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R E V I E W Open Access
Mesenchymal stem cell therapies for liver
cirrhosis: MSCs as “conducting cells”for
improvement of liver fibrosis and
regeneration
Atsunori Tsuchiya
*
, Suguru Takeuchi, Takayuki Watanabe, Tomoaki Yoshida, Shunsuke Nojiri, Masahiro Ogawa and
Shuji Terai
*
Abstract
Mesenchymal stem cells (MSCs) can be cultured relatively easily and can be obtained not only from the bone
marrow, but also from medical waste such as adipose tissue and umbilical cord tissue. Because of its low
antigenicity, allogeneic MSC injection is safe. MSCs have been evaluated in more than 900 clinical trials in a variety
of fields, with more than 50 clinical trials related to liver diseases. Experiments have suggested that MSCs function
as “conducting cells”to affect various “effective cells”such as T cells, B cells, and macrophages. Recent clinical trials
have focused on allogeneic MSCs. Thus, studies are needed to determine the most effective cell source, culture
conditions, cell numbers, administration frequency, administration route, cost, safety, and liver disease treatments.
Recently, the functions of exosomes have gained attention, and cell-free therapy may become possible as an
alternative therapy for liver disease. In this review, we introduce general information, mechanism, representative
clinical study data, recently started or planned clinical trials, and possibility of cell-free therapy of MSCs.
Keywords: Liver cirrhosis, Acute on chronic, Mesenchymal stem cell, Cell therapy
Background
The liver, which is a vital organ, has many functions
such as protein, triglyceride, cholesterol, and glycogen
synthesis; detoxication; drug metabolism; and bile secre-
tion, and has a high regenerative potential. However, the
liver cannot withstand long-term chronic injury, severe
acute injury, and acute on chronic injury. Chronic liver
injuries such as those caused by hepatitis B virus (HBV)
and hepatitis C virus infections, non-alcoholic steatohe-
patitis (NASH), and alcoholic liver injury have been
widely studied. Because of the recent development of
anti-viral drugs, it is easy to control HBV [1] and eradi-
cate hepatitis C virus [2]. In contrast, the number of pa-
tients with NASH and alcoholic liver disease is
increasing and no effective drugs except conventional
alimentary therapy and exercise therapy are available;
thus, development of new therapies for these diseases is
becoming important [3]. Long-term damaged conditions
gradually result in the loss of liver function and accumu-
lation of extracellular matrix (ECM), finally leading to
liver cirrhosis. Particularly, the prognosis of patients with
decompensated liver cirrhosis is poor. Hepatic stellate cells
are central players in liver fibrosis and the major precursors of
activated myofibroblasts, which produce ECM during liver fi-
brosis [4,5]. A recent study reported that fibrosis, rather than
steatosis, determines the prognosis of patients [6,7]. In acute
liver injury such as hepatitis B, hepatitis A, and drug-induced
liver injury, patients with excessive damage cannot be suffi-
ciently treated by physicians. Additionally, acute on chronic
liver failure (ACLF), the definition of which slightly differs by
region [8–11], is also a recently focused disease condition.
Recently proposed diagnostic criteria for ACLF in Japan in-
clude “patients with cirrhosis and a Child–Pugh score of 5–9
should be diagnosed as having ACLF when a deterioration
of liver function (serum bilirubin level ≥5.0 mg/dL and pro-
thrombin time value ≤40% of the standardized values and/or
© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
* Correspondence: atsunori@med.niigata-u.ac.jp;terais@med.niigata-u.ac.jp
Division of Gastroenterology and Hepatology, Graduate School of Medical
and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku,
Niigata 951-8510, Japan
Inflammation and Regeneration
Tsuchiya et al. Inflammation and Regeneration (2019) 39:18
https://doi.org/10.1186/s41232-019-0107-z
international normalization rate ≥1.5) caused by severe liver
damage develops within 28 days after acute insults, such as
alcohol abuse, bacterial infection, gastrointestinal bleeding,
or the exacerbation of underlying liver diseases”[11]. These
chronic, acute, and acute on chronic liver injuries can cause
death. Although liver transplantation can be conducted, the
shortage of donor organs is a serious problem. Cell therapies
maybeusefulfortreatingthesediseases.Wefirstlyshowed
that autologous bone marrow cell infusion (ABMi) therapy
was effective for the decompensation of liver cirrhosis pa-
tients [12]. Several clinical cases in this study [13]have
shown that bone marrow-derived cells can improve liver fi-
brosis and subsequently improve liver function. Therefore,
recently, we shifted our focus to cell therapies using mesen-
chymal stem cells. Mesenchymal stem cells (MSCs) have
been widely examined in clinical trials to evaluate their safety
and effectiveness in improving liver fibrosis and liver func-
tion. Positive results have been observed in numerous studies
of animal models [14–17].
