes to the liver healing process after tissue injury, thus challenging the dogma of BM as giving rise to only hematopoietic cell lineages. It has been reported that BM-derived SCs can differentiate into a variety of adult cell types that express non-hematopoietic cell markers[69-72], including hepatocytes[157]. The group of Grompe first suggested that functional hepatocytes may arise from hematopoietic SCs (HSCs)[66], and in the early 2000s, several groups demonstrated that SCs originating in the BM or circulating outside the liver participated in liver regeneration, not only in experimental animal models[67] but also in human liver[157,158]. Numerous studies followed, highlighting the contribution of HSCs in ameliorating liver damage.

Hepatic injury caused by surgical liver resection or cirrhosis in humans, triggered BM CD34+ or CD133+/c-kit+/bcrp-1+ cell trafficking towards the liver and putatively the differentiation of various populations of hematopoietic progenitor cells into HLCs[159-161]. BM cell transplantation or infusion of macrophages in a mouse model of liver fibrosis indicated that the migrated to the liver cells, reduced liver fibrosis and significantly improved survival rate compared with control injured mice[162,163], while BM-derived hepatocytes were identified in lethally irradiated mice transplanted with HSCs[164]. In patients with malignant liver lesions, a combination of portal vein embolization (PVE) and administration of CD133+ BMSCs substantially increased hepatic regeneration compared with PVE alone[165], while cirrhotic patients safely underwent autologous BM cell infusion and improved their Child-Pugh score and albumin levels (Table 1)[166].

G-CSF mobilization as a source of large numbers of putatively liver-repopulating cells

HSCs can easily be forced to leave the BM and circulate into the peripheral blood from where they can be apheresed and subsequently enriched by their surface expression of CD34 or/and CD133. Mobilization of BM-resident HSCs occurs at a low magnitude under specific stimuli such as tissue injury[159,167] or in high amounts after pharmacological priming with cytostatic drugs, chemokines, or hematopoietic cytokines[168,169]. Granulocyte-colony stimulating factor (G-CSF) is a hematopoietic growth factor and the most widely used mobilizing agent[170]. G-CSF, as a means of forced circulation of large numbers of HSCs, has been extensively investigated for its hepatic regenerative effect, both in animal models of liver injury[171-174] as well as in clinical trials[175-177]. In general, two approaches have been explored for liver population with mobilized HSCs, both in animal models and clinical trials; G-CSF-mobilization alone or G-CSF-mobilization followed by infusion of autologous mobilized HSCs.

As seen with BM transplantation in liver injury models and despite the higher numbers of HSCs potentially accessing the liver by G-CSF mobilization, the true contribution of mobilized HSCs to liver repopulation is low. We and others[171,173] have shown that G-CSF mobilization of BM chimeras in induced acute and chronic liver injury models results in liver regeneration and improves survival, but the vast majority of cells repopulating the liver originate in situ. In a comparative study of all currently available mobilizing agents (G-CSF, Plerixafor, Plerifaxor + G-CSF) with regard to their liver repopulating potential, we have shown that all mobilizing modalities ameliorate liver fibrosis, by acting differentially during the healing process. In all cases, liver recovery was not ultimately mediated by the HSCs but either from a paracrine or “bystander” signaling effect of the mobilized HSCs that triggered endogenous repair mechanisms and stimulated tissue progenitor cells and/or a direct “trophic” effect of the mobilizing agents in the liver. These effects, however, are difficult to be experimentally dissected to definitively address this question[174].

Clinical studies that evaluated G-CSF mobilization in patients with advanced liver disease provided conflicting results (Table 1). In trials in end-stage liver cirrhosis or alcoholic steatohepatitis patients, G-CSF was well tolerated[175,178], and the mobilized HSCs were shown to coexpress epithelial and SC markers[175] and to induce HPCs to proliferate within 7 d of administration[178]. In acute-on-chronic liver failure (ACLF) patients, mobilization of HSCs with G-CSF promoted hepatic regeneration, and more than doubled the percentage of ACLF patients who survived for 2 mo; it also significantly reduced CTP, MELD, and SOFA scores and prevented the development of sepsis, hepatorenal syndrome, and hepatic encephalopathy[179]. Similarly, a recent randomized open study showed that the administration of G-CSF was safe and improved liver function as well as survival in patients with severe alcoholic hepatitis[180]. In an interesting case report, experimental plasmapheresis with plasma-exchange (PA-PE), as a process to eliminate circulating toxic factors, was combined with G-CSF in a patient with ACLF[181]. This regimen induced mobilization of HSCs and a rapid and long lasting clinical improvement associated with a ductular reaction, in which HPCs expressing G-CSF receptor (G-CSFR) were observed. PA-PE might have modulated the liver microenvironment thus providing a conducive milieu to G-CSF-mediated amplification of endogenous HPCs that promoted liver regeneration. Given that G-CSFR was expressed by HPCs, G-CSF might also be directly involved in modifying the HPC niche exerting a “hepatotrophic effect”[181]. In contrast, other clinical studies reported on the safety and tolerability of G-CSF mobilization but could not demonstrate significant clinical improvement, despite effective mobilization[182,183].

The relatively easy access to large quantities of HSCs by mobilization followed by cytapheresis, renders them ideally suited as liver repopulating cells. Thus, several groups have investigated G-CSF mobilization followed by infusion of autologous mobilized HSCs, an approach that forces a maximum SC dose to circulate at a given time, thus increasing the number of SCs that potentially home to the liver and initiate the recovery process.

We previously assessed the safety and efficacy of boost iv infusions of mobilized peripheral blood SCs (mPBSCs) in two patients with end-stage alcoholic liver cirrhosis. The patients tolerated well three mobilization rounds and infusions of mPBSCs that resulted in lasting amelioration in the clinical course of a previously decompensated disease, during a 30 mo follow-up[176]. In another study, a significant biochemical and histopathological improvement was achieved in a patient with drug-induced acute liver failure after intraportal administration of mobilized CD34+ BMSCs[184].

A phase I study was performed to determine the safety and tolerability of G-CSF administration, followed by collection and intraportal or intrahepatic reinfusion of circulating CD34+ cells into patients with liver failure. An improvement of the hepatic function without significant side effects in short and long term follow-up was observed in more than 50% of the subjects[177,185]. In another trial, following G-CSF mobilization and leukapheresis, the autologous CD34+ cells were expanded in vitro and injected into the hepatic artery of nine patients with alcoholic liver cirrhosis (ALC). The clinical and biochemical improvement in the study group was encouraging while it proved safe to mobilize, expand, and reinfuse autologous CD34+ cells in ALC patients[186]. In one of the largest trials, 40 patients with decompensated, hepatitis B virus-related liver cirrhosis were randomized to receive G-CSF alone or in combination with leukapheresis and reinfusion of peripheral blood monocytes (PBMC). A significant biochemical and clinical improvement was observed in both groups, but the subjects receiving G-CSF plus PBMC infusion experienced greater and longer-lasting clinical benefits during the follow-up period[187].

Considerations on the use of HSCs as liver-repopulating cells

The concept of BM-derived liver regeneration has been strongly questioned. Despite an improvement in several parameters of liver function, both in preclinical and clinical studies, it has become clear that, in the absence of selective pressure, the true contribution of BM to liver regeneration is extremely low in effectively supporting per se liver recovery[188-190]. The current belief is that the clinical benefit observed in the injured liver after HSC therapy is produced by the activation of endogenous progenitor cells through paracrine signaling interaction between donor and host cells providing cytokines and growth factors[190-192], rather than by transdifferentiation of BMSCs into parenchymal liver cells[158] or cell fusion with resident target cells in the host tissue[193,194].

Overall, from the various published studies on the use of HSCs as a cell therapy source for liver diseases, it seems that mobilization of HSCs, apheresis, and re-infusion is safe, while improving quality of life and disease parameters. As such, this approach may help to “bridge” patients to liver transplantation or reverse a decompensated cirrhosis to a compensated stage. In addition, the use of autologous mobilized HSCs as a cell source for liver regeneration is not associated with ethical concerns and can provide easy access to, and high yields of, SCs without the risk of rejection or need for immunosuppression. However, efficacy still needs to be confirmed, and the route of delivery, the amount of infused cells, and the timing of infusions need to be clarified, standardized, and validated in well-designed large clinical trials.

Liver tissue engineering

Liver tissue engineering endeavours to provide novel tools for end-stage liver diseases which will, ideally, replace organ transplantation. Therapeutic approaches towards this goal include implantable hepatic tissue engineered constructs and bioartificial liver (BAL) devices.

