Mesenchymal Stem Cell Therapy
of Pulmonary Fibrosis: Improvement
with Target Combination
, Tina Emily Shih
, Kang-Yun Lu
, Horng-Jyh Harn
, and Li-Ing Ho
Although the clinical application of new drugs has been shown to be effective in slowing disease progression and improving the
quality of life in patients with pulmonary fibrosis, the damaged lung tissue does not recover with these drugs. Thus, there is an
urgent need to establish regenerative therapy, such as stem cell therapy or tissue engineering. Moreover, the clinical appli-
cation of mesenchymal stem cell (MSC) therapy has been shown to be safe in humans with idiopathic pulmonary fibrosis (IPF).
It seems that a combination of MSC transplantation and pharmaceutical therapy might have additional benefits; however, the
experimental design for its efficacy is still lacking. In this review, we provide an overview of the mechanisms that were
identified when IPF was treated with MSC transplantation or new drugs. To maximize the therapeutic effect, we suggest that
MSC transplantation is combined with drug application for synergistic effects. This review provides clinicians and scientists
with the most efficient medical options, in the hope that this will spur on future research and lead to an eventual cure for this
pulmonology, pharmacology, stem cell therapy
Idiopathic pulmonary fibrosis (IPF) is a specific form of
chronic and progressive fibrosing interstitial pneumonia of
. It occurs mainly in older adults (median
age at diagnosis 66 years, range 55–75 years)
, is limited to
the lungs, and is characterizedbyfibroblastproliferation
and extracellular matrix remodeling
, which results in pro-
gressively worsening dyspnea and pulmonary function,
usually with poor prognosis. The diagnosis of IPF requires
the histopathologic and/or radiologic pattern of usual
interstitial pneumonitis on high-resolution computed
tomography. Other known causes of interstitial lung dis-
ease (ILD) (e.g. connective tissue diseases, drug toxicity,
and other environmental exposures) must be excluded
first. IPF is a fatal lung disease, with median survival
ranging from 3 to 5 years
. The majority of patients
demonstrate a slow and gradual progression over many
years, and some patients remain stable while others have
an accelerated decline
. A small minority of IPF patients
(approximately 5–10%) may suffer from acute exacerba-
. The incidence of IPF is reported to be an
estimated 4.6 to 16.3 cases per 100,000 worldwide. Based
on healthcare claims data from the United States, an esti-
mated prevalence of between 14.0 and 42.7 per 100,000
persons was reported
Buddhist Tzu Chi Bioinnovation Center, Tzu Chi Foundation, Hualien,
Department of Life Sciences, Agricultural Biotechnology Center, National
Chung Hsing University, Taichung, Taiwan
Graduate Institute of Basic Medical Science, China Medical University,
Department of Pathology, Buddhist Tzu Chi General Hospital, Tzu Chi
University, Hualien, Taiwan
Division of Respiratory Therapy, Department of Chest Medicine, Taipei
Veterans General Hospital, Taipei, Taiwan
Submitted: March 9, 2018. Revised: May 1, 2018. Accepted: May 7, 2018.
Horng-Jyh Harn, Buddhist Tzu Chi Bioinnovation Center, Tzu Chi
Foundation, No. 707, Sec., 3 Chung Yang Road, Hualien 970, Taiwan.
Li-Ing Ho, Division of Respiratory Care, Department of Chest Medicine,
Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Road, Beitou
District, Taipei, 11267, Taiwan.
ªThe Author(s) 2018
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The antifibrotic drugs nintedanib and pirfenidone havebeen
shown to significantly reduce the decline in forced vital capac-
ity (FVC), decrease acute exacerbation, and improve mortality
rates in patients with IPF in several studies
. Recently, they
have been recommended conditionally in several guidelines
for the treatment of IPF
; however, current medication can
only slow the progression of IPF but does not reverse the
fibrosis process. There is still a lack of effective options for
treating IPF, although abundant possible targets from animal
studies have shown theirpotential. Even though some off label
drugs, such as inhaled NAC, could shorten the time of
investigation through meta-analysis, the response is relatively
limited compared with specific target therapy
studies have provided results for both stem cell and pharmaco-
logical treatments, but data on a combination of these are still
lacking. In this review, we have summarized the experimental
and clinical evidence and possible mechanisms of action to
present the potential options for this intractable disease.
