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Historical Perspectives and Advances in the Mesenchymal Stem Cell Research forthe Treatment of Liver Diseases
Chien-Wei Lee, Yu-Fan Chen, Hao-Hsiang Wu, Oscar K. Lee
PII: S0016-5085(17)36280-7DOI: 10.1053/j.gastro.2017.09.049Reference: YGAST 61495
To appear in: GastroenterologyAccepted Date: 27 September 2017
Please cite this article as: Lee C-W, Chen Y-F, Wu H-H, Lee OK, Historical Perspectives and Advancesin the Mesenchymal Stem Cell Research for the Treatment of Liver Diseases, Gastroenterology (2017),doi: 10.1053/j.gastro.2017.09.049.
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Historical Perspectives and Advances in the Mesenchymal Stem Cell Research for the
Treatment of Liver Diseases
Short Title: Stem Cell Therapy for Liver Diseases
Chien-Wei Lee1,2,#
, Yu-Fan Chen2,3,#
, Hao-Hsiang Wu2,4,#
and Oscar K. Lee2,3,5,6,*
1Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei,
Taiwan;
2Stem Cell Research Center, National Yang-Ming University, Taipei, Taiwan;
3Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan;
4Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan;
5Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan;
6Taipei City Hospital, Taipei, Taiwan.
#These authors contributed equally to this manuscript
Grant Support: The authors acknowledge financial support from the Ministry of Science and
Technology, Taiwan (MOST103-2314-B-010-053-MY3, MOST 106-2321-B-010-008, MOST
106-2911-I-010-502 and MOST 106-3114-B-010-002). This study was also supported by
Aiming for the Top University Plan, a grant from Ministry of Education.
Abbreviations: BAL, bioartificial liver system; GVHD, graft-versus-host disease; HESC, human
embryonic stem cell; HGF, hepatocyte growth factor; HLC, hepatocyte-like cell; HPSC, human
pluripotent stem cell; HSC, hepatic stellate cell; IDO, indoleamine 2,3-dioxygenase; iPSCs,
induced pluripotent stem cells; MSC, mesenchymal stem cell; PSC, pluripotent stem cell
*Correspondence: Oscar K. Lee, MD, PhD
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Taipei City Hospital, No. 145, Zhengzhou Road, Datong District, Taipei 10341, Taiwan
Tel.: +886-2-2559-6131; Fax: +886-2-2559-9051; E-mail: DAV47@tpech.gov.tw
Conflicts of Interest: The authors disclose no conflicts.
Author Contributions: Chien-Wei Lee, Yu-Fan Chen, and Hao-Hsiang Wu wrote the
manuscript; Oscar K. Lee provided feedback and edited the manuscript; Oscar K. Lee
supervised the literature search.
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Abstract
Liver transplantation is the only effective therapy for patients with decompensated cirrhosis
and fulminant liver failure. However, due to a shortage of donor livers and complications
associated with immune suppression, there is an urgent need for new therapeutic strategies
for patients with end-stage liver diseases. Given their unique function in self-renewal and
differentiation potential, stem cells might be used to regenerate damaged liver tissue.
Recent studies have shown that stem cell-based therapies can improve liver function in a
mouse model of hepatic failure. Moreover, acellular liver scaffolds, seeded with hepatocytes,
produced functional bioengineered livers for organ transplantation in pre-clinical studies.
The therapeutic potential of stem cells or their differentiated progenies will depend on their
capacity to differentiate into mature and functional cell types after transplantation. It will
also be important to devise methods to overcome their genomic instability, immune
reactivity, and tumorigenic potential. We review directions and advances in the use of
mesenchymal stem cells and their derived hepatocytes for liver regeneration. We also
discuss the potential applications of hepatocytes derived from human pluripotent stem cells
and challenges to using these cells in treating end-stage liver disease.
Keywords: Stem Cell Therapy; Pluripotent Stem Cells; Hepatocytes; Regenerative Medicine
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Despite the success of transplantation of hematopoietic stem cells, few other cell-based
therapies have been successfully translated into clinical application. The dearth of cell-based
therapies is unfortunate as the potential and demand for such therapies are apparent. One
field with exciting developments in cell-based therapies is the field of liver diseases.
Acute liver failure, end-stage liver diseases, and inherited metabolic disorders usually
lead to morbidity and mortality, and are associated with a variety of etiologies (toxic injury,
viral infections, and autoimmune and genetic disorders). In the United States, approximately
30,000 deaths each year are caused by chronic liver disease; the incidence of such deaths
increases by 3 % each year.1 The only curative treatment for end-stage liver disease is liver
transplantation. However, there are more than 15,000 patients on the wait list for a liver in
the United States—approximately 50% of them will not receive a transplant. Liver disease is
the leading cause of premature death in the United Kingdom, resulting in the loss of a
greater number of life-years than many other causes.2 Liver transplantation, the best
treatment option, is limited by high cost and shortage of donor organs. Moreover,
long-term survival is hampered by the graft vs host disease (GVHD) and side effects of
life-long immunosuppression.3
Transplantation of hepatocytes has been considered as an alternative to
transplantation of organs, but faces multiple problems, including the shortage of high
quantity cell sources, challenges to expansion in vitro, concerns of allogeneic rejection and
xenozoonosis, and the fact that hepatocytes spontaneously and quickly lose hepatic
characteristics in vitro.4-6
Stem cells, including induced pluripotent stem cells (iPSCs),
mesenchymal stem cells (MSCs), fetal liver stem cells, fetal biliary tree stem cells,
chemically-induced liver progenitors, and bone marrow CD45+ cells, could provide
alternatives to organ and hepatocyte transplantation, and may offer solutions to the
above-mentioned problems.7, 8
Among them, MSCs have been investigated in detail and
hold great promise for clinical application, as a personalized cell therapy. This is because
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they can be conveniently isolated and expanded in culture, are immune modulatory, and
allogeneic cells to not pose a xenozoonosis risk. MSCs also provide trophic support, have the
potential to differentiate into hepatocyte-like cells (HLCs), and there are no ethical issues
are associated with their use.9-11
We review the role of MSCs in HLC generation and liver
regenerative medicine, and to point to new technologies for clinical application.
In Treatment of Liver Disease
MSCs were first isolated from the bone marrow in 1968, by Friedenstein et al.12
These cells
can be also isolated from other adult somatic tissues, such as the adipose tissue and
umbilical cord blood. Given the self-renewal abilities of MSC, and their therapeutic potential
in tissue engineering and regenerative medicine, MSCs are considered as an ideal cell source
for transplantation. The safety and feasibility of MSC-based therapies have been
demonstrated in clinical trials for many diseases, including GVHD, heart diseases,
osteoarthritis, bone and cartilage injuries, diabetes and its complications, cancer, spinal cord
injury, multiple sclerosis, liver cirrhosis, respiratory disorders, Crohn’s disease, autoimmune
diseases, and others.13
MSCs can localize to damaged liver and eliminate liver fibrosis. Migration of MSCs is
facilitated by release of several molecules from the damaged liver that interact with
different receptors expressed by the MSCs.14-16
MSCs might be used to treat different types
of liver disease because they trans-differentiate in vitro and MSC-derived HLCs can
substitute for injured hepatocytes to restore liver function, have immunosuppressive and
anti-inflammatory effects, promote survival of resident hepatocytes, and direct
differentiation in vivo (Figure 1).