Implantable engineered cellular tissues provide an alternative method of cell delivery and are gaining ground in the field of regenerative medicine. They are generated mainly by immobilizing or encapsulating cells using biomaterial scaffolds. Biomaterial scaffolds provide 3-dimensional (3D) structures resembling the extracellular matrix environment in vivo, and have been used in association with an appropriate induction medium to promote BM-derived MSC differentiation into HLCs[195]. Apart from alginate scaffolds[195], derived from natural polysaccharide-based biomaterials, 3D nanofibrous scaffolds of synthetic polymer-based biomaterials, allowing easy control of the quality and reproducibility of the product, have been used to investigate the hepatic differentiation potential of human BM-MSCs. The nanofibrous scaffolds enhanced SC differentiation into functional HLCs expressing liver specific markers compared with 2D culture systems[196].

Similarly, the topographic properties of ultraweb nanofibers enhanced the differentiation of MSCs to HLCs which maintained functionality in long-term cultures. Differentiated HLCs homed to and engrafted into the injured liver of fibrotic mice, enhanced serum albumin, and rescued recipients from liver failure[197]. In another study, collagen-coated poly 3D scaffolds, supplemented with hepatocyte differentiation medium, provided a suitable environment for differentiation of BM-MSCs into mature hepatocytes over the control, monolayer culture system[198]. Recently, poly 3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate scaffolds, made up by biodegradable polyester produced by bacteria, provided higher viability and attachment of human UC Wharton’s jelly-MSCs than other polymers tested, ultimately promoting the recovery of the injured liver after transplantation in mice[199].

BAL devices contain functional hepatocytes that supply important molecules to support hepatic function and to remove circulating toxins. This technology, however, is limited by the complexity of liver function and the shortage of human livers to provide adequate numbers of hepatocytes. Thus, ex vivo differentiated hepatocytes from alternative sources have been investigated. A BAL device seeded with ESC-derived hepatocytes or primary hepatocytes which was subcutaneously implanted in 90% hepatectomized mice, improved liver function and prolonged survival over control mice, while ESC-derived hepatocytes in BAL developed characteristics nearly identical to those of primary hepatocytes[200].

Very recently, 3D printing technologies, by fabricating complex 3D tissue engineering scaffolds and providing patient-specific tissue models showed promise in revolutionizing liver regenerative medicine towards customized transplantation approaches[201].

For all the above technologies however, challenges still remain and dictate an in depth, understanding of the specific molecular, mechanisms and signaling pathways in the hepatic microenvironment that affect hepatic cell lineages and regulate efficient differentiation of SCs[202].

CONCLUSION

SC-based liver regeneration is an exciting and dynamic area of research showing remarkable advancement in liver medicine, both in basic science and in the translational field. The clinical translation for liver cell therapies however, from only a promise for cure to a treatment reality for end stage liver diseases, requires deeper understanding of SC and liver biology, and the remaining unsolved aspects to be addressed.

Up to date there has been a lack of uniformity in preclinical and clinical studies, as regards the type and the extent of injury of the liver parenchyma, the source and dose of SCs, the therapeutic timing and route of administration of SCs, and the primary endpoints. In addition, positive results in animal models have not always been translated to successful clinical trials, as clear evidence of therapeutic benefit has usually been lacking from clinical trials. As such, carefully designed clinical trials will help to elucidate the most appropriate SC therapy for different liver diseases by considering the background and severity of the target disease as well as the putative functional roles of different SCs and the intended biological action by their infusion.