Treatment Strategies in IPF
Compared with other diseases of the respiratory system, IPF
is hard to predict and prognosticate. The main cause of IPF is
still unclear, but it may involve genetic, environmental, or
. Bleomycin (BLM) is commonly used to
induce symptoms of IPF in animal models, as it produces an
oxidative stress specific to alveolar epithelial cells
. In these
models, the immune cells and fibroblasts gradually infiltrate
the lungs of BLM-treated mice. On the other hand,
differentiation and proliferation of myofibroblasts from
fibroblasts produce excessive extracellular matrix. Conse-
quently, anti-inflammatories have been commonly used as
a treatment option in previous studies; however, the treat-
ment was stopped in one trial due to an increasing risk of
death in IPF patients with no clinical benefit
inducers, such as transforming growth factor b(TGF-b) and
fibroblast growth factor (FGF), have been used as targets for
blockage by inhibitors or antibodies
. In recent years, there
is evidence of an increasing trend on the use of stem cell
therapy in IPF; its use almost comparable to studies on new
drug development and compound studies (Fig 1). This trend
suggests the potential benefit of stem cell treatment in IPF.
The first successful stem cell transplantation was carried out
50 years ago
, but even now there are potential exciting
applications that deserve our attention.
Developmental Drugs for Treatment of IPF
The two Food and Drug Administration (FDA)-approved
pharmacological targets for treatment of IPF are TGF-b(pir-
fenidone) and PDGF/VEGF/FGF (nintedanib). The efficacy
of pirfenidone is impressive, as it was found to significantly
lower the relative risk of death compared to the placebo
group at week 52
. The data collected from four phase III
trials showed that the mean life expectancy was 8.72 years
for patients given pirfenidone versus 6.24 years for those
receiving best supportive care
. On the other hand, in a
52-week phase III trial involving 1,061 subjects, nintedanib
was found to slow disease progression, but there was no
statistically significant difference for the primary endpoint
Although the preclinical studies are quite epromising, the
human trials did not show consistent results, not including
the cases waiting for FDA approval. Potential developmental
drugs provide additional possible targets for improving cur-
rent therapy. Pamrevlumab, an anti-connective tissue growth
factor antibody (FG3019), is under phase III trials
(NCT01890265). Another drug that targets alpha v beta 6
(avb6) integrin has also completed a phase II trial involving
IPF participants (NCT01371304). In short, new drug devel-
opment for IPF is a highly risky and ineffective business.
Percentage relative to total IPF studies
Stem cells New drugs
Fig. 1. Publications of new drugs or stem cells development and each percentage of total IPF studies.
Current Stem Cell Therapies for IPF
Despite the fact that MSC therapy has been used in the clinic
for approximately 10 years, more than 75%of studies are
still in phase II or earlier
. Lung diseases account for 23 of
the 493 transplantation studies, according to https://www.
clinicaltrials.gov/. More recently, an allogeneic bone mar-
row MSC (BMSC) transplantation study in IPF patients
assigned three cohorts to a single IV infusion of 20, 100,
or 200 10
. There is also a case report of a
56-year-old man with IPF who received human umbilical
cord-derived mesenchymal stem cell (HUC-MSC) trans-
plantation with intravenous infusion
. Both studies,
observed over 1 year, did not register any adverse events.
The authors of a phase I trial of adipose-derived stem cell
(ADSC) treatment for IPF reported on their experiences of
acquiring FDA approval (NCT01385644). The protocol used
three rounds of endobronchial infusion with Stromal vascu-
lar fraction (SVF), totaling 1.510
cells, and the cell fate
was traced by
. These reports suggest that
stem cell transplantation in IPF is initially safe and with
some benefits, and the standardized protocol might encour-
age scientists to explore the potential for MSC therapy in IPF
patients. Data from previous clinical studies suggest that
the transplanted cell type is important for IPF treatment.
Of the problems that may arise between the MSC source and
the receiver during allograft, placenta-derived MSCs such as
umbilical cord blood or amnion stem cell provides less com-
. It has been well-established that management
of host rejection through HLA typing in placenta-derived
MSCs can be performed easily in clinical applications.