In this review, we describe the general information of
MSCs, mechanisms of MSC therapies (i.e., the conduct-
ing effect of MSCs), recently published outcomes of
MSC therapy, clinical trials that have recently started or
will begin soon, and recent research trends using extra-
cellular vesicles obtained from MSCs.
General information of MSCs
MSCs have been used in many fields to treat a variety of
diseases such as neural, heart, liver, intestinal, and lung
diseases. According to ClinicalTrials.Gov, more than 900
clinical trials have been registered in a variety of fields
and are increasing by nearly 100 trials each year. MSCs
can be obtained not only from the bone marrow, but
also from medical waste such as umbilical cord tissue,
adipose tissue, amniotic tissue, and dental pulp. These
cells are relatively easy to expand, maintain, and cryopre-
serve, while maintaining their viability. MSCs are positive
for the common markers CD73, CD90, and CD105 and
show differential potential towards adipocytes, osteoblasts,
and chondroblasts under appropriate conditions. The cells
are used to replace damaged cells or tissues mainly in the
orthopedic field; however, their main functions are deter-
mined by trophic factors including chemokines, cytokines,
growth factors, and exosomes, and MSCs exhibit anti-in-
flammation, anti-oxidant, angiogenesis, and anti-fibrosis ef-
fects [4,5]. Of these functions, MSCs are most commonly
applied to achieve anti-inflammation effects. MSCs produce
various factors such as nitric oxide/indoleamine 2,3-dioxy-
genase, interleukin (IL)-10, tumor necrosis factor-inducible
gene-6, and prostaglandin E2; inhibit T cell activation and
expansion; induce regulatory T cells; alter the polarity of
macrophages to the anti-inflammatory phenotype; and con-
trol the function of dendritic cells, B cells, and natural killer
cells [18,19]. Another important characteristic of MSCs is
that they generally have low immunogenicity. MSCs ex-
press low or modest levels of major histocompatibility com-
plex class I molecules and lack expression of major
histocompatibility complex class II and co-stimulatory mol-
ecules, such as CD40, CD80, and CD86 (B7–2), leading to
low immunogenicity, suggesting that MSCs can avoid im-
mune responses in recipients; thus, injection of autologous
or allogenic MSCs has been employed in clinical studies.
For example, Lalu et al. performed a meta-analysis of the
safety of MSCs in clinical trials and found that autologous
and allogenic MSC therapies are related to transient fever
but not related to infusion toxicity, organ system complica-
tions, infection, death, and malignancies [20]. Allogenic
MSC therapy has the potential to be applied in many
patients.
MSCs function as “conducting cells”in liver
disease
The mechanisms of MSCs for treating liver diseases have
been evaluated from various perspectives in basic stud-
ies. MSCs have anti-inflammatory effects and reduce
damages to hepatocytes [21]. These anti-inflammatory
effects and decreases in hepatocyte damage reduce the
activation of hepatic stellate cells [22] and direct the ef-
fects of MSCs to reduce hepatic stellate cell activation
[23]. Additionally, we recently reported the effects
against macrophages. MSCs change the polarity of mac-
rophages towards an anti-inflammatory phenotype, in-
crease the production of matrix metalloproteinases to
reduce the ECM, and increase the ability of phagocytosis
of hepatocyte debris (during this process, macrophages
increase the levels of pro-regenerative factors) (Fig. 1)
[14]. When we administered bone marrow-derived
MSCs with macrophages produced by culturing bone
marrow cells for 7 days, host macrophages and neutro-
phils were also recruited to the liver.