Footnotes

P- Reviewer: Liu L S- Editor: Ma YJ L- Editor: Cant MR E- Editor: Liu XM

References
1.  Kim WR, Therneau TM, Benson JT, Kremers WK, Rosen CB, Gores GJ, Dickson ER. Deaths on the liver transplant waiting list: an analysis of competing risks. Hepatology. 2006;43:345-351.  [PubMed]  [DOI]
2.  Zarrinpar A, Busuttil RW. Liver transplantation: past, present and future. Nat Rev Gastroenterol Hepatol. 2013;10:434-440.  [PubMed]  [DOI]
3.  Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology. 2006;43:S45-S53.  [PubMed]  [DOI]
4.  Michalopoulos GK, DeFrances MC. Liver regeneration. Science. 1997;276:60-66.  [PubMed]  [DOI]
5.  Gramignoli R, Vosough M, Kannisto K, Srinivasan RC, Strom SC. Clinical hepatocyte transplantation: practical limits and possible solutions. Eur Surg Res. 2015;54:162-177.  [PubMed]  [DOI]
6.  Gupta S, Gorla GR, Irani AN. Hepatocyte transplantation: emerging insights into mechanisms of liver repopulation and their relevance to potential therapies. J Hepatol. 1999;30:162-170.  [PubMed]  [DOI]
7.  Stéphenne X, Najimi M, Sokal EM. Hepatocyte cryopreservation: is it time to change the strategy? World J Gastroenterol. 2010;16:1-14.  [PubMed]  [DOI]
8.  Terry C, Dhawan A, Mitry RR, Hughes RD. Cryopreservation of isolated human hepatocytes for transplantation: State of the art. Cryobiology. 2006;53:149-159.  [PubMed]  [DOI]
9.  Bird TG, Lorenzini S, Forbes SJ. Activation of stem cells in hepatic diseases. Cell Tissue Res. 2008;331:283-300.  [PubMed]  [DOI]
10.  Dan YY, Yeoh GC. Liver stem cells: a scientific and clinical perspective. J Gastroenterol Hepatol. 2008;23:687-698.  [PubMed]  [DOI]
11.  Papp V, Rókusz A, Dezső K, Bugyik E, Szabó V, Pávai Z, Paku S, Nagy P. Expansion of hepatic stem cell compartment boosts liver regeneration. Stem Cells Dev. 2014;23:56-65.  [PubMed]  [DOI]
12.  Kung JW, Forbes SJ. Stem cells and liver repair. Curr Opin Biotechnol. 2009;20:568-574.  [PubMed]  [DOI]
13.  Duncan AW, Dorrell C, Grompe M. Stem cells and liver regeneration. Gastroenterology. 2009;137:466-481.  [PubMed]  [DOI]
14.  Kordes C, Häussinger D. Hepatic stem cell niches. J Clin Invest. 2013;123:1874-1880.  [PubMed]  [DOI]
15.  Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, Ridgway RA, Seo SS, Spee B, Van Rooijen N. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med. 2012;18:572-579.  [PubMed]  [DOI]
16.  Spee B, Carpino G, Schotanus BA, Katoonizadeh A, Vander Borght S, Gaudio E, Roskams T. Characterisation of the liver progenitor cell niche in liver diseases: potential involvement of Wnt and Notch signalling. Gut. 2010;59:247-257.  [PubMed]  [DOI]
17.  Wanless IR, Nakashima E, Sherman M. Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis. Arch Pathol Lab Med. 2000;124:1599-1607.  [PubMed]  [DOI]
18.  Falkowski O, An HJ, Ianus IA, Chiriboga L, Yee H, West AB, Theise ND. Regeneration of hepatocyte ‘buds’ in cirrhosis from intrabiliary stem cells. J Hepatol. 2003;39:357-364.  [PubMed]  [DOI]
19.  Stueck AE, Wanless IR. Hepatocyte buds derived from progenitor cells repopulate regions of parenchymal extinction in human cirrhosis. Hepatology. 2015;61:1696-1707.  [PubMed]  [DOI]
20.  Kordes C, Sawitza I, Götze S, Häussinger D. Hepatic stellate cells support hematopoiesis and are liver-resident mesenchymal stem cells. Cell Physiol Biochem. 2013;31:290-304.  [PubMed]  [DOI]
21.  Kordes C, Sawitza I, Götze S, Herebian D, Häussinger D. Hepatic stellate cells contribute to progenitor cells and liver regeneration. J Clin Invest. 2014;124:5503-5515.  [PubMed]  [DOI]
22.  Schmelzer E, Zhang L, Bruce A, Wauthier E, Ludlow J, Yao HL, Moss N, Melhem A, McClelland R, Turner W. Human hepatic stem cells from fetal and postnatal donors. J Exp Med. 2007;204:1973-1987.  [PubMed]  [DOI]
23.  Shiojiri N, Koike T. Differentiation of biliary epithelial cells from the mouse hepatic endodermal cells cultured in vitro. Tohoku J Exp Med. 1997;181:1-8.  [PubMed]  [DOI]
24.  Shiojiri N, Mizuno T. Differentiation of functional hepatocytes and biliary epithelial cells from immature hepatocytes of the fetal mouse in vitro. Anat Embryol (Berl). 1993;187:221-229.  [PubMed]  [DOI]
25.  Haruna Y, Saito K, Spaulding S, Nalesnik MA, Gerber MA. Identification of bipotential progenitor cells in human liver development. Hepatology. 1996;23:476-481.  [PubMed]  [DOI]
26.  Oertel M, Menthena A, Chen YQ, Teisner B, Jensen CH, Shafritz DA. Purification of fetal liver stem/progenitor cells containing all the repopulation potential for normal adult rat liver. Gastroenterology. 2008;134:823-832.  [PubMed]  [DOI]
27.  Cantz T, Zuckerman DM, Burda MR, Dandri M, Göricke B, Thalhammer S, Heckl WM, Manns MP, Petersen J, Ott M. Quantitative gene expression analysis reveals transition of fetal liver progenitor cells to mature hepatocytes after transplantation in uPA/RAG-2 mice. Am J Pathol. 2003;162:37-45.  [PubMed]  [DOI]
28.  Sandhu JS, Petkov PM, Dabeva MD, Shafritz DA. Stem cell properties and repopulation of the rat liver by fetal liver epithelial progenitor cells. Am J Pathol. 2001;159:1323-1334.  [PubMed]  [DOI]
29.  Khan AA, Shaik MV, Parveen N, Rajendraprasad A, Aleem MA, Habeeb MA, Srinivas G, Raj TA, Tiwari SK, Kumaresan K. Human fetal liver-derived stem cell transplantation as supportive modality in the management of end-stage decompensated liver cirrhosis. Cell Transplant. 2010;19:409-418.  [PubMed]  [DOI]
30.  Cardinale V, Carpino G, Gentile R, Napoletano C, Rahimi H, Franchitto A, Semeraro R, Nuti M, Onori P, Berloco PB. Transplantation of human fetal biliary tree stem/progenitor cells into two patients with advanced liver cirrhosis. BMC Gastroenterol. 2014;14:204.  [PubMed]  [DOI]
31.  Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282:1145-1147.  [PubMed]  [DOI]
32.  Woo DH, Kim SK, Lim HJ, Heo J, Park HS, Kang GY, Kim SE, You HJ, Hoeppner DJ, Kim Y. Direct and indirect contribution of human embryonic stem cell-derived hepatocyte-like cells to liver repair in mice. Gastroenterology. 2012;142:602-611.  [PubMed]  [DOI]
33.  Hay DC, Fletcher J, Payne C, Terrace JD, Gallagher RC, Snoeys J, Black JR, Wojtacha D, Samuel K, Hannoun Z. Highly efficient differentiation of hESCs to functional hepatic endoderm requires ActivinA and Wnt3a signaling. Proc Natl Acad Sci USA. 2008;105:12301-12306.  [PubMed]  [DOI]
34.  Brolén G, Sivertsson L, Björquist P, Eriksson G, Ek M, Semb H, Johansson I, Andersson TB, Ingelman-Sundberg M, Heins N. Hepatocyte-like cells derived from human embryonic stem cells specifically via definitive endoderm and a progenitor stage. J Biotechnol. 2010;145:284-294.  [PubMed]  [DOI]
35.  Moriya K, Yoshikawa M, Saito K, Ouji Y, Nishiofuku M, Hayashi N, Ishizaka S, Fukui H. Embryonic stem cells develop into hepatocytes after intrasplenic transplantation in CCl4-treated mice. World J Gastroenterol. 2007;13:866-873.  [PubMed]  [DOI]
36.  Yamamoto H, Quinn G, Asari A, Yamanokuchi H, Teratani T, Terada M, Ochiya T. Differentiation of embryonic stem cells into hepatocytes: biological functions and therapeutic application. Hepatology. 2003;37:983-993.  [PubMed]  [DOI]
37.  Kiskinis E, Eggan K. Progress toward the clinical application of patient-specific pluripotent stem cells. J Clin Invest. 2010;120:51-59.  [PubMed]  [DOI]
38.  Zaret KS, Grompe M. Generation and regeneration of cells of the liver and pancreas. Science. 2008;322:1490-1494.  [PubMed]  [DOI]
39.  Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861-872.  [PubMed]  [DOI]