Hepatocyte Differentiation
Transplanted MSC-derived HLCs increase hepatic function at the engraftment site in models
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of acute and chronic liver failure. In 2004, Shu et al17
demonstrated the differentiation of rat
bone marrow MSCs into albumin- and cytokeratin 18-expressing HLCs. In the same year, we
reported a 2-step protocol for the induction of HLCs from human bone marrow MSCs—these
cells have hepatocyte-specific gene expression patterns and hepatocyte-specific functions,
including urea and glycogen production.18
Based on these findings, successful differentiation
of MSCs from other tissue origin into HLCs was also reported. HLCs have been derived from
umbilical cord blood and bone marrow-derived MSCs.19, 20
Furthermore, adipose
tissue-derived MSCs were also successfully induced to differentiate into HLCs.21
In the last decade, different groups established several hepatic differentiation protocols
for MSCs (summarized in Table 1). MSCs are more efficiently induced into HLCs in mice via a
2-step hepatic differentiation protocol18,21
than by the hepatic differentiation protocol
described by Shu et al.17
Transplantation of MSC-derived hepatocytes can restore liver
function to mice with carbon tetrachloride (CCl4)-induced liver failure.22
Co-culture of MSCs
with primary liver cells induces differentiation of MSCs into HLCs 23
. MSC-derived HLCs,
formed by co-culture with primary hepatocytes, integrate into injured liver and reduce
fibrosis 24
. Incubation of MSCs with injured liver tissue was reported to increase expression
of hepatocyte-specific genes in MSCs.25
These observations provide evidence for alternative
methods of inducing differentiation of MSCs into HLCs, via interactions with liver cells, and
the possibility of tissue integration after stem cell transplantation.
Small Inhibitors in Hepatocyte Differentiation
Differentiation of MSCs into hepatocytes involves in the mesenchymal to epithelial transition.
An inhibitor of RAC1 (NSC23766) maintains the epithelial morphology of MSCs, accelerates
upregulation of hepatocyte marker genes, and induces hepatocyte cell functions, by altering
actin polymerization during differentiation.26
Chromatin-remodeling agents, such as valproic
acid, 5-aza-2'-deoxycytidine, and trichostatin A, promote differentiation of MSCs into
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hepatocytes, indicating epigenetic regulation of this transition. hepatocytes.27-29
Manipulating hepatocyte differentiation of MSCs, via intracellular and extracellular factors,
might promote hepatic maturation, accelerate cell differentiation, or increase proliferation.
Mechanical Forces and Microenvironment Architecture
Mechanical forces and the architecture of the microenvironment affect differentiation
of MSCs into hepatocytes. Continuous flow of fluid over microfluidic chips increases the
ability of MSCs to uptake low-density lipoprotein as they differentiate into hepatocytes 30
.
Low shear stress increases differentiation of MSCs into hepatocytes.31
To mimic the
3-dimensional (3D) microenvironment and architecture of the liver, some groups fabricated
artificial 3D scaffolds and investigated whether they induce differentiation of MSCs more
efficiently than 2D culture. MSCs were reported to increase differentiation into hepatocytes
on poly-ε-caprolactone/collagen/polyethersulfone nanofiber scaffolds 32
. Poly-L-lactic acid
nanofiber scaffolds were also reported to increase the expression of hepatocyte-specific
genes by differentiating MSCs.33
Interestingly, during the differentiation of MSCs into
hepatocytes on artificial 3D scaffolds, MSCs form hepatic spheroids that express markers of
hepatocytes and undergo glycogen storage, urea production, albumin secretion, and
cytochrome P450 activity.34
Despite reports indicating the potential of MSCs to differentiate into hepatocytes,
MSC-derived HLCs are similar to fetal hepatocytes and do not reach full maturity in vitro 33
.
Moreover, different types of stem cell sources for the induction of HLCs have been reported;
these were generated using a modified differentiation protocol.35
Therefore, the maturation
process of MSCs during hepatic differentiation requires improvement.
Anti-inflammatory Effects
The liver is an immunologically complex organ. It contains specialized immune cells,
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including Kupffer cells; antigen-presenting liver sinusoidal endothelial cells and dendritic
cells; and liver-resident lymphocytes.36
In addition, the hepatocytes and hepatic stellate cells
(HSCs) affect the immune response in the liver by activating T cells.37-39
The liver
microenvironment and immune response maintain liver homeostasis.
Inflammation is one of the most characteristic features of different liver diseases and is
present at all disease stages.40
MSCs modulate innate and adaptive immune responses.41
MSC-derived prostaglandin E2 and indoleamine 2,3-dioxygenase (IDO) reduces proliferation,
cytolytic activity, and cytokine secretion of natural killer cells.42
MSCs also repress the
activity of Kupffer cells, reducing secretion of the inflammatory cytokine tumor necrosis
factor;43
they also convert M1 macrophages (inflammatory) to M2 macrophages
(anti-inflammatory), by secreting prostaglandin E2.44
MSC-derived human leukocyte antigen
G inactivates dendritic cells;45
MSC-derived interleukin 6 (IL6) and hepatocyte growth factor
(HGF) inhibit the maturation of monocytes into dendritic cells, reducing their inflammatory
potential and changing activated CD4+ T cells from T-helper 1 to T-helper 2 phenotypes.
46
MSCs also inhibit proliferation of CD8+ T cells and increase the rate of conversion of CD4+ T
cells from T-helper 1 to T-helper 2 phenotypes by secreting heme oxygenase 1 and IDO.47-50
Furthermore, MSCs induce the development of regulatory T cells to modulate CD4+ T cell
polarization.51
MSCs directly inhibit B cell proliferation and terminal differentiation through soluble
factors and cell contacts.52
MSCs also act as immunosuppressors following liver
transplantation in mice.53
Only a few studies reported the use of immunosuppression during
liver transplantation but they indicated that liver transplantation with MSC infusion might
prevent acute rejection by regulating T-cell expansion and increasing serum levels of
IL10.54-57
MSC-derived IDO increases survival of patients with refractory chronic GVHD by
stimulating CD5+ regulatory B cells to produce IL10; this is associated with reduced
inflammatory cytokine production by T cells.58
Collectively, MSCs convert the overall
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immune response to less inflammatory (or more tolerant) response by altering the
secretome of the immune cells.59
Most of the immunomodulatory features of MSCs are attributed to their secretome and
proteome. However, the spectrum of secretory factors of MSCs differs from that of
MSCs-derived hepatocyte-like cells and hepatocytes.27, 60
Although immunoregulation by
MSCs participates in liver repair and liver transplantation43, 54, 61
, the immunomodulatory
features of MSCs are typically reported in other organs rather than in the liver. Therefore,
further investigations are indispensable to determine whether immunomodulation by MSCs
is crucial in liver regeneration.