The results with amniotic stem cells are the most abundant
results in clinical studies. Although their primary endpoints
were usually for safety and not efficacy, stem cells still hold
promise for better outcomes than most known drugs
Mechanisms of Stem Cell Therapy in IPF
The progression of IPF is a complex event consisting, at
minimum, of epithelial-dependent fibroblast-activated pro-
cesses and poor response to anti-inflammatories. These
effects involve downstream pathways of epithelial mesench-
ymal transition (EMT) and an immune response
, as shown
in Fig 2. Some EMT regulators like WISP-1 and BMP4 have
been found to have a role in fibroblast differentiation or
collagen production through Wnt and BMP pathways,
. In regard to an immune response, the PGE2
pathways can prevent Fas ligand-induced apoptosis in myofi-
broblasts and fibroblasts; however, due to the lower expression
of PGE2, alveolar type II cells are still sensitive toapoptosis
The differences in expression might explain the apoptosis in
alveolar epithelial cells but not in myofibroblasts or fibroblasts.
Targeting of cell cycle-related proteins has also been reported
as a potential treatment for IPF. S-phase kinase-associated pro-
tein 2 (Skp2) is an effector protein that enhances degradation of
and is essential for the progression of IPF. Increased
expression of p27 with an antagonist for Skp2, SZL-P1-41,
could inhibit BLM-induced pulmonary fibrosis
ally, treatment with BLM in fibroblasts also induces ER
stress-related proteins, such as GRP78, CHOP, and ATF4,
and enhances proliferation of fibroblasts through a PI3K/
. The activation of the PI3K/Akt pathway is
another upstream regulator of EMT
and makes the
response more unpredictable and irreversible. Although
there are few connections betweeneachsignalingpathway,
the evidence has shown that the use of each inhibitor, such as
LY294002 and Tauroursodeoxycholic acid (TUDCA), is
efficient at ameliorating pulmonary fibrosis.
Regulation of Immune Response or Secretome
Bone marrow (BM)-derived MSCs are used more often in
mechanism studies than in clinical studies
because the source is easier to obtain. It is thought that
the injected cells could repair lung tissue with its immuno-
modulatory effects. From the immunological perspective,
the BM-derived MSCs had lower levels of expression of the
immunosuppressive molecules PDL-1 and CD1a than
placenta-derived MSCs, and IFN-ginduction also showed
lower potential to stimulate T cell proliferation in BM-
. However, placenta-derived MSCs had a
suppressive effect in cytokine-stimulated natural killer lym-
, though the cell type is still hard to ascertain.
Furthermore, the process of IPF is usually accompanied by
inflammation and profibrotic cytokinesis. To produce an
Fig. 2. Mechanism assuming that the fibrogenesis consists of alveo-
lar cell apoptosis and immune cell infiltration (left). The trans-
planted stem cells circulate through the pulmonary artery
(bottom) and act through immunomodulation, secretion of growth
factor, and differentiation into alveolar-like cells (right).
Chuang et al 3
anti-inflammatory effect, MSCs reduce IL-1b, IL-6, TNF-a,
TGF-b, and vascular endothelial growth factor (VEGF) in
BLM-induced lung injury
. Although these studies did not
find leftover stem cells in injured lungs, the secreted circu-
lating mediators were taken into account to benefit the ther-
apeutic effects for IPF
Stem cell therapy also benefits from secretion of isolated
exosomes that contain proteins and RNA from their own cell
. These extracellular vesicles of between 10 and
100 nm in size, called exosomes, allow communication
between distal cells and their cargos
. The effects induced
by exosomes may be associated with the modulation of the
immune response and suppression of macrophage pheno-
. To confirm this theory of stem cell secretion, Tan
et al. purified exosomes from amniotic stem cells and admi-
nistered them intranasally. They found that pulmonary
capacity was recovered in the exosome-treated groups in
BLM-induced pulmonary fibrosis
. Moreover, the specific
delivery potential of exosomes has been reported to be due to
exosomes instead of MSCs alone a better proposition. How-
ever, a contradictory result suggested that MSC-isolated
microvesicles (MV) reduced pulmonary fibrosis, and that
MSCs have a better treatment effect than MV
nately, these authors did not reveal the amount of MSCs used
for isolating the MV, and the result is also lacking in dosage
effectiveness. Nevertheless, these studies suggest that the
treatment potential of MSC therapy is positive regardless of
its presence in the lung tissue.