40.  Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature. 2007;448:313-317.  [PubMed]  [DOI]
41.  Baum C, Kustikova O, Modlich U, Li Z, Fehse B. Mutagenesis and oncogenesis by chromosomal insertion of gene transfer vectors. Hum Gene Ther. 2006;17:253-263.  [PubMed]  [DOI]
42.  Papapetrou EP, Lee G, Malani N, Setty M, Riviere I, Tirunagari LM, Kadota K, Roth SL, Giardina P, Viale A. Genomic safe harbors permit high β-globin transgene expression in thalassemia induced pluripotent stem cells. Nat Biotechnol. 2011;29:73-78.  [PubMed]  [DOI]
43.  Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K. Induced pluripotent stem cells generated without viral integration. Science. 2008;322:945-949.  [PubMed]  [DOI]
44.  Kim D, Kim CH, Moon JI, Chung YG, Chang MY, Han BS, Ko S, Yang E, Cha KY, Lanza R. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell. 2009;4:472-476.  [PubMed]  [DOI]
45.  Warren L, Manos PD, Ahfeldt T, Loh YH, Li H, Lau F, Ebina W, Mandal PK, Smith ZD, Meissner A. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell. 2010;7:618-630.  [PubMed]  [DOI]
46.  Hou P, Li Y, Zhang X, Liu C, Guan J, Li H, Zhao T, Ye J, Yang W, Liu K. Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science. 2013;341:651-654.  [PubMed]  [DOI]
47.  Sterneckert JL, Reinhardt P, Schöler HR. Investigating human disease using stem cell models. Nat Rev Genet. 2014;15:625-639.  [PubMed]  [DOI]
48.  Ko HC, Gelb BD. Concise review: drug discovery in the age of the induced pluripotent stem cell. Stem Cells Transl Med. 2014;3:500-509.  [PubMed]  [DOI]
49.  Song Z, Cai J, Liu Y, Zhao D, Yong J, Duo S, Song X, Guo Y, Zhao Y, Qin H. Efficient generation of hepatocyte-like cells from human induced pluripotent stem cells. Cell Res. 2009;19:1233-1242.  [PubMed]  [DOI]
50.  Zhang Q, Yang Y, Zhang J, Wang GY, Liu W, Qiu DB, Hei ZQ, Ying QL, Chen GH. Efficient derivation of functional hepatocytes from mouse induced pluripotent stem cells by a combination of cytokines and sodium butyrate. Chin Med J (Engl). 2011;124:3786-3793.  [PubMed]  [DOI]
51.  Takayama K, Inamura M, Kawabata K, Katayama K, Higuchi M, Tashiro K, Nonaka A, Sakurai F, Hayakawa T, Furue MK. Efficient generation of functional hepatocytes from human embryonic stem cells and induced pluripotent stem cells by HNF4α transduction. Mol Ther. 2012;20:127-137.  [PubMed]  [DOI]
52.  Chen YF, Tseng CY, Wang HW, Kuo HC, Yang VW, Lee OK. Rapid generation of mature hepatocyte-like cells from human induced pluripotent stem cells by an efficient three-step protocol. Hepatology. 2012;55:1193-1203.  [PubMed]  [DOI]
53.  Espejel S, Roll GR, McLaughlin KJ, Lee AY, Zhang JY, Laird DJ, Okita K, Yamanaka S, Willenbring H. Induced pluripotent stem cell-derived hepatocytes have the functional and proliferative capabilities needed for liver regeneration in mice. J Clin Invest. 2010;120:3120-3126.  [PubMed]  [DOI]
54.  Asgari S, Moslem M, Bagheri-Lankarani K, Pournasr B, Miryounesi M, Baharvand H. Differentiation and transplantation of human induced pluripotent stem cell-derived hepatocyte-like cells. Stem Cell Rev. 2013;9:493-504.  [PubMed]  [DOI]
55.  Chiang CH, Wu WW, Li HY, Chien Y, Sun CC, Peng CH, Lin AT, Huang CS, Lai YH, Chiou SH. Enhanced antioxidant capacity of dental pulp-derived iPSC-differentiated hepatocytes and liver regeneration by injectable HGF-releasing hydrogel in fulminant hepatic failure. Cell Transplant. 2015;24:541-559.  [PubMed]  [DOI]
56.  Uygun BE, Yarmush ML, Uygun K. Application of whole-organ tissue engineering in hepatology. Nat Rev Gastroenterol Hepatol. 2012;9:738-744.  [PubMed]  [DOI]
57.  Takebe T, Sekine K, Enomura M, Koike H, Kimura M, Ogaeri T, Zhang RR, Ueno Y, Zheng YW, Koike N. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature. 2013;499:481-484.  [PubMed]  [DOI]
58.  Garate Z, Davis BR, Quintana-Bustamante O, Segovia JC. New frontier in regenerative medicine: site-specific gene correction in patient-specific induced pluripotent stem cells. Hum Gene Ther. 2013;24:571-583.  [PubMed]  [DOI]
59.  van de Ven C, Collins D, Bradley MB, Morris E, Cairo MS. The potential of umbilical cord blood multipotent stem cells for nonhematopoietic tissue and cell regeneration. Exp Hematol. 2007;35:1753-1765.  [PubMed]  [DOI]
60.  Newsome PN, Johannessen I, Boyle S, Dalakas E, McAulay KA, Samuel K, Rae F, Forrester L, Turner ML, Hayes PC. Human cord blood-derived cells can differentiate into hepatocytes in the mouse liver with no evidence of cellular fusion. Gastroenterology. 2003;124:1891-1900.  [PubMed]  [DOI]
61.  Di Campli C, Piscaglia AC, Pierelli L, Rutella S, Bonanno G, Alison MR, Mariotti A, Vecchio FM, Nestola M, Monego G. A human umbilical cord stem cell rescue therapy in a murine model of toxic liver injury. Dig Liver Dis. 2004;36:603-613.  [PubMed]  [DOI]
62.  Campard D, Lysy PA, Najimi M, Sokal EM. Native umbilical cord matrix stem cells express hepatic markers and differentiate into hepatocyte-like cells. Gastroenterology. 2008;134:833-848.  [PubMed]  [DOI]
63.  Teramoto K, Asahina K, Kumashiro Y, Kakinuma S, Chinzei R, Shimizu-Saito K, Tanaka Y, Teraoka H, Arii S. Hepatocyte differentiation from embryonic stem cells and umbilical cord blood cells. J Hepatobiliary Pancreat Surg. 2005;12:196-202.  [PubMed]  [DOI]
64.  Chien CC, Yen BL, Lee FK, Lai TH, Chen YC, Chan SH, Huang HI. In vitro differentiation of human placenta-derived multipotent cells into hepatocyte-like cells. Stem Cells. 2006;24:1759-1768.  [PubMed]  [DOI]
65.  Huang HI. Isolation of human placenta-derived multipotent cells and in vitro differentiation into hepatocyte-like cells. Curr Protoc Stem Cell Biol. 2007;Chapter 1:Unit 1E.1.  [PubMed]  [DOI]
66.  Lagasse E, Connors H, Al-Dhalimy M, Reitsma M, Dohse M, Osborne L, Wang X, Finegold M, Weissman IL, Grompe M. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med. 2000;6:1229-1234.  [PubMed]  [DOI]
67.  Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Murase N, Boggs SS, Greenberger JS, Goff JP. Bone marrow as a potential source of hepatic oval cells. Science. 1999;284:1168-1170.  [PubMed]  [DOI]
68.  Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM. Bone marrow cells regenerate infarcted myocardium. Nature. 2001;410:701-705.  [PubMed]  [DOI]
69.  Ferrari G, Cusella-De Angelis G, Coletta M, Paolucci E, Stornaiuolo A, Cossu G, Mavilio F. Muscle regeneration by bone marrow-derived myogenic progenitors. Science. 1998;279:1528-1530.  [PubMed]  [DOI]
70.  Brazelton TR, Rossi FM, Keshet GI, Blau HM. From marrow to brain: expression of neuronal phenotypes in adult mice. Science. 2000;290:1775-1779.  [PubMed]  [DOI]
71.  Ianus A, Holz GG, Theise ND, Hussain MA. In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J Clin Invest. 2003;111:843-850.  [PubMed]  [DOI]
72.  Schwartz RE, Reyes M, Koodie L, Jiang Y, Blackstad M, Lund T, Lenvik T, Johnson S, Hu WS, Verfaillie CM. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest. 2002;109:1291-1302.  [PubMed]  [DOI]
73.  Nakamura T, Torimura T, Sakamoto M, Hashimoto O, Taniguchi E, Inoue K, Sakata R, Kumashiro R, Murohara T, Ueno T. Significance and therapeutic potential of endothelial progenitor cell transplantation in a cirrhotic liver rat model. Gastroenterology. 2007;133:91-107.e1.  [PubMed]  [DOI]
74.  Wang L, Wang X, Xie G, Wang L, Hill CK, DeLeve LD. Liver sinusoidal endothelial cell progenitor cells promote liver regeneration in rats. J Clin Invest. 2012;122:1567-1573.  [PubMed]  [DOI]