Anti-fibrotic Effects
Clinical chronic liver inflammation caused by viral infection, alcoholic liver disease,
nonalcoholic steatohepatitis, and autoimmune diseases results in liver fibrosis and
cirrhosis.62
Hepatic inflammation activates HSCs to produce extracellular matrix; this
precedes and promotes progression of liver fibrosis. MSCs reduce or reverse liver fibrosis via
their immunomodulatory and anti-inflammatory effects.63, 64
On the other hand, MSCs
directly inactivate HSCs by secreting IL10 and tumor necrosis factor, and induce HSC
apoptosis through HGF, nerve growth factor signaling via p75, and Fas–FasL pathway.65
MSCs
might therefore be used in treatment of hepatic fibrosis.65
MSCs can degrade ECM directly,
by secreting matrix metalloproteinases,66
or indirectly, by stimulating the immune cells to
increase the production of these enzymes.67
MSCs were shown to reduce liver fibrosis in
mice by secreting cytokines and matrix metalloproteinases.68-72
DLK1 contributes to HSC
activation; MSC transplantation reduced activation of HSCs by DLK1 and liver fibrosis.73
Liver Regeneration and Direct MSC Differentiation In Vivo
The immunomodulatory activities and anti-fibrotic effects of MSCs are important for liver
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regeneration. MSCs are also directly involved in maintaining the hepatocyte pool, by
repressing hepatocyte apoptosis and stimulating hepatocyte proliferation, and by secreting
factors such as HGF that maintain liver function.74
Christ et al. reported an in vitro
differentiation protocol for generating hepatocytes from bone marrow and adipose tissue
MSC.75
They showed that MSC-derived hepatocyte-like cells engraft more efficiently than
undifferentiated cells.76
In addition, transplantation of MSCs, MSC-derived brown adipocytes,
or MSC lysates into obese mice reduced fat accumulation and hepatocyte lipotoxicity,
restoring liver functions.77, 78
Although rare, transplanted MSCs can spontaneously
differentiate into hepatocytes in rat79
and this may also, at least partially, contribute to liver
regeneration.
MSC-based Treatments
MSC-derived microvesicles
Microvesicles are extracellular vesicles that contain exosomes and microparticles. Exosomes
are small extracellular vesicles (30–120 nm in diameter) derived from budding membranes
of multi-vesicular bodies; microparticles are large cell-derived vesicles (100 nm to 1 µm)
derived from budding of the cell membrane. Microvesicles can interact with local or distal
cells and transfer molecules such as RNAs, microRNAs (miRNAs), and proteins, for
intercellular communication through a paracrine effect.
Stem cell-derived exosomes and micro-vesicles have been tested in models of liver
diseases.80-84
Injection of MSC-derived exosomes reduced fibrosis in livers of mice following
CCl4 injections, by suppressing expression of collagen and tumor growth factor beta 1.85
MSC-derived exosomes upregulate expression of priming-phase genes during liver
regeneration, leading to increased number of proliferating cell nuclear antigen-positive cells
and levels of cyclin D1 in livers of mice with CCl4-induced fibrosis. MSC-derived exosomes
also inhibit acetaminophen- and H2O2-induced apoptosis of hepatocytes.86
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Exosome miRNAs contribute to development of liver disease in animal models. 87
Exosome miRNA125b, derived from MSCs, reduces activation of the hedgehog pathway in
HSCs, by reducing levels of Smo expression and subsequent CCl4-induced liver fibrosis in
rat.88
MSC-derived exosomes also increase expression of anti-inflammatory cytokines and
the proportion of T-regulatory cells in mice with concanavalin A-induced liver injury,
supporting their immunosuppressive effects.89
MSC-derived exosomes might therefore be
developed for treatment of liver diseases, but additional studies are needed to elucidate
mechanisms of MSC-derived exosomes in liver regeneration. Studies with large animal
models are necessary to translate the findings into clinical practice.
Bioartificial liver (BAL) systems
In 1956, researchers 90
demonstrated that a fresh bovine liver homogenate metabolizes
salicylic acids and ketone bodies, and produces urea from ammonium chloride. In 1967,
some case reports indicated that cross-circulation and exchange transfusion supported livers
of patients in acute comas.91
Accordingly, BAL was developed as a therapy of acute liver
failures.
BAL systems are extracorporeal systems consisting of a bioreactor and biocomponents
(hepatocytes), connected to patient circulation and supporting liver functions. Many studies
indicate that BAL systems improve the survival in animal models.92-94
Matsumura et al
reported clinical application of a BAL system in 1987.95
Eleven BAL device systems are now
available. Among them, the Extracorporeal Liver Assist Device and the HepatAssist are being
tested in clinical trials.96, 97
Since human hepatocyte sources are limited, stem cell-derived HLCs might be used as
substitutes in the BAL system. A BAL system with human fetal fibroblast-derived HLCs was
reported to prolong survival of pigs with acute liver failure in 2016.98
Highly functional HLCs
have been generated from human pluripotent stem cells .99, 100
Human pluripotent stem cell
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(HPSC)-derived HLCs are an ideal cell source for a clinical-grade BAL system. BAL systems
might be developed as alternative strategies for patients with acute liver failure. The use of
BAL systems could also extend the wait time for a suitable liver donor for patients with
end-stage liver disease.
Organ bioengineering
Organ bioengineering involving decellularized organs has recently enabled the development
of a bone fide ECM architecture for stem cell differentiation. Researchers have induced
hepatic differentiation of MSCs on ECM sheets derived from decellularized liver, and
demonstrated efficient transplantation of these cells into mice with CCl4-induced liver
failure101
. Direct infusion of MSCs into de-cellularized liver could be more efficient in
induction of hepatic differentiation.102
Loss of biliary structure or impaired blood supply in
donor livers suppresses liver regeneration after transplantation 103
, so re-cellularization of
liver tissues with a combination of liver sinusoidal endothelial cells, bile duct cells, and
hepatocytes is essential. This strategy might be used in transplantation.
Although the use of MSC-based therapy and recellularized liver tissue is a more
cost-and time-effective option than whole-organ transplantation, the recelluarization
protocol should be optimized and the limitations need to be addressed before future clinical
applications.104, 105
These include, the route of administration or recellularization (e.g., direct
injection or continuous perfusion at a physiological pressure), potential immunogenicity, lack
of hepatic non-parenchymal cells, the possibility of small-for-size syndrome, and differences
in the vascular infrastructure of recellularized and normal liver tissues.106-108
Trials of MSC-Based Therapies
Anti-inflammatory and anti-fibrotic effects of MSCs have been observed in animal models,109,
110so several clinical trials of human MSCs had been conducted in patients with liver
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fibrosis.7, 111-114
To evaluate MSC transplantation in patients, serum creatinine and bilirubin
are used as a therapeutic index in patients with advanced liver fibrosis.115, 116
Evaluation of
the endpoints in these studies revealed the safety and efficacy of human MSC
transplantation. Jang et al reported a reduction of collagen deposition in the histological
analyses of the liver from patients after MSC transplantation in 2014 114
. In 2016, MSC
transplantation was tested in a phase 2 trial of patients with alcoholic cirrhosis.117
MSC
transplantation was reported to reduce collagen deposition and model for end-stage liver
disease scores and increased liver function in these patients. Based on the results of these
studies, we anticipate phase 3 clinical trials in the near future. Although these studies
indicate the therapeutic potential of MSC transplantation for patients with liver fibrosis,
studies are needed to determine the appropriate therapeutic window, MSC dosage, and
mechanisms of fibrosis reduction.