The behaviors of macrophages after administration
showed differences between studies. Some studies re-
ported that administered MSCs can migrate to and func-
tion in the liver [24]. However, our recent studies of a
liver cirrhosis mouse model using two-photon excitation
microscopy revealed that when bone marrow-derived
macrophages (green fluorescent protein-labeled) and
MSCs (DsRed-labeled) were administered at the same
time via the tail vein, most MSCs migrated to the lung
and a low percentage of MSCs migrated to the liver,
which disappeared from both the lung and liver after 7
days. In contrast, macrophages migrated to both the
lung and liver, where they remained for 7 days. Particu-
larly, in the liver, administered macrophages migrated to
the damaged area where excess ECM and hepatocyte
debris were detected. Furthermore, we observed that the
administered GFP-positive macrophages phagocytosed
the debris in hepatocytes in the liver [14].
Tsuchiya et al. Inflammation and Regeneration (2019) 39:18 Page 2 of 6
While some aspects of the mechanisms of MSCs remain
unclear, these results revealed that MSCs function indir-
ectly as “conducting cells,”while macrophages, T cells, B
cells, and other cells function directly as “effective cells.”
Summary of MSC therapies from recently
published papers
Many reports have been published describing the results of
clinical trials using MSCs. Zhao et al. reported a meta-ana-
lysis of previously published papers up to June 2017. They
evaluated 23 reports of studies comparing MSC therapy to
conventional treatment. The authors concluded that MSC-
based therapy is relatively safe and improved liver function
during the first 6 months after administration. A single in-
jection administration via the hepatic artery and MSCs de-
rived from the bone marrow are optimal in terms of
improving liver function [25]. The analyzed cases were
quite heterogenous and included papers only written in
Chinese; thus, next, we show two representative studies.
Suk et al. reported a phase II study using bone marrow-de-
rived MSCs for treating alcoholic liver cirrhosis. An MSC
culture from 10 to 20 ml of bone marrow aspirated 1 month
before the first injection was administered one or two times
(5 × 10
7
cells/time)viathehepaticarteryandcomparedto
the control. Results of biopsy performed 6 months after cell
administration revealed 25% (one-time cell administration)
and 37% (two administrations) reductions in the fibrosis area.
Furthermore, the Child-Pugh scores of both the single and
double administration groups were improved significantly at
12 months after cell injection [26].
Lin et al. reported an open-label non-blinded random-
ized controlled study using 1.0–10 × 10
5
cells/kg of allo-
geneic bone marrow cells for treating patients with
HBV-related ACLF once per week for 4 weeks; these
subjects were followed for 24 weeks. The clinical labora-
tory results showed that serum total bilirubin and model
for end-stage liver disease scores were improved com-
pared to those obtained after standard medical therapy.
The authors further observed that the incidences of se-
vere infection and mortality from multiple organ failure
were reduced after cell administration [27].
Two representative cases of cirrhosis and ACLF of MSC
therapy were shown above, both of which were treated
safely and showed some favorable effects. Based on these
studies, additional clinical studies were designed. The next
section describes recently designed clinical trials.