75.  Ueno T, Nakamura T, Torimura T, Sata M. Angiogenic cell therapy for hepatic fibrosis. Med Mol Morphol. 2006;39:16-21.  [PubMed]  [DOI]
76.  Taniguchi E, Kin M, Torimura T, Nakamura T, Kumemura H, Hanada S, Hisamoto T, Yoshida T, Kawaguchi T, Baba S. Endothelial progenitor cell transplantation improves the survival following liver injury in mice. Gastroenterology. 2006;130:521-531.  [PubMed]  [DOI]
77.  Beaudry P, Hida Y, Udagawa T, Alwayn IP, Greene AK, Arsenault D, Folkman J, Heymach JV, Ryeom S, Puder M. Endothelial progenitor cells contribute to accelerated liver regeneration. J Pediatr Surg. 2007;42:1190-1198.  [PubMed]  [DOI]
78.  Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143-147.  [PubMed]  [DOI]
79.  Lee OK, Kuo TK, Chen WM, Lee KD, Hsieh SL, Chen TH. Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood. 2004;103:1669-1675.  [PubMed]  [DOI]
80.  Sottile V, Halleux C, Bassilana F, Keller H, Seuwen K. Stem cell characteristics of human trabecular bone-derived cells. Bone. 2002;30:699-704.  [PubMed]  [DOI]
81.  De Bari C, Dell’Accio F, Tylzanowski P, Luyten FP. Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum. 2001;44:1928-1942.  [PubMed]  [DOI]
82.  Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13:4279-4295.  [PubMed]  [DOI]
83.  In ‘t Anker PS, Scherjon SA, Kleijburg-van der Keur C, de Groot-Swings GM, Claas FH, Fibbe WE, Kanhai HH. Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells. 2004;22:1338-1345.  [PubMed]  [DOI]
84.  In ‘t Anker PS, Scherjon SA, Kleijburg-van der Keur C, Noort WA, Claas FH, Willemze R, Fibbe WE, Kanhai HH. Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation. Blood. 2003;102:1548-1549.  [PubMed]  [DOI]
85.  in ‘t Anker PS, Noort WA, Scherjon SA, Kleijburg-van der Keur C, Kruisselbrink AB, van Bezooijen RL, Beekhuizen W, Willemze R, Kanhai HH, Fibbe WE. Mesenchymal stem cells in human second-trimester bone marrow, liver, lung, and spleen exhibit a similar immunophenotype but a heterogeneous multilineage differentiation potential. Haematologica. 2003;88:845-852.  [PubMed]  [DOI]
86.  Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood. 2007;110:3499-3506.  [PubMed]  [DOI]
87.  El-Badri NS, Maheshwari A, Sanberg PR. Mesenchymal stem cells in autoimmune disease. Stem Cells Dev. 2004;13:463-472.  [PubMed]  [DOI]
88.  Ringdén O, Uzunel M, Rasmusson I, Remberger M, Sundberg B, Lönnies H, Marschall HU, Dlugosz A, Szakos A, Hassan Z. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation. 2006;81:1390-1397.  [PubMed]  [DOI]
89.  Bunnell BA, Deng W, Robinson CM, Waldron PR, Bivalacqua TJ, Baber SR, Hyman AL, Kadowitz PJ. Potential application for mesenchymal stem cells in the treatment of cardiovascular diseases. Can J Physiol Pharmacol. 2005;83:529-539.  [PubMed]  [DOI]
90.  Minguell JJ, Erices A. Mesenchymal stem cells and the treatment of cardiac disease. Exp Biol Med (Maywood). 2006;231:39-49.  [PubMed]  [DOI]
91.  McTaggart SJ, Atkinson K. Mesenchymal stem cells: immunobiology and therapeutic potential in kidney disease. Nephrology (Carlton). 2007;12:44-52.  [PubMed]  [DOI]
92.  Shu SN, Wei L, Wang JH, Zhan YT, Chen HS, Wang Y. Hepatic differentiation capability of rat bone marrow-derived mesenchymal stem cells and hematopoietic stem cells. World J Gastroenterol. 2004;10:2818-2822.  [PubMed]  [DOI]
93.  Lange C, Bassler P, Lioznov MV, Bruns H, Kluth D, Zander AR, Fiegel HC. Liver-specific gene expression in mesenchymal stem cells is induced by liver cells. World J Gastroenterol. 2005;11:4497-4504.  [PubMed]  [DOI]
94.  Luk JM, Wang PP, Lee CK, Wang JH, Fan ST. Hepatic potential of bone marrow stromal cells: development of in vitro co-culture and intra-portal transplantation models. J Immunol Methods. 2005;305:39-47.  [PubMed]  [DOI]
95.  Lee KD, Kuo TK, Whang-Peng J, Chung YF, Lin CT, Chou SH, Chen JR, Chen YP, Lee OK. In vitro hepatic differentiation of human mesenchymal stem cells. Hepatology. 2004;40:1275-1284.  [PubMed]  [DOI]
96.  Seo MJ, Suh SY, Bae YC, Jung JS. Differentiation of human adipose stromal cells into hepatic lineage in vitro and in vivo. Biochem Biophys Res Commun. 2005;328:258-264.  [PubMed]  [DOI]
97.  Banas A, Teratani T, Yamamoto Y, Tokuhara M, Takeshita F, Osaki M, Kato T, Okochi H, Ochiya T. Rapid hepatic fate specification of adipose-derived stem cells and their therapeutic potential for liver failure. J Gastroenterol Hepatol. 2009;24:70-77.  [PubMed]  [DOI]
98.  Zheng YB, Gao ZL, Xie C, Zhu HP, Peng L, Chen JH, Chong YT. Characterization and hepatogenic differentiation of mesenchymal stem cells from human amniotic fluid and human bone marrow: a comparative study. Cell Biol Int. 2008;32:1439-1448.  [PubMed]  [DOI]
99.  Ishkitiev N, Yaegaki K, Calenic B, Nakahara T, Ishikawa H, Mitiev V, Haapasalo M. Deciduous and permanent dental pulp mesenchymal cells acquire hepatic morphologic and functional features in vitro. J Endod. 2010;36:469-474.  [PubMed]  [DOI]
100.  Ling L, Ni Y, Wang Q, Wang H, Hao S, Hu Y, Jiang W, Hou Y. Transdifferentiation of mesenchymal stem cells derived from human fetal lung to hepatocyte-like cells. Cell Biol Int. 2008;32:1091-1098.  [PubMed]  [DOI]
101.  Kern S, Eichler H, Stoeve J, Klüter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells. 2006;24:1294-1301.  [PubMed]  [DOI]
102.  Zhu X, He B, Zhou X, Ren J. Effects of transplanted bone-marrow-derived mesenchymal stem cells in animal models of acute hepatitis. Cell Tissue Res. 2013;351:477-486.  [PubMed]  [DOI]
103.  Cho KA, Ju SY, Cho SJ, Jung YJ, Woo SY, Seoh JY, Han HS, Ryu KH. Mesenchymal stem cells showed the highest potential for the regeneration of injured liver tissue compared with other subpopulations of the bone marrow. Cell Biol Int. 2009;33:772-777.  [PubMed]  [DOI]
104.  Cao H, Yang J, Yu J, Pan Q, Li J, Zhou P, Li Y, Pan X, Li J, Wang Y. Therapeutic potential of transplanted placental mesenchymal stem cells in treating Chinese miniature pigs with acute liver failure. BMC Med. 2012;10:56.  [PubMed]  [DOI]
105.  Pascual-Miguelañez I, Salinas-Gomez J, Fernandez-Luengas D, Villar-Zarra K, Clemente LV, Garcia-Arranz M, Olmo DG. Systemic treatment of acute liver failure with adipose derived stem cells. J Invest Surg. 2015;28:120-126.  [PubMed]  [DOI]
106.  Salomone F, Barbagallo I, Puzzo L, Piazza C, Li Volti G. Efficacy of adipose tissue-mesenchymal stem cell transplantation in rats with acetaminophen liver injury. Stem Cell Res. 2013;11:1037-1044.  [PubMed]  [DOI]
107.  Manzini BM, da Silva Santos Duarte A, Sankaramanivel S, Ramos AL, Latuf-Filho P, Escanhoela C, Kharmandayan P, Olalla Saad ST, Boin I, Malheiros Luzo ÂC. Useful properties of undifferentiated mesenchymal stromal cells and adipose tissue as the source in liver-regenerative therapy studied in an animal model of severe acute fulminant hepatitis. Cytotherapy. 2015;17:1052-1065.  [PubMed]  [DOI]
108.  Sato Y, Araki H, Kato J, Nakamura K, Kawano Y, Kobune M, Sato T, Miyanishi K, Takayama T, Takahashi M. Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion. Blood. 2005;106:756-763.  [PubMed]  [DOI]
109.  Li J, Zhang L, Xin J, Jiang L, Li J, Zhang T, Jin L, Li J, Zhou P, Hao S. Immediate intraportal transplantation of human bone marrow mesenchymal stem cells prevents death from fulminant hepatic failure in pigs. Hepatology. 2012;56:1044-1052.  [PubMed]  [DOI]
110.  Xin J, Ding W, Hao S, Jiang L, Zhou Q, Wu T, Shi D, Cao H, Li L, Li J. Human bone marrow mesenchymal stem cell-derived hepatocytes express tissue inhibitor of metalloproteinases 4 and follistatin. Liver Int. 2015;35:2301-2310.  [PubMed]  [DOI]