HPSC Administration
Advantages
In 1998, Thomson et al118
reported isolation of human embryonic stem cells (HESCs) from
blastocysts and confirmed that these cells maintained the potential to differentiate into all 3
embryonic germ layers. These cells became powerful tools used in developmental biology,
drug discovery, and regenerative medicine because of their ability to self-renew indefinitely
and their ability to differentiate into any cell lineage. Despite their great medical potential,
there was controversy over use of HESCs, because generation of HESCs involves the
destruction of a human embryo. Another important issue is the immunogenicity of HESCs.
In 2006, Takahashi et al119
reported reprogramming of fibroblasts into iPSCs by
expression of 4 transcription factors (OCT3/4, SOX2, KLF4, and c-Myc). The generation of
human iPSCs was reported by same group in 2007.120
iPSC generation does not involve
destruction of human embryos, and these cells can be generated in an autologous,
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patient-specific manner, and differentiated into various cell types. The unlimited supply of
these cells provides the patients with an alternative autologous, rather than allogeneic,
transplantation option.
Patients with acute liver failure or chronic liver disease are ideal candidates for
cell-based transplantation. Patients with acute liver failure require an immediate restoration
of the liver function by liver or hepatocyte transplantation, but only 10% or fewer of
required liver transplantations are performed.121
As an immediately available and
inexhaustible cell source, PSC-derived hepatocytes might be used to treat these patients.
Transplantation of PSC-derived hepatocytes by a direct splenic injection improves liver
function and prolongs survival of mice with CCl4-induced liver injury.122-124
MSCs are available from the human bone marrow, fat, umbilical cord, dental pulp, and
PSCs. Among these alternatives, human PSCs with extended in vitro culture are the best
sources for MSC production.125
In addition, PSC-derived MSCs have higher telomerase
activity,125
are less sensitive to inflammatory cytokines such as interferon gamma,126
and
have stronger immunomodulation than bone marrow-derived MSCs.127
PSC-derived MSCs
therefore provide an ideal source for clinical application. Researchers have generated
decellularized liver tissues with 3D anatomical structures, including a microvascular network,
that is difficult to manufacture in vitro.128
HPSC-derived hepatic cells could therefore provide
an ideal cell source to develop a BAL system, because of their similarity to primary human
hepatocytes. By studying the liver development, scientists might identify the factors
required for direct differentiation of HPSCs into hepatocytes.129
Challenges
It is important to maintain the genomic stability of PSCs to be used in cell-based therapies.
Cultured PSCs and reprogrammed cells acquire genomic abnormalities, such as large
chromosomal aberrations,130, 131
variations in gene copy numbers,132-134
and somatic
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mutations in coding regions.135, 136
For example, shortly after derivation, 10% of PSCs contain
at least 1 large chromosomal aberration, indicating that large chromosomal aberrations
occur early in the PSC culture process. Interestingly, levels of serum response factor, a
transcription factor, were reported to be reduced in diploid HPSCs. So reduced expression of
serum response factor could contribute to chromosomal instability in these cells.137
A similar
mechanism might operate during the initiation of chromosome instability in diploid cells.
Similarly, DNA analysis studies indicated that iPSC cell lines already contain copy number
variations during early stages of passage, so copy number variations might be induced by the
reprogramming process. Genomic instability is a feature of cancer, so the maintenance of
PSC genomic stability is important.
Some challenges of using HPSCs for therapeutic purposes are linked with the availability
of a homogeneous supply of mature PSC-derived cells. Alarmingly, Zhao et al138
showed that
cells derived from iPSCs induced immune response in syngeneic mice. Providing
HPSC-derived cells for use in clinical therapies requires further, substantial development.
Nonetheless, the utility of PSC-derived cells has been demonstrated in treatment of diabetes,
liver diseases, retinal diseases, muscular dystrophies, and heart diseases.139
Future Directions
An unlimited supply of hepatocytes is needed for cell-based, regenerative treatments for
patients with liver disease. HPSCs are more suitable candidates for generation of functional
hepatocytes than other types of stem cells. Nevertheless, genomic aberrations and the need
for rapid generation of mature and functional hepatocytes challenge their clinical application.
MSCs can suppress activated immune cells, and have anti-inflammatory and anti-fibrotic
effects, so they have been studied for their effects during immune rejection following
allogeneic transplantation and liver regeneration.
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MSCs might also protect the liver from injury, by producing trophic factors (IL10 and
HGF).110
MSC transplantation has been tested, with promising results, in several clinical trials,
and is a possible alternative approach for treatment of patients with liver diseases. MSCs can
reduce collagen deposition in patients with alcoholic liver cirrhosis.114
Although studies have
found MSC transplantation to be safe in preclinical and clinical trials,140, 141
some
chromosomal aberrations have been reported in cultured cells.142-144
Long-term culture
expansion may cause genomic instability and lead to transformation of mouse MSCs,
although this is rarely observed in human MSCs.145-148
Stem cell therapies hold a great
promise for liver regenerative medicine. Mechanistic and clinical studies should foster a
closer collaboration between the academic and industry researchers, to make the most of
the therapeutic potential of MSCs.
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References :
1. Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2010. Natl Vital Stat Rep
2013;61:1-117.
2. Owen A, Newsome PN. Mesenchymal stromal cell therapy in liver disease:
opportunities and lessons to be learnt? Am J Physiol Gastrointest Liver Physiol
2015;309:G791-800.
3. Londono MC, Rimola A, O'Grady J, et al. Immunosuppression minimization vs.
complete drug withdrawal in liver transplantation. J Hepatol 2013;59:872-9.
4. Chen Y, Wong PP, Sjeklocha L, et al. Mature hepatocytes exhibit unexpected plasticity
by direct dedifferentiation into liver progenitor cells in culture. Hepatology
2012;55:563-74.
5. Huebert RC, Rakela J. Cellular therapy for liver disease. Mayo Clin Proc
2014;89:414-24.
6. Ferrer JR, Chokechanachaisakul A, Wertheim JA. New Tools in Experimental Cellular
Therapy for the Treatment of Liver Diseases. Curr Transplant Rep 2015;2:202-210.
7. Nicolas CT, Wang Y, Nyberg SL. Cell therapy in chronic liver disease. Curr Opin
Gastroenterol 2016;32:189-94.
8. Katsuda T, Kawamata M, Hagiwara K, et al. Conversion of Terminally Committed
Hepatocytes to Culturable Bipotent Progenitor Cells with Regenerative Capacity. Cell
Stem Cell 2017;20:41-55.
9. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human
mesenchymal stem cells. Science 1999;284:143-7.
10. Makino S, Fukuda K, Miyoshi S, et al. Cardiomyocytes can be generated from marrow
stromal cells in vitro. J Clin Invest 1999;103:697-705.
11. Wislet-Gendebien S, Hans G, Leprince P, et al. Plasticity of cultured mesenchymal
stem cells: switch from nestin-positive to excitable neuron-like phenotype. Stem Cells
2005;23:392-402.
12. Friedenstein AJ, Petrakova KV, Kurolesova AI, et al. Heterotopic of bone marrow.
Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation
1968;6:230-47.
13. Campbell A, Brieva T, Raviv L, et al. Concise Review: Process Development
Considerations for Cell Therapy. Stem Cells Transl Med 2015;4:1155-63.