Evidence for Differentiation into
Functional Alveolar Cells
The injected MSCs were found in the lung epithelium and
expressed an epithelium-like phenotype
; but researchers
also found that their presence is not necessary for an effect,
since the condition medium could also inhibit the effect
of inflammatory cytokines and macrophage-produced
. The anti-inflammatory molecule TSG-6 can be
secreted and homed to the injury site of myocardiocytes by
the embolized-MSCs in the lung
. Evidence of MSC differ-
entiation into lung epithelial cells was found in nude mice
engrafted with amnion-derived stem cells
CXCR4/SDF1 axis is thought to be involved in stem cell
plasticity. However, in immunocompetent mice, injection
of allogenic amnion-derived stem cells did not find labeled
cells in lung, brain, heart, spleen, liver, and kidney
seems that the ability to engraft is determined by the innate
immune responses. Although the cost is higher and time-
scale longer, autogenic MSC transplantation is still consid-
ered better than allogenic MSC transplantation in IPF.
Influential Factors for Clinical Outcome
Data from a large-scale meta-analysis indicate that the most
important factors for stem cell therapies are dosage and time
. A double dosage of autologous stem cell transplan-
tation produced a two-fold better outcome (10%vs 20%)ina
study on humans
. Ghadiri et al. summarized five clinical
studies in IPF patients involving autogenic or allogenic MSC
therapy; however, four of them are still under patient recruit-
. The route of transplantation is also conflicting, since
animal studies did not compare the efficiency between intra-
venous and intranasal transplantation. Interestingly, MSC
transplantation via the intraperitoneal route is also effective
for treating IPF, which suggests that direct contact of stem
cells with lung tissue is not necessary
Comparison of Drugs and Stem Cells
in Clinical Potential
Intravenous injection of ADSC on day 3, 6, and 9 after BLM-
induction in mice has comparable therapeutic effects with
the approved drug pirfenidone
. However, there are no ben-
eficial effects when injected on day 14, 17, and 20, due to its
diminished response of anti-inflammation and inhibited
. In current pharmacological studies, the
targeting of drugs to specific organs or tissues is still under
investigation. In the case of stem cell transplantation, tissue
repair from migrating stem cells is a natural characteristic of
, which is also found in bleomycin-induced lung
injury or infarcted myocardium
. On the other hand,
pharmacological applications have more detailed studies for
absorption, distribution, metabolism, and excretion, and the
mechanisms are clear in most clinical drugs. The manufac-
turing process of MSCs is determined by the donor and
source (i.e. autogenic transplantation of MSCs is more
expensive than allogenic). But the effect of engraftment in
autogenic transplantation is more impressive than other
known drugs and might apply to regenerative medicine.
Advancements in MSC purification and modification might
be a future goal when the limits of current medication
Problems and Future Breakthroughs
The ethical issues in stem cell transplantation include the
potential of these cells to develop into a human being
However, MSCs lack such potential, so this issue is not
relevant here. Other concerns that arise are the promotion
of tumor growth and metastasis, and overestimating thera-
. One of the problems we encountered in
this review was characterizaton of the culturing method or
media, since little is known about which characteristics
would be changed from their original niche
transplantation is performed once a culture and expansion
method, which is as similar to the natural niche as possible,
. Considering the economic concerns, HLA-
matched banking for allogenic transplantation and mass pro-
duction is rational
. Although it is not necessary to evaluate
the effects of graft-versus-host disease, cases with
immunosuppressive agents should be evaluated with the
total adding effect.
Recently, a convincing new drug has been discovered that
slows the decline of Forced Vital Capacity (FVC) as well as
prolonging survival, but it does not rebuild the normal struc-
ture of lung tissue. The final goal of therapy should be the
recovery of pulmonary histological structure or retainment
of the cellular functions of each cell type. While there is no
evidence suggesting MSC differentiates into alveolar epithe-
lial cells, the theory that supplies remaining lung progenitor
cell proliferation is still expectable. MSC transplantation is
as effective as pharmaceutical therapies, but has relatively
unclear mechanisms of action.
Here we have listed mechanisms sufficient for treating
IPF, such as immunomodulatory effect, secretion of cyto-
kines, and suppression of myofibroblast differentiation;