111.  Xagorari A, Siotou E, Yiangou M, Tsolaki E, Bougiouklis D, Sakkas L, Fassas A, Anagnostopoulos A. Protective effect of mesenchymal stem cell-conditioned medium on hepatic cell apoptosis after acute liver injury. Int J Clin Exp Pathol. 2013;6:831-840.  [PubMed]  [DOI]
112.  van Poll D, Parekkadan B, Cho CH, Berthiaume F, Nahmias Y, Tilles AW, Yarmush ML. Mesenchymal stem cell-derived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo. Hepatology. 2008;47:1634-1643.  [PubMed]  [DOI]
113.  Parekkadan B, van Poll D, Suganuma K, Carter EA, Berthiaume F, Tilles AW, Yarmush ML. Mesenchymal stem cell-derived molecules reverse fulminant hepatic failure. PLoS One. 2007;2:e941.  [PubMed]  [DOI]
114.  Zagoura DS, Roubelakis MG, Bitsika V, Trohatou O, Pappa KI, Kapelouzou A, Antsaklis A, Anagnou NP. Therapeutic potential of a distinct population of human amniotic fluid mesenchymal stem cells and their secreted molecules in mice with acute hepatic failure. Gut. 2012;61:894-906.  [PubMed]  [DOI]
115.  Zhang S, Chen L, Liu T, Zhang B, Xiang D, Wang Z, Wang Y. Human umbilical cord matrix stem cells efficiently rescue acute liver failure through paracrine effects rather than hepatic differentiation. Tissue Eng Part A. 2012;18:1352-1364.  [PubMed]  [DOI]
116.  Yuan S, Jiang T, Zheng R, Sun L, Cao G, Zhang Y. Effect of bone marrow mesenchymal stem cell transplantation on acute hepatic failure in rats. Exp Ther Med. 2014;8:1150-1158.  [PubMed]  [DOI]
117.  Fang B, Shi M, Liao L, Yang S, Liu Y, Zhao RC. Systemic infusion of FLK1(+) mesenchymal stem cells ameliorate carbon tetrachloride-induced liver fibrosis in mice. Transplantation. 2004;78:83-88.  [PubMed]  [DOI]
118.  Zhao DC, Lei JX, Chen R, Yu WH, Zhang XM, Li SN, Xiang P. Bone marrow-derived mesenchymal stem cells protect against experimental liver fibrosis in rats. World J Gastroenterol. 2005;11:3431-3440.  [PubMed]  [DOI]
119.  Jang YO, Kim MY, Cho MY, Baik SK, Cho YZ, Kwon SO. Effect of bone marrow-derived mesenchymal stem cells on hepatic fibrosis in a thioacetamide-induced cirrhotic rat model. BMC Gastroenterol. 2014;14:198.  [PubMed]  [DOI]
120.  Yu F, Ji S, Su L, Wan L, Zhang S, Dai C, Wang Y, Fu J, Zhang Q. Adipose-derived mesenchymal stem cells inhibit activation of hepatic stellate cells in vitro and ameliorate rat liver fibrosis in vivo. J Formos Med Assoc. 2015;114:130-138.  [PubMed]  [DOI]
121.  Wang Y, Lian F, Li J, Fan W, Xu H, Yang X, Liang L, Chen W, Yang J. Adipose derived mesenchymal stem cells transplantation via portal vein improves microcirculation and ameliorates liver fibrosis induced by CCl4 in rats. J Transl Med. 2012;10:133.  [PubMed]  [DOI]
122.  Seki A, Sakai Y, Komura T, Nasti A, Yoshida K, Higashimoto M, Honda M, Usui S, Takamura M, Takamura T. Adipose tissue-derived stem cells as a regenerative therapy for a mouse steatohepatitis-induced cirrhosis model. Hepatology. 2013;58:1133-1142.  [PubMed]  [DOI]
123.  Aurich H, Sgodda M, Kaltwasser P, Vetter M, Weise A, Liehr T, Brulport M, Hengstler JG, Dollinger MM, Fleig WE. Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo. Gut. 2009;58:570-581.  [PubMed]  [DOI]
124.  Kamada Y, Yoshida Y, Saji Y, Fukushima J, Tamura S, Kiso S, Hayashi N. Transplantation of basic fibroblast growth factor-pretreated adipose tissue-derived stromal cells enhances regression of liver fibrosis in mice. Am J Physiol Gastrointest Liver Physiol. 2009;296:G157-G167.  [PubMed]  [DOI]
125.  Tang WP, Akahoshi T, Piao JS, Narahara S, Murata M, Kawano T, Hamano N, Ikeda T, Hashizume M. Basic fibroblast growth factor-treated adipose tissue-derived mesenchymal stem cell infusion to ameliorate liver cirrhosis via paracrine hepatocyte growth factor. J Gastroenterol Hepatol. 2015;30:1065-1074.  [PubMed]  [DOI]
126.  Shams S, Mohsin S, Nasir GA, Khan M, Khan SN. Mesenchymal Stem Cells Pretreated with HGF and FGF4 Can Reduce Liver Fibrosis in Mice. Stem Cells Int. 2015;2015:747245.  [PubMed]  [DOI]
127.  Mohsin S, Shams S, Ali Nasir G, Khan M, Javaid Awan S, Khan SN, Riazuddin S. Enhanced hepatic differentiation of mesenchymal stem cells after pretreatment with injured liver tissue. Differentiation. 2011;81:42-48.  [PubMed]  [DOI]
128.  Parekkadan B, van Poll D, Megeed Z, Kobayashi N, Tilles AW, Berthiaume F, Yarmush ML. Immunomodulation of activated hepatic stellate cells by mesenchymal stem cells. Biochem Biophys Res Commun. 2007;363:247-252.  [PubMed]  [DOI]
129.  Oyagi S, Hirose M, Kojima M, Okuyama M, Kawase M, Nakamura T, Ohgushi H, Yagi K. Therapeutic effect of transplanting HGF-treated bone marrow mesenchymal cells into CCl4-injured rats. J Hepatol. 2006;44:742-748.  [PubMed]  [DOI]
130.  Lin N, Hu K, Chen S, Xie S, Tang Z, Lin J, Xu R. Nerve growth factor-mediated paracrine regulation of hepatic stellate cells by multipotent mesenchymal stromal cells. Life Sci. 2009;85:291-295.  [PubMed]  [DOI]
131.  Li T, Zhu J, Ma K, Liu N, Feng K, Li X, Wang S, Bie P. Autologous bone marrow-derived mesenchymal stem cell transplantation promotes liver regeneration after portal vein embolization in cirrhotic rats. J Surg Res. 2013;184:1161-1173.  [PubMed]  [DOI]
132.  Rabani V, Shahsavani M, Gharavi M, Piryaei A, Azhdari Z, Baharvand H. Mesenchymal stem cell infusion therapy in a carbon tetrachloride-induced liver fibrosis model affects matrix metalloproteinase expression. Cell Biol Int. 2010;34:601-605.  [PubMed]  [DOI]
133.  Mohamadnejad M, Alimoghaddam K, Mohyeddin-Bonab M, Bagheri M, Bashtar M, Ghanaati H, Baharvand H, Ghavamzadeh A, Malekzadeh R. Phase 1 trial of autologous bone marrow mesenchymal stem cell transplantation in patients with decompensated liver cirrhosis. Arch Iran Med. 2007;10:459-466.  [PubMed]  [DOI]
134.  Kharaziha P, Hellström PM, Noorinayer B, Farzaneh F, Aghajani K, Jafari F, Telkabadi M, Atashi A, Honardoost M, Zali MR. Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection: a phase I-II clinical trial. Eur J Gastroenterol Hepatol. 2009;21:1199-1205.  [PubMed]  [DOI]
135.  Amer ME, El-Sayed SZ, El-Kheir WA, Gabr H, Gomaa AA, El-Noomani N, Hegazy M. Clinical and laboratory evaluation of patients with end-stage liver cell failure injected with bone marrow-derived hepatocyte-like cells. Eur J Gastroenterol Hepatol. 2011;23:936-941.  [PubMed]  [DOI]
136.  Peng L, Xie DY, Lin BL, Liu J, Zhu HP, Xie C, Zheng YB, Gao ZL. Autologous bone marrow mesenchymal stem cell transplantation in liver failure patients caused by hepatitis B: short-term and long-term outcomes. Hepatology. 2011;54:820-828.  [PubMed]  [DOI]
137.  El-Ansary M, Abdel-Aziz I, Mogawer S, Abdel-Hamid S, Hammam O, Teaema S, Wahdan M. Phase II trial: undifferentiated versus differentiated autologous mesenchymal stem cells transplantation in Egyptian patients with HCV induced liver cirrhosis. Stem Cell Rev. 2012;8:972-981.  [PubMed]  [DOI]
138.  Amin MA, Sabry D, Rashed LA, Aref WM, el-Ghobary MA, Farhan MS, Fouad HA, Youssef YA. Short-term evaluation of autologous transplantation of bone marrow-derived mesenchymal stem cells in patients with cirrhosis: Egyptian study. Clin Transplant. 2013;27:607-612.  [PubMed]  [DOI]
139.  Jang YO, Kim YJ, Baik SK, Kim MY, Eom YW, Cho MY, Park HJ, Park SY, Kim BR, Kim JW. Histological improvement following administration of autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: a pilot study. Liver Int. 2014;34:33-41.  [PubMed]  [DOI]