14. Chen J, Li Y, Katakowski M, et al. Intravenous bone marrow stromal cell therapy
reduces apoptosis and promotes endogenous cell proliferation after stroke in female
rat. J Neurosci Res 2003;73:778-86.
15. Ruster B, Gottig S, Ludwig RJ, et al. Mesenchymal stem cells display coordinated
rolling and adhesion behavior on endothelial cells. Blood 2006;108:3938-44.
16. Ma HC, Shi XL, Ren HZ, et al. Targeted migration of mesenchymal stem cells modified
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
18
with CXCR4 to acute failing liver improves liver regeneration. World J Gastroenterol
2014;20:14884-94.
17. Shu SN, Wei L, Wang JH, et al. Hepatic differentiation capability of rat bone
marrow-derived mesenchymal stem cells and hematopoietic stem cells. World J
Gastroenterol 2004;10:2818-22.
18. Lee KD, Kuo TK, Whang-Peng J, et al. In vitro hepatic differentiation of human
mesenchymal stem cells. Hepatology 2004;40:1275-84.
19. Lee OK, Kuo TK, Chen WM, et al. Isolation of multipotent mesenchymal stem cells
from umbilical cord blood. Blood 2004;103:1669-75.
20. Hong SH, Gang EJ, Jeong JA, et al. In vitro differentiation of human umbilical cord
blood-derived mesenchymal stem cells into hepatocyte-like cells. Biochem Biophys
Res Commun 2005;330:1153-61.
21. Banas A, Teratani T, Yamamoto Y, et al. Adipose tissue-derived mesenchymal stem
cells as a source of human hepatocytes. Hepatology 2007;46:219-28.
22. Kuo TK, Hung SP, Chuang CH, et al. Stem cell therapy for liver disease: parameters
governing the success of using bone marrow mesenchymal stem cells.
Gastroenterology 2008;134:2111-21, 2121.e1-3.
23. Qihao Z, Xigu C, Guanghui C, et al. Spheroid formation and differentiation into
hepatocyte-like cells of rat mesenchymal stem cell induced by co-culture with liver
cells. DNA Cell Biol 2007;26:497-503.
24. Li TZ, Kim JH, Cho HH, et al. Therapeutic potential of bone-marrow-derived
mesenchymal stem cells differentiated with growth-factor-free coculture method in
liver-injured rats. Tissue Eng Part A 2010;16:2649-59.
25. Mohsin S, Shams S, Ali Nasir G, et al. Enhanced hepatic differentiation of
mesenchymal stem cells after pretreatment with injured liver tissue. Differentiation
2011;81:42-8.
26. Teng NY, Liu YS, Wu HH, et al. Promotion of mesenchymal-to-epithelial transition by
Rac1 inhibition with small molecules accelerates hepatic differentiation of
mesenchymal stromal cells. Tissue Eng Part A 2015;21:1444-54.
27. Lee CW, Huang WC, Huang HD, et al. DNA Methyltransferases Modulate Hepatogenic
Lineage Plasticity of Mesenchymal Stromal Cells. Stem Cell Reports 2017;9:247-263.
28. An SY, Han J, Lim HJ, et al. Valproic acid promotes differentiation of hepatocyte-like
cells from whole human umbilical cord-derived mesenchymal stem cells. Tissue Cell
2014;46:127-35.
29. Ye D, Li T, Heraud P, et al. Effect of Chromatin-Remodeling Agents in Hepatic
Differentiation of Rat Bone Marrow-Derived Mesenchymal Stem Cells In Vitro and In
Vivo. Stem Cells Int 2016;2016:3038764.
30. Ju X, Li D, Gao N, et al. Hepatogenic differentiation of mesenchymal stem cells using
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
19
microfluidic chips. Biotechnol J 2008;3:383-91.
31. Yen MH, Wu YY, Liu YS, et al. Efficient generation of hepatic cells from mesenchymal
stromal cells by an innovative bio-microfluidic cell culture device. Stem Cell Res Ther
2016;7:120.
32. Kazemnejad S, Allameh A, Soleimani M, et al. 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;24:278-87.
33. Ghaedi M, Soleimani M, Shabani I, et al. Hepatic differentiation from human
mesenchymal stem cells on a novel nanofiber scaffold. Cell Mol Biol Lett
2012;17:89-106.
34. Chitrangi S, Nair P, Khanna A. Three-dimensional polymer scaffolds for enhanced
differentiation of human mesenchymal stem cells to hepatocyte-like cells: a
comparative study. J Tissue Eng Regen Med 2016.
35. Lee HJ, Jung J, Cho KJ, et al. Comparison of in vitro hepatogenic differentiation
potential between various placenta-derived stem cells and other adult stem cells as
an alternative source of functional hepatocytes. Differentiation 2012;84:223-31.
36. Jenne CN, Kubes P. Immune surveillance by the liver. Nat Immunol
2013;14:996-1006.
37. Winau F, Hegasy G, Weiskirchen R, et al. Ito cells are liver-resident antigen-presenting
cells for activating T cell responses. Immunity 2007;26:117-29.
38. Vinas O, Bataller R, Sancho-Bru P, et al. Human hepatic stellate cells show features of
antigen-presenting cells and stimulate lymphocyte proliferation. Hepatology
2003;38:919-29.
39. Gao D, Li J, Orosz CG, et al. Different costimulation signals used by CD4(+) and CD8(+)
cells that independently initiate rejection of allogenic hepatocytes in mice.
Hepatology 2000;32:1018-28.
40. Seki E, Schwabe RF. Hepatic inflammation and fibrosis: functional links and key
pathways. Hepatology 2015;61:1066-79.
41. Prockop DJ, Oh JY. Mesenchymal stem/stromal cells (MSCs): role as guardians of
inflammation. Mol Ther 2012;20:14-20.
42. Spaggiari GM, Capobianco A, Abdelrazik H, et al. Mesenchymal stem cells inhibit
natural killer-cell proliferation, cytotoxicity, and cytokine production: role of
indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 2008;111:1327-33.
43. Hong IH, Han SY, Ki MR, et al. Inhibition of kupffer cell activity improves
transplantation of human adipose-derived stem cells and liver functions. Cell
Transplant 2013;22:447-59.
44. Prockop DJ. Concise review: two negative feedback loops place mesenchymal
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
20
stem/stromal cells at the center of early regulators of inflammation. Stem Cells
2013;31:2042-6.
45. Naji A, Rouas-Freiss N, Durrbach A, et al. Concise review: combining human
leukocyte antigen G and mesenchymal stem cells for immunosuppressant biotherapy.
Stem Cells 2013;31:2296-303.
46. Deng Y, Zhang Y, Ye L, et al. Umbilical Cord-derived Mesenchymal Stem Cells Instruct
Monocytes Towards an IL10-producing Phenotype by Secreting IL6 and HGF. Sci Rep
2016;6:37566.
47. Meisel R, Zibert A, Laryea M, et al. Human bone marrow stromal cells inhibit
allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan
degradation. Blood 2004;103:4619-21.
48. Ezquer F, Ezquer M, Contador D, et al. The antidiabetic effect of mesenchymal stem
cells is unrelated to their transdifferentiation potential but to their capability to
restore Th1/Th2 balance and to modify the pancreatic microenvironment. Stem Cells
2012;30:1664-74.