Recently started or planned clinical trials
To describe recent trends in clinical trials using MSCs, we
evaluated clinical studies which began or will begin after 1
January 2017 according to ClinicalTrials.gov. Thirteen clin-
ical trials were registered; 1 case was a follow-up study of a
clinical trial, and thus, we excluded this case and analyzed
the other 12 cases. As shown in Tables 1, 8 of 12 (66.7%)
cases were from China and 1 case (8.3%) each occurred in
Germany, Japan, Taiwan, and Singapore (Fig. 2a). Four of
12 cases (33.3%) were ACLF, 7 of 12 cases (58.3%) were cir-
rhosis in which each study’s etiology of cirrhosis slightly dif-
fered, and 1 case (8.3%) was a target for primary biliary
cholangitis (Fig. 2b). Five of 12 (41.6%) cases were treated
with allogeneic MSCs, and 2 of 12 cases were treated with
autologous MSCs (16.7%). In 5 of 12 cases, it was unclear
whether allogeneic or autologous cells were used; however,
based on the study design and disease condition, allogeneic
MSCs were administered in most cases, suggesting that
allogeneic cases were increased compared to previously
Fig. 1 Mechanisms of MSCs for liver disease. MSCs have various effects including the reduction of hepatocyte injury and inflammation.
Additionally, MSCs affect macrophages and increase matrix metalloproteinase expression and phagocytosis, promoting the regenerative process
Tsuchiya et al. Inflammation and Regeneration (2019) 39:18 Page 3 of 6
Table 1 Recently started or planned clinical trials
Country Conditions Auto/
Allo
Origin Cell number Cell injection
times
Route Phase Study design
1 China ACLF N/A N/A 1–10 × 10
5
/kg 4 Peripheral
vein
I/II Randomized/open label
2 China ACLF N/A N/A 0.1–1×10
6
/kg 3 Peripheral
vein
N/A Randomized/double
blind
3 Germany ACLF Allo Skin (ABCB5+
cells)
2×10
6
/kg 3 Peripheral
vein
I/II Non-randomized/open
label
4 China Cirrhosis N/A N/A N/A N/A N/A I/II Non-randomized/open
label
5 China Cirrhosis Allo UC 1.5 × 10
6
/kg 2~4 Peripheral
vein
II Non-randomized/open
label
6 China Cirrhosis (HBV, HCV) N/A N/A 1 × 10
6
/kg 4 Peripheral
vein
N/A Randomized/single
blind
7 Japan Cirrhosis (NASH,
HCV)
Allo AD N/A 1 Peripheral
vein
I/II Non-randomized/open
label
8 Taiwan ACLF Allo AD 0.5–2×10
6
/kg N/A Peripheral
vein
I Non-randomized/open
label
9 Singapore Cirrhosis Auto BM 0.5–1×10
6
/kg N/A Peripheral
vein
I/II Non-randomized/open
label
10 China Alcoholic liver
cirrhosis
Auto BM 5 × 10
7
cells/10
ml
1 Hepatic
artery
I Non-randomized/open
label
11 China Cirrhosis (HBV) Allo UC 6 × 10
7
(30 ml) N/A Peripheral
vein
I Non-randomized/open
label
12 China PBC N/A N/A 0.1–1×10
6
/kg 3 Peripheral
vein
N/A Randomized/double
blind
Fig. 2 Recent trends in clinical trials using MSCs. Proportion of country (a), disease conditions (b), autologous or allogeneic (c), and tissue origin
of MSCs (d) in recent clinical trials
Tsuchiya et al. Inflammation and Regeneration (2019) 39:18 Page 4 of 6
reported frequencies (allogeneic, 53%; autologous, 45%)
(Fig. 2c). Regarding the cell origin, 1 case (8.3%) occurred
in the skin, while the other cases occurred in the bone
marrow (2 cases; 16.7%), adipose tissue (2 cases; 16.7%),
and umbilical cord tissue (2 cases; 16.7%). The cases of
bone marrow origin were all autologous cases (Fig. 2d).
The cell numbers employed in the trials slightly differed;
approximately 0.1–1.0 × 10
6
cells/kg were injected 1–4
times, cell administration in 10 of the 12 cases (83.3%)
was performed via the peripheral vein, and 1 case (8.3%)
involved autologous bone marrow case from the hepatic
artery, suggesting that the recent trend in administration
is the peripheral vein. However, further studies of direct
infusion of MSCs are necessary to achieve efficient effects.
All clinical trials are still in phase I or/and II.
Recent research trend of using extracellular
vesicles obtained from MSCs
Although most MSCs were trapped in the lung, they
showed therapeutic effects. To explain this phenomenon,
extracellular vesicles (EVs) have been evaluated [28–34].