140.  Zhang Z, Lin H, Shi M, Xu R, Fu J, Lv J, Chen L, Lv S, Li Y, Yu S. Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients. J Gastroenterol Hepatol. 2012;27 Suppl 2:112-120.  [PubMed]  [DOI]
141.  Shi M, Zhang Z, Xu R, Lin H, Fu J, Zou Z, Zhang A, Shi J, Chen L, Lv S. Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients. Stem Cells Transl Med. 2012;1:725-731.  [PubMed]  [DOI]
142.  Wang L, Li J, Liu H, Li Y, Fu J, Sun Y, Xu R, Lin H, Wang S, Lv S. Pilot study of umbilical cord-derived mesenchymal stem cell transfusion in patients with primary biliary cirrhosis. J Gastroenterol Hepatol. 2013;28 Suppl 1:85-92.  [PubMed]  [DOI]
143.  Mohamadnejad M, Alimoghaddam K, Bagheri M, Ashrafi M, Abdollahzadeh L, Akhlaghpoor S, Bashtar M, Ghavamzadeh A, Malekzadeh R. Randomized placebo-controlled trial of mesenchymal stem cell transplantation in decompensated cirrhosis. Liver Int. 2013;33:1490-1496.  [PubMed]  [DOI]
144.  Baertschiger RM, Serre-Beinier V, Morel P, Bosco D, Peyrou M, Clément S, Sgroi A, Kaelin A, Buhler LH, Gonelle-Gispert C. Fibrogenic potential of human multipotent mesenchymal stromal cells in injured liver. PLoS One. 2009;4:e6657.  [PubMed]  [DOI]
145.  di Bonzo LV, Ferrero I, Cravanzola C, Mareschi K, Rustichell D, Novo E, Sanavio F, Cannito S, Zamara E, Bertero M. Human mesenchymal stem cells as a two-edged sword in hepatic regenerative medicine: engraftment and hepatocyte differentiation versus profibrogenic potential. Gut. 2008;57:223-231.  [PubMed]  [DOI]
146.  Kisseleva T, Uchinami H, Feirt N, Quintana-Bustamante O, Segovia JC, Schwabe RF, Brenner DA. Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis. J Hepatol. 2006;45:429-438.  [PubMed]  [DOI]
147.  Meier RP, Mahou R, Morel P, Meyer J, Montanari E, Muller YD, Christofilopoulos P, Wandrey C, Gonelle-Gispert C, Bühler LH. Microencapsulated human mesenchymal stem cells decrease liver fibrosis in mice. J Hepatol. 2015;62:634-641.  [PubMed]  [DOI]
148.  Djouad F, Plence P, Bony C, Tropel P, Apparailly F, Sany J, Noël D, Jorgensen C. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood. 2003;102:3837-3844.  [PubMed]  [DOI]
149.  Zhu W, Xu W, Jiang R, Qian H, Chen M, Hu J, Cao W, Han C, Chen Y. Mesenchymal stem cells derived from bone marrow favor tumor cell growth in vivo. Exp Mol Pathol. 2006;80:267-274.  [PubMed]  [DOI]
150.  Yu JM, Jun ES, Bae YC, Jung JS. Mesenchymal stem cells derived from human adipose tissues favor tumor cell growth in vivo. Stem Cells Dev. 2008;17:463-473.  [PubMed]  [DOI]
151.  Pan Q, Fouraschen SM, de Ruiter PE, Dinjens WN, Kwekkeboom J, Tilanus HW, van der Laan LJ. Detection of spontaneous tumorigenic transformation during culture expansion of human mesenchymal stromal cells. Exp Biol Med (Maywood). 2014;239:105-115.  [PubMed]  [DOI]
152.  Khakoo AY, Pati S, Anderson SA, Reid W, Elshal MF, Rovira II, Nguyen AT, Malide D, Combs CA, Hall G. Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi’s sarcoma. J Exp Med. 2006;203:1235-1247.  [PubMed]  [DOI]
153.  Qiao L, Xu Z, Zhao T, Zhao Z, Shi M, Zhao RC, Ye L, Zhang X. Suppression of tumorigenesis by human mesenchymal stem cells in a hepatoma model. Cell Res. 2008;18:500-507.  [PubMed]  [DOI]
154.  Lu YR, Yuan Y, Wang XJ, Wei LL, Chen YN, Cong C, Li SF, Long D, Tan WD, Mao YQ. The growth inhibitory effect of mesenchymal stem cells on tumor cells in vitro and in vivo. Cancer Biol Ther. 2008;7:245-251.  [PubMed]  [DOI]
155.  Gao P, Ding Q, Wu Z, Jiang H, Fang Z. Therapeutic potential of human mesenchymal stem cells producing IL-12 in a mouse xenograft model of renal cell carcinoma. Cancer Lett. 2010;290:157-166.  [PubMed]  [DOI]
156.  Abdel aziz MT, El Asmar MF, Atta HM, Mahfouz S, Fouad HH, Roshdy NK, Rashed LA, Sabry D, Hassouna AA, Taha FM. Efficacy of mesenchymal stem cells in suppression of hepatocarcinorigenesis in rats: possible role of Wnt signaling. J Exp Clin Cancer Res. 2011;30:49.  [PubMed]  [DOI]
157.  Alison MR, Poulsom R, Jeffery R, Dhillon AP, Quaglia A, Jacob J, Novelli M, Prentice G, Williamson J, Wright NA. Hepatocytes from non-hepatic adult stem cells. Nature. 2000;406:257.  [PubMed]  [DOI]
158.  Theise ND, Nimmakayalu M, Gardner R, Illei PB, Morgan G, Teperman L, Henegariu O, Krause DS. Liver from bone marrow in humans. Hepatology. 2000;32:11-16.  [PubMed]  [DOI]
159.  De Silvestro G, Vicarioto M, Donadel C, Menegazzo M, Marson P, Corsini A. Mobilization of peripheral blood hematopoietic stem cells following liver resection surgery. Hepatogastroenterology. 2004;51:805-810.  [PubMed]  [DOI]
160.  Gehling UM, Willems M, Dandri M, Petersen J, Berna M, Thill M, Wulf T, Müller L, Pollok JM, Schlagner K. Partial hepatectomy induces mobilization of a unique population of haematopoietic progenitor cells in human healthy liver donors. J Hepatol. 2005;43:845-853.  [PubMed]  [DOI]
161.  Gehling UM, Willems M, Schlagner K, Benndorf RA, Dandri M, Petersen J, Sterneck M, Pollok JM, Hossfeld DK, Rogiers X. Mobilization of hematopoietic progenitor cells in patients with liver cirrhosis. World J Gastroenterol. 2010;16:217-224.  [PubMed]  [DOI]
162.  Sakaida I, Terai S, Yamamoto N, Aoyama K, Ishikawa T, Nishina H, Okita K. Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice. Hepatology. 2004;40:1304-1311.  [PubMed]  [DOI]
163.  Thomas JA, Pope C, Wojtacha D, Robson AJ, Gordon-Walker TT, Hartland S, Ramachandran P, Van Deemter M, Hume DA, Iredale JP. Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function. Hepatology. 2011;53:2003-2015.  [PubMed]  [DOI]
164.  Theise ND, Badve S, Saxena R, Henegariu O, Sell S, Crawford JM, Krause DS. Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology. 2000;31:235-240.  [PubMed]  [DOI]
165.  Fürst G, Schulte am Esch J, Poll LW, Hosch SB, Fritz LB, Klein M, Godehardt E, Krieg A, Wecker B, Stoldt V. Portal vein embolization and autologous CD133+ bone marrow stem cells for liver regeneration: initial experience. Radiology. 2007;243:171-179.  [PubMed]  [DOI]
166.  Terai S, Ishikawa T, Omori K, Aoyama K, Marumoto Y, Urata Y, Yokoyama Y, Uchida K, Yamasaki T, Fujii Y. Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. Stem Cells. 2006;24:2292-2298.  [PubMed]  [DOI]
167.  Lemoli RM, Catani L, Talarico S, Loggi E, Gramenzi A, Baccarani U, Fogli M, Grazi GL, Aluigi M, Marzocchi G. Mobilization of bone marrow-derived hematopoietic and endothelial stem cells after orthotopic liver transplantation and liver resection. Stem Cells. 2006;24:2817-2825.  [PubMed]  [DOI]
168.  To LB, Haylock DN, Simmons PJ, Juttner CA. The biology and clinical uses of blood stem cells. Blood. 1997;89:2233-2258.  [PubMed]  [DOI]
169.  Mohty M, Ho AD. In and out of the niche: perspectives in mobilization of hematopoietic stem cells. Exp Hematol. 2011;39:723-729.  [PubMed]  [DOI]
170.  Metcalf D. The molecular control of cell division, differentiation commitment and maturation in haemopoietic cells. Nature. 1989;339:27-30.  [PubMed]  [DOI]
171.  Yannaki E, Athanasiou E, Xagorari A, Constantinou V, Batsis I, Kaloyannidis P, Proya E, Anagnostopoulos A, Fassas A. G-CSF-primed hematopoietic stem cells or G-CSF per se accelerate recovery and improve survival after liver injury, predominantly by promoting endogenous repair programs. Exp Hematol. 2005;33:108-119.  [PubMed]  [DOI]
172.  Quintana-Bustamante O, Alvarez-Barrientos A, Kofman AV, Fabregat I, Bueren JA, Theise ND, Segovia JC. Hematopoietic mobilization in mice increases the presence of bone marrow-derived hepatocytes via in vivo cell fusion. Hepatology. 2006;43:108-116.  [PubMed]  [DOI]
173.  Piscaglia AC, Shupe TD, Oh SH, Gasbarrini A, Petersen BE. Granulocyte-colony stimulating factor promotes liver repair and induces oval cell migration and proliferation in rats. Gastroenterology. 2007;133:619-631.  [PubMed]  [DOI]
174.  Tsolaki E, Athanasiou E, Gounari E, Zogas N, Siotou E, Yiangou M, Anagnostopoulos A, Yannaki E. Hematopoietic stem cells and liver regeneration: differentially acting hematopoietic stem cell mobilization agents reverse induced chronic liver injury. Blood Cells Mol Dis. 2014;53:124-132.  [PubMed]  [DOI]
175.  Gaia S, Smedile A, Omedè P, Olivero A, Sanavio F, Balzola F, Ottobrelli A, Abate ML, Marzano A, Rizzetto M. Feasibility and safety of G-CSF administration to induce bone marrow-derived cells mobilization in patients with end stage liver disease. J Hepatol. 2006;45:13-19.  [PubMed]  [DOI]
176.  Yannaki E, Anagnostopoulos A, Kapetanos D, Xagorari A, Iordanidis F, Batsis I, Kaloyannidis P, Athanasiou E, Dourvas G, Kitis G. Lasting amelioration in the clinical course of decompensated alcoholic cirrhosis with boost infusions of mobilized peripheral blood stem cells. Exp Hematol. 2006;34:1583-1587.  [PubMed]  [DOI]
177.  Gordon MY, Levicar N, Pai M, Bachellier P, Dimarakis I, Al-Allaf F, M’Hamdi H, Thalji T, Welsh JP, Marley SB. Characterization and clinical application of human CD34+ stem/progenitor cell populations mobilized into the blood by granulocyte colony-stimulating factor. Stem Cells. 2006;24:1822-1830.  [PubMed]  [DOI]
178.  Spahr L, Lambert JF, Rubbia-Brandt L, Chalandon Y, Frossard JL, Giostra E, Hadengue A. Granulocyte-colony stimulating factor induces proliferation of hepatic progenitors in alcoholic steatohepatitis: a randomized trial. Hepatology. 2008;48:221-229.  [PubMed]  [DOI]
179.  Garg V, Garg H, Khan A, Trehanpati N, Kumar A, Sharma BC, Sakhuja P, Sarin SK. Granulocyte colony-stimulating factor mobilizes CD34(+) cells and improves survival of patients with acute-on-chronic liver failure. Gastroenterology. 2012;142:505-512.e1.  [PubMed]  [DOI]
180.  Singh V, Sharma AK, Narasimhan RL, Bhalla A, Sharma N, Sharma R. Granulocyte colony-stimulating factor in severe alcoholic hepatitis: a randomized pilot study. Am J Gastroenterol. 2014;109:1417-1423.  [PubMed]  [DOI]
181.  Piscaglia AC, Arena V, Passalacqua S, Gasbarrini A. A case of granulocyte-colony stimulating factor/plasmapheresis-induced activation of granulocyte-colony stimulating factor-positive hepatic progenitors in acute-on-chronic liver failure. Hepatology. 2015;62:649-652.  [PubMed]  [DOI]
182.  Di Campli C, Zocco MA, Saulnier N, Grieco A, Rapaccini G, Addolorato G, Rumi C, Santoliquido A, Leone G, Gasbarrini G. Safety and efficacy profile of G-CSF therapy in patients with acute on chronic liver failure. Dig Liver Dis. 2007;39:1071-1076.  [PubMed]  [DOI]
183.  Lorenzini S, Isidori A, Catani L, Gramenzi A, Talarico S, Bonifazi F, Giudice V, Conte R, Baccarani M, Bernardi M. Stem cell mobilization and collection in patients with liver cirrhosis. Aliment Pharmacol Ther. 2008;27:932-939.  [PubMed]  [DOI]
184.  Gasbarrini A, Rapaccini GL, Rutella S, Zocco MA, Tittoto P, Leone G, Pola P, Gasbarrini G, Di Campli C. Rescue therapy by portal infusion of autologous stem cells in a case of drug-induced hepatitis. Dig Liver Dis. 2007;39:878-882.  [PubMed]  [DOI]
185.  Levicar N, Pai M, Habib NA, Tait P, Jiao LR, Marley SB, Davis J, Dazzi F, Smadja C, Jensen SL. Long-term clinical results of autologous infusion of mobilized adult bone marrow derived CD34+ cells in patients with chronic liver disease. Cell Prolif. 2008;41 Suppl 1:115-125.  [PubMed]  [DOI]
186.  Pai M, Zacharoulis D, Milicevic MN, Helmy S, Jiao LR, Levicar N, Tait P, Scott M, Marley SB, Jestice K. Autologous infusion of expanded mobilized adult bone marrow-derived CD34+ cells into patients with alcoholic liver cirrhosis. Am J Gastroenterol. 2008;103:1952-1958.  [PubMed]  [DOI]
187.  Han Y, Yan L, Han G, Zhou X, Hong L, Yin Z, Zhang X, Wang S, Wang J, Sun A. Controlled trials in hepatitis B virus-related decompensate liver cirrhosis: peripheral blood monocyte transplant versus granulocyte-colony-stimulating factor mobilization therapy. Cytotherapy. 2008;10:390-396.  [PubMed]  [DOI]
188.  Kallis YN, Alison MR, Forbes SJ. Bone marrow stem cells and liver disease. Gut. 2007;56:716-724.  [PubMed]  [DOI]
189.  Wagers AJ, Sherwood RI, Christensen JL, Weissman IL. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science. 2002;297:2256-2259.  [PubMed]  [DOI]
190.  Thorgeirsson SS, Grisham JW. Hematopoietic cells as hepatocyte stem cells: a critical review of the evidence. Hepatology. 2006;43:2-8.  [PubMed]  [DOI]
191.  Loffredo FS, Steinhauser ML, Gannon J, Lee RT. Bone marrow-derived cell therapy stimulates endogenous cardiomyocyte progenitors and promotes cardiac repair. Cell Stem Cell. 2011;8:389-398.  [PubMed]  [DOI]
192.  Tang XL, Rokosh G, Sanganalmath SK, Yuan F, Sato H, Mu J, Dai S, Li C, Chen N, Peng Y. Intracoronary administration of cardiac progenitor cells alleviates left ventricular dysfunction in rats with a 30-day-old infarction. Circulation. 2010;121:293-305.  [PubMed]  [DOI]
193.  Wang X, Willenbring H, Akkari Y, Torimaru Y, Foster M, Al-Dhalimy M, Lagasse E, Finegold M, Olson S, Grompe M. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature. 2003;422:897-901.  [PubMed]  [DOI]
194.  Vassilopoulos G, Wang PR, Russell DW. Transplanted bone marrow regenerates liver by cell fusion. Nature. 2003;422:901-904.  [PubMed]  [DOI]
195.  Lin N, Lin J, Bo L, Weidong P, Chen S, Xu R. Differentiation of bone marrow-derived mesenchymal stem cells into hepatocyte-like cells in an alginate scaffold. Cell Prolif. 2010;43:427-434.  [PubMed]  [DOI]
196.  Kazemnejad S, Allameh A, Soleimani M, Gharehbaghian A, Mohammadi Y, Amirizadeh N, Jazayery M. Biochemical and molecular characterization of hepatocyte-like cells derived from human bone marrow mesenchymal stem cells on a novel three-dimensional biocompatible nanofibrous scaffold. J Gastroenterol Hepatol. 2009;24:278-287.  [PubMed]  [DOI]
197.  Piryaei A, Valojerdi MR, Shahsavani M, Baharvand H. Differentiation of bone marrow-derived mesenchymal stem cells into hepatocyte-like cells on nanofibers and their transplantation into a carbon tetrachloride-induced liver fibrosis model. Stem Cell Rev. 2011;7:103-118.  [PubMed]  [DOI]
198.  Li J, Tao R, Wu W, Cao H, Xin J, Li J, Guo J, Jiang L, Gao C, Demetriou AA. 3D PLGA scaffolds improve differentiation and function of bone marrow mesenchymal stem cell-derived hepatocytes. Stem Cells Dev. 2010;19:1427-1436.  [PubMed]  [DOI]
199.  Li P, Zhang J, Liu J, Ma H, Liu J, Lie P, Wang Y, Liu G, Zeng H, Li Z. Promoting the recovery of injured liver with poly (3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate) scaffolds loaded with umbilical cord-derived mesenchymal stem cells. Tissue Eng Part A. 2015;21:603-615.  [PubMed]  [DOI]
200.  Soto-Gutiérrez A, Kobayashi N, Rivas-Carrillo JD, Navarro-Alvarez N, Zhao D, Okitsu T, Noguchi H, Basma H, Tabata Y, Chen Y. Reversal of mouse hepatic failure using an implanted liver-assist device containing ES cell-derived hepatocytes. Nat Biotechnol. 2006;24:1412-1419.  [PubMed]  [DOI]
201.  Chia HN, Wu BM. Recent advances in 3D printing of biomaterials. J Biol Eng. 2015;9:4.  [PubMed]  [DOI]
202.  Li YS, Harn HJ, Hsieh DK, Wen TC, Subeq YM, Sun LY, Lin SZ, Chiou TW. Cells and materials for liver tissue engineering. Cell Transplant. 2013;22:685-700.  [PubMed]  [DOI]