49. Woo J, Iyer S, Cornejo MC, et al. Stress protein-induced immunosuppression:
inhibition of cellular immune effector functions following overexpression of haem
oxygenase (HSP 32). Transpl Immunol 1998;6:84-93.
50. Soleymaninejadian E, Pramanik K, Samadian E. Immunomodulatory properties of
mesenchymal stem cells: cytokines and factors. Am J Reprod Immunol 2012;67:1-8.
51. Sun L, Akiyama K, Zhang H, et al. Mesenchymal stem cell transplantation reverses
multiorgan dysfunction in systemic lupus erythematosus mice and humans. Stem
Cells 2009;27:1421-32.
52. Augello A, Tasso R, Negrini SM, et al. Bone marrow mesenchymal progenitor cells
inhibit lymphocyte proliferation by activation of the programmed death 1 pathway.
Eur J Immunol 2005;35:1482-90.
53. Vandermeulen M, Gregoire C, Briquet A, et al. Rationale for the potential use of
mesenchymal stromal cells in liver transplantation. World J Gastroenterol
2014;20:16418-32.
54. Wan CD, Cheng R, Wang HB, et al. Immunomodulatory effects of mesenchymal stem
cells derived from adipose tissues in a rat orthotopic liver transplantation model.
Hepatobiliary Pancreat Dis Int 2008;7:29-33.
55. Wang JW, Liu YB, Xu B, et al. [The study on immunomodulation of donor
mesenchymal stem cells on discordant liver xenotransplantation]. Zhonghua Wai Ke
Za Zhi 2005;43:1254-8.
56. Wang Y, Zhang A, Ye Z, et al. Bone marrow-derived mesenchymal stem cells inhibit
acute rejection of rat liver allografts in association with regulatory T-cell expansion.
Transplant Proc 2009;41:4352-6.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
21
57. Sun Z, Li T, Wen H, et al. Immunological effect induced by mesenchymal stem cells in
a rat liver transplantation model. Exp Ther Med 2015;10:401-406.
58. Peng Y, Chen X, Liu Q, et al. Mesenchymal stromal cells infusions improve refractory
chronic graft versus host disease through an increase of CD5+ regulatory B cells
producing interleukin 10. Leukemia 2015;29:636-46.
59. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic
immune cell responses. Blood 2005;105:1815-22.
60. An SY, Jang YJ, Lim HJ, et al. Milk Fat Globule-EGF Factor 8, Secreted by Mesenchymal
Stem Cells, Protects Against Liver Fibrosis in Mice. Gastroenterology
2017;152:1174-1186.
61. Ryu KH, Kim SY, Kim YR, et al. Tonsil-derived mesenchymal stem cells alleviate
concanavalin A-induced acute liver injury. Exp Cell Res 2014;326:143-54.
62. Koyama Y, Brenner DA. Liver inflammation and fibrosis. The Journal of Clinical
Investigation 2017;127:55-64.
63. Huang B, Cheng X, Wang H, et al. Mesenchymal stem cells and their secreted
molecules predominantly ameliorate fulminant hepatic failure and chronic liver
fibrosis in mice respectively. J Transl Med 2016;14:45.
64. Li Q, Zhou X, Shi Y, et al. In vivo tracking and comparison of the therapeutic effects of
MSCs and HSCs for liver injury. PLoS One 2013;8:e62363.
65. Akiyama K, Chen C, Wang D, et al. Mesenchymal-stem-cell-induced
immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell
2012;10:544-55.
66. Higashiyama R, Inagaki Y, Hong YY, et al. Bone marrow-derived cells express matrix
metalloproteinases and contribute to regression of liver fibrosis in mice. Hepatology
2007;45:213-22.
67. Haldar D, Henderson NC, Hirschfield G, et al. Mesenchymal stromal cells and liver
fibrosis: a complicated relationship. FASEB J 2016;30:3905-3928.
68. Huang CK, Lee SO, Lai KP, et al. Targeting androgen receptor in bone marrow
mesenchymal stem cells leads to better transplantation therapy efficacy in liver
cirrhosis. Hepatology 2013;57:1550-63.
69. Iwamoto T, Terai S, Hisanaga T, et al. Bone-marrow-derived cells cultured in
serum-free medium reduce liver fibrosis and improve liver function in
carbon-tetrachloride-treated cirrhotic mice. Cell Tissue Res 2013;351:487-95.
70. Li B, Shao Q, Ji D, et al. Mesenchymal stem cells mitigate cirrhosis through BMP7. Cell
Physiol Biochem 2015;35:433-40.
71. Meier RP, Mahou R, Morel P, et al. Microencapsulated human mesenchymal stem
cells decrease liver fibrosis in mice. J Hepatol 2015;62:634-41.
72. Chen X, Gan Y, Li W, et al. The interaction between mesenchymal stem cells and
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
22
steroids during inflammation. Cell Death Dis 2014;5:e1009.
73. Pan RL, Wang P, Xiang LX, et al. Delta-like 1 serves as a new target and contributor to
liver fibrosis down-regulated by mesenchymal stem cell transplantation. J Biol Chem
2011;286:12340-8.
74. van Poll D, Parekkadan B, Cho CH, et al. Mesenchymal stem cell-derived molecules
directly modulate hepatocellular death and regeneration in vitro and in vivo.
Hepatology 2008;47:1634-43.
75. Aurich I, Mueller LP, Aurich H, et al. Functional integration of hepatocytes derived
from human mesenchymal stem cells into mouse livers. Gut 2007;56:405-15.
76. Aurich H, Sgodda M, Kaltwasser P, et al. Hepatocyte differentiation of mesenchymal
stem cells from human adipose tissue in vitro promotes hepatic integration in vivo.
Gut 2009;58:570-81.
77. Lee CW, Hsiao WT, Lee OK. Mesenchymal stromal cell-based therapies reduce obesity
and metabolic syndromes induced by a high-fat diet. Transl Res 2016.
78. Ji AT, Chang YC, Fu YJ, et al. Niche-dependent regulations of metabolic balance in
high-fat diet-induced diabetic mice by mesenchymal stromal cells. Diabetes
2015;64:926-36.
79. Oh SH, Witek RP, Bae SH, et al. Bone marrow-derived hepatic oval cells differentiate
into hepatocytes in 2-acetylaminofluorene/partial hepatectomy-induced liver
regeneration. Gastroenterology 2007;132:1077-87.
80. Biancone L, Bruno S, Deregibus MC, et al. Therapeutic potential of mesenchymal
stem cell-derived microvesicles. Nephrol Dial Transplant 2012;27:3037-42.
81. Lai RC, Yeo RWY, Lim SK. Mesenchymal stem cell exosomes. Seminars in Cell &
Developmental Biology 2015;40:82-88.
82. Sato K, Meng F, Glaser S, et al. Exosomes in liver pathology. J Hepatol
2016;65:213-21.
83. Hirsova P, Ibrahim SH, Verma VK, et al. Extracellular vesicles in liver pathobiology:
Small particles with big impact. Hepatology 2016;64:2219-2233.
84. Han C, Sun X, Liu L, et al. Exosomes and Their Therapeutic Potentials of Stem Cells.
Stem Cells Int 2016;2016:7653489.