EVs include apoptotic bodies (50–4000 nm in diameter),
microvesicles (MVs; 100–1000 nm in diameter), and exo-
somes (40–100 nm in diameter), among which exosomes
are the most widely studied [31]. Exosomes are lipid vesi-
cles produced by multivesicular bodies prior to extracellular
secretion. They can be sedimented by ultra-centrifugation
and include endosome-derived components as well as
many bioactive molecules such as proteins, lipids, mRNAs,
microRNAs (miRNAs), long non-coding RNAs, transfer
RNA, genomic DNA, cDNA, and mitochondrial DNA [35].
Exosome membranes are enriched in cholesterol, sphingo-
myelin, ceramide, and lipid raft proteins. Exosomes are cell
type-specific; however, they contain evolutionarily con-
served sets of proteins including tetraspanins (CD81, CD63,
and CD9), heat shock proteins (HSP60, HSP70, and
HSP90), AlIX, and tumor susceptibility gene 101 and have
been reported to have multiple functions including angio-
genesis, cell proliferation, and collagen reduction. MSCs are
relatively easy to expand and well-known to produce abun-
dant exosomes and thus are theoretically ideal tools for de-
veloping cell-free therapies [28,30–32,34]. Haga et al.
reported that mouse bone marrow-derived MSC EVs have
therapeutic effects for hepatic failure induced by D-galact-
osamine (D-gal) and tumor necrosis factor α. In this experi-
ment, high levels of EVs were observed after 6 h in the liver
and spleen. Jiang et al. reported that exosomes derived from
human umbilical cord-derived MSCs alleviate acute liver
failure (lipopolysaccharide/D-galactosamine-induced liver
injury model) [36]. They reported that MSC exosomes re-
duced the activation of the NLRP3 inflammasome, IL-1β,
and IL-6 in macrophages. Borrelli et al. reported the use of
drug-loaded EVs for treating hepatocellular carcinoma.
Exosomes contain diverse and numerous miRNAs, and
thus, determining the roles of miRNA is very difficult. Fer-
guson et al. reported that most previous studies used a can-
didate approach with specific miRNAs to assess their
therapeutic effects; however, this approach may not fully
capture the various biological effects induced by miRNAs
in the MSC exosomes of recipient cells [29]. System-level
studies are thus needed.
Conclusions
MSCs are attractive cell therapies that function as “con-
ducting cells”against many types of immune cells and in-
duce a variety of therapeutic effects. However, several
years have passed since the first MSC theories were postu-
lated, and thus, these clinical studies must be evaluated to
determine whether MSC therapies are indeed effective in
human liver diseases. In recent clinical trials, the trend of
MSC therapy appears to have shifted from administration
of autologous cells towards allogeneic cells. This research
area is very attractive for developing effective anti-fibrotic
therapies. Studies are needed to determine the most ef-
fective cell source, culture condition, cell number, admin-
istration frequency, and administration route, at low cost
for treating specific liver diseases. Cell-free therapy using
exosomes is an attractive approach.
Abbreviations
ACLF: Acute on chronic liver failure; ECM: Extracellular matrix; EV: Extracellular
vesicle; MSC: Mesenchymal stem cell
Acknowledgements
The authors thank Dr. Yusuke Watanabe and Dr. Yuichi Kojima for their
cooperation.
Authors’contributions
AT, ST, TW, TY, SN, and MO analyzed and interpreted the previous literature
and clinical study patient. AT and ST were the major contributors in writing
the manuscript. All authors read and approved the final manuscript.
Funding
This work was supported by a Grant-in-Aid for Scientific Research (C) (18
K07903) from the Ministry of Education, Science, Technology, Sports, and Cul-
ture of Japan and by the Research Program on Hepatitis from AMED to Shuji
Terai (17fk0210101h0001).
Availability of data and materials
All data generated or analyzed during this study are included in this
published article.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Received: 5 April 2019 Accepted: 8 August 2019
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