85. Li T, Yan Y, Wang B, et al. Exosomes derived from human umbilical cord mesenchymal
stem cells alleviate liver fibrosis. Stem Cells Dev 2013;22:845-54.
86. Tan CY, Lai RC, Wong W, et al. Mesenchymal stem cell-derived exosomes promote
hepatic regeneration in drug-induced liver injury models. Stem Cell Res Ther
2014;5:76.
87. Lou G, Chen Z, Zheng M, et al. Mesenchymal stem cell-derived exosomes as a new
therapeutic strategy for liver diseases. Exp Mol Med 2017;49:e346.
88. Hyun J, Wang S, Kim J, et al. MicroRNA125b-mediated Hedgehog signaling influences
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
23
liver regeneration by chorionic plate-derived mesenchymal stem cells. Sci Rep
2015;5:14135.
89. Tamura R, Uemoto S, Tabata Y. Immunosuppressive effect of mesenchymal stem
cell-derived exosomes on a concanavalin A-induced liver injury model. Inflammation
and Regeneration 2016;36:26.
90. F. S. Prime ricerche per la realizzazione di un fegato artificiale. Chir Patol Sperim.
1956;4:1401-1404.
91. Burnell JM, Dawborn JK, Epstein RB, et al. Acute hepatic coma treated by
cross-circulation or exchange transfusion. N Engl J Med 1967;276:935-43.
92. Suh KS, Lilja H, Kamohara Y, et al. Bioartificial liver treatment in rats with fulminant
hepatic failure: effect on DNA-binding activity of liver-enriched and
growth-associated transcription factors. J Surg Res 1999;85:243-50.
93. Flendrig LM, Calise F, Di Florio E, et al. Significantly improved survival time in pigs
with complete liver ischemia treated with a novel bioartificial liver. Int J Artif Organs
1999;22:701-9.
94. Sosef MN, Abrahamse LS, van de Kerkhove MP, et al. Assessment of the
AMC-bioartificial liver in the anhepatic pig. Transplantation 2002;73:204-9.
95. Matsumura KN, Guevara GR, Huston H, et al. Hybrid bioartificial liver in hepatic
failure: preliminary clinical report. Surgery 1987;101:99-103.
96. van de Kerkhove MP, Hoekstra R, Chamuleau RA, et al. Clinical application of
bioartificial liver support systems. Ann Surg 2004;240:216-30.
97. Nicolas CT, Hickey RD, Chen HS, et al. Concise Review: Liver Regenerative Medicine:
From Hepatocyte Transplantation to Bioartificial Livers and Bioengineered Grafts.
Stem Cells 2017;35:42-50.
98. Shi XL, Gao Y, Yan Y, et al. Improved survival of porcine acute liver failure by a
bioartificial liver device implanted with induced human functional hepatocytes. Cell
Res 2016;26:206-16.
99. Hannoun Z, Steichen C, Dianat N, et al. The potential of induced pluripotent stem cell
derived hepatocytes. J Hepatol 2016;65:182-199.
100. Sakiyama R, Blau BJ, Miki T. Clinical translation of bioartificial liver support systems
with human pluripotent stem cell-derived hepatic cells. World J Gastroenterol
2017;23:1974-1979.
101. Ji R, Zhang N, You N, et al. The differentiation of MSCs into functional hepatocyte-like
cells in a liver biomatrix scaffold and their transplantation into liver-fibrotic mice.
Biomaterials 2012;33:8995-9008.
102. Jiang WC, Cheng YH, Yen MH, et al. Cryo-chemical decellularization of the whole liver
for mesenchymal stem cells-based functional hepatic tissue engineering.
Biomaterials 2014;35:3607-17.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
24
103. op den Dries S, Westerkamp AC, Karimian N, et al. Injury to peribiliary glands and
vascular plexus before liver transplantation predicts formation of non-anastomotic
biliary strictures. J Hepatol 2014;60:1172-9.
104. Pan XN, Zheng LQ, Lai XH. Bone marrow-derived mesenchymal stem cell therapy for
decompensated liver cirrhosis: a meta-analysis. World J Gastroenterol
2014;20:14051-7.
105. Kim G, Eom YW, Baik SK, et al. Therapeutic Effects of Mesenchymal Stem Cells for
Patients with Chronic Liver Diseases: Systematic Review and Meta-analysis. J Korean
Med Sci 2015;30:1405-15.
106. Franco D. Towards a bioengineered liver. J Hepatol 2014;60:455-6.
107. Collin de l'Hortet A, Takeishi K, Guzman-Lepe J, et al. Liver-Regenerative
Transplantation: Regrow and Reset. Am J Transplant 2016;16:1688-96.
108. Bao J, Shi Y, Sun H, et al. Construction of a portal implantable functional
tissue-engineered liver using perfusion-decellularized matrix and hepatocytes in rats.
Cell Transplant 2011;20:753-66.
109. Christ B, Bruckner S, Winkler S. The Therapeutic Promise of Mesenchymal Stem Cells
for Liver Restoration. Trends Mol Med 2015;21:673-86.
110. Berardis S, Dwisthi Sattwika P, Najimi M, et al. Use of mesenchymal stem cells to
treat liver fibrosis: current situation and future prospects. World J Gastroenterol
2015;21:742-58.
111. Eom YW, Shim KY, Baik SK. Mesenchymal stem cell therapy for liver fibrosis. Korean J
Intern Med 2015;30:580-9.
112. Zhang Z, Lin H, Shi M, et al. Human umbilical cord mesenchymal stem cells improve
liver function and ascites in decompensated liver cirrhosis patients. J Gastroenterol
Hepatol 2012;27 Suppl 2:112-20.
113. Amin MA, Sabry D, Rashed LA, et al. Short-term evaluation of autologous
transplantation of bone marrow-derived mesenchymal stem cells in patients with
cirrhosis: Egyptian study. Clin Transplant 2013;27:607-12.
114. Jang YO, Kim YJ, Baik SK, et al. Histological improvement following administration of
autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: a
pilot study. Liver Int 2014;34:33-41.
115. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients
with end-stage liver disease. Hepatology 2001;33:464-70.
116. Than NN, Tomlinson CL, Haldar D, et al. Clinical effectiveness of cell therapies in
patients with chronic liver disease and acute-on-chronic liver failure: a systematic
review protocol. Syst Rev 2016;5:100.
117. Suk KT, Yoon JH, Kim MY, et al. Transplantation with autologous bone marrow-derived
mesenchymal stem cells for alcoholic cirrhosis: Phase 2 trial. Hepatology
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
25
2016;64:2185-2197.
118. Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell lines derived
from human blastocysts. Science 1998;282:1145-7.
119. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic
and adult fibroblast cultures by defined factors. Cell 2006;126:663-76.
120. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult
human fibroblasts by defined factors. Cell 2007;131:861-72.
121. Muller SA, Mehrabi A, Schmied BM, et al. Partial liver transplantation-living donor
liver transplantation and split liver transplantation. Nephrol Dial Transplant 2007;22
Suppl 8:viii13-viii22.
122. Chen YF, Tseng CY, Wang HW, et al. Rapid generation of mature hepatocyte-like cells
from human induced pluripotent stem cells by an efficient three-step protocol.
Hepatology 2012;55:1193-203.
123. Vosough M, Omidinia E, Kadivar M, et al. Generation of functional hepatocyte-like
cells from human pluripotent stem cells in a scalable suspension culture. Stem Cells
Dev 2013;22:2693-705.
124. Woo DH, Kim SK, Lim HJ, et al. Direct and indirect contribution of human embryonic
stem cell-derived hepatocyte-like cells to liver repair in mice. Gastroenterology
2012;142:602-11.
125. Lian Q, Zhang Y, Zhang J, et al. Functional mesenchymal stem cells derived from
human induced pluripotent stem cells attenuate limb ischemia in mice. Circulation
2010;121:1113-23.
126. Sun YQ, Zhang Y, Li X, et al. Insensitivity of Human iPS Cells-Derived Mesenchymal
Stem Cells to Interferon-gamma-induced HLA Expression Potentiates Repair
Efficiency of Hind Limb Ischemia in Immune Humanized NOD Scid Gamma Mice.
Stem Cells 2015;33:3452-67.
127. Zhang Y, Liao S, Yang M, et al. Improved cell survival and paracrine capacity of human
embryonic stem cell-derived mesenchymal stem cells promote therapeutic potential
for pulmonary arterial hypertension. Cell Transplant 2012;21:2225-39.
128. Uygun BE, Soto-Gutierrez A, Yagi H, et al. Organ reengineering through development
of a transplantable recellularized liver graft using decellularized liver matrix. Nat Med
2010;16:814-20.
129. Gerbal-Chaloin S, Funakoshi N, Caillaud A, et al. Human induced pluripotent stem
cells in hepatology: beyond the proof of concept. Am J Pathol 2014;184:332-47.
130. Ben-David U, Kopper O, Benvenisty N. Expanding the boundaries of embryonic stem
cells. Cell Stem Cell 2012;10:666-77.
131. Lund RJ, Narva E, Lahesmaa R. Genetic and epigenetic stability of human pluripotent
stem cells. Nat Rev Genet 2012;13:732-44.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
26
132. Hussein SM, Batada NN, Vuoristo S, et al. Copy number variation and selection during
reprogramming to pluripotency. Nature 2011;471:58-62.
133. Laurent LC, Ulitsky I, Slavin I, et al. Dynamic changes in the copy number of
pluripotency and cell proliferation genes in human ESCs and iPSCs during
reprogramming and time in culture. Cell Stem Cell 2011;8:106-18.
134. Martins-Taylor K, Nisler BS, Taapken SM, et al. Recurrent copy number variations in
human induced pluripotent stem cells. Nat Biotechnol 2011;29:488-91.
135. Gore A, Li Z, Fung HL, et al. Somatic coding mutations in human induced pluripotent
stem cells. Nature 2011;471:63-7.
136. Abyzov A, Mariani J, Palejev D, et al. Somatic copy number mosaicism in human skin
revealed by induced pluripotent stem cells. Nature 2012;492:438-42.
137. Lamm N, Ben-David U, Golan-Lev T, et al. Genomic Instability in Human Pluripotent
Stem Cells Arises from Replicative Stress and Chromosome Condensation Defects.
Cell Stem Cell 2016;18:253-261.
138. Zhao T, Zhang ZN, Rong Z, et al. Immunogenicity of induced pluripotent stem cells.
Nature 2011;474:212-5.
139. Fox IJ, Daley GQ, Goldman SA, et al. Stem cell therapy. Use of differentiated
pluripotent stem cells as replacement therapy for treating disease. Science
2014;345:1247391.
140. Wei X, Yang X, Han ZP, et al. Mesenchymal stem cells: a new trend for cell therapy.
Acta Pharmacol Sin 2013;34:747-54.
141. Keating A. Mesenchymal stromal cells: new directions. Cell Stem Cell
2012;10:709-16.
142. Barkholt L, Flory E, Jekerle V, et al. Risk of tumorigenicity in mesenchymal stromal
cell-based therapies--bridging scientific observations and regulatory viewpoints.
Cytotherapy 2013;15:753-9.
143. Grigorian AS, Kruglyakov PV, Taminkina UA, et al. Alterations of cytological and
karyological profile of human mesenchymal stem cells during in vitro culturing. Bull
Exp Biol Med 2010;150:125-30.
144. Ben-David U, Mayshar Y, Benvenisty N. Large-scale analysis reveals acquisition of
lineage-specific chromosomal aberrations in human adult stem cells. Cell Stem Cell
2011;9:97-102.
145. Josse C, Schoemans R, Niessen NA, et al. Systematic chromosomal aberrations found
in murine bone marrow-derived mesenchymal stem cells. Stem Cells Dev
2010;19:1167-73.
146. Miura M, Miura Y, Padilla-Nash HM, et al. Accumulated chromosomal instability in
murine bone marrow mesenchymal stem cells leads to malignant transformation.
Stem Cells 2006;24:1095-103.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
27
147. Foudah D, Redaelli S, Donzelli E, et al. Monitoring the genomic stability of in vitro
cultured rat bone-marrow-derived mesenchymal stem cells. Chromosome Res
2009;17:1025-39.
148. Rosland GV, Svendsen A, Torsvik A, et al. Long-term cultures of bone marrow-derived
human mesenchymal stem cells frequently undergo spontaneous malignant
transformation. Cancer Res 2009;69:5331-9.
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Table 1. Current MSC hepatic differentiation protocols
Cell Source Differentiation Protocol Cell Characteristics Reference
Rat bone marrow
DMEM-LG and MCDB-201
(6:4) supplemented with 0.5%
FBS, 1 µM dexamethasone,
10 ng/mL EGF, and ITS+
(Insulin-Transferrin-Selenium)
premix
Round cells expressing
CK18 and albumin [17]
Human bone marrow
Induction: IMDM
supplemented with 20 ng/mL
HGF, 10 ng/mL FGF2, and
0.61 g/L nicotinamide
Maturation: IMDM
supplemented with 20 ng/mL
oncostatin M, 1 µM
dexamethasone, and 50
mg/mL ITS+ premix
Cuboidal cells with
abundant intracellular
granules, expressing
liver-specific genes;
glycogen storage, urea
production, and LDL uptake
[18]
Human umbilical cord blood
Induction: IMDM
supplemented with 10% FBS,
0.5 µM dexamethasone, 50
mg/mL ITS+ premix, and 50
ng/mL HGF
Maturation: IMDM
supplemented with 10% FBS,
0.5 µM dexamethasone, 50
mg/mL ITS+ premix, and 50
ng/mL oncostatin M
Round cells expressing
liver-specific genes; LDL
uptake
[19]
Human adipose tissue
Hepatic commitment:
HCM-modified William’s E
medium supplemented with
150 ng/mL HGF, 300 ng/mL
FGF1, and 25 ng/mL FGF4
Maturation: HCM-modified
William’s E medium
supplemented with 30 ng/mL
oncostatin M and 0.2 µM
dexamethasone
Round cells expressing
liver-specific genes;
glycogen storage, urea
production, and LDL uptake
[21]
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Rat bone marrow Co-cultured with primary liver
cells and injured liver tissue
Spheroids expressing
liver-specific genes;
glycogen storage
[23,24,25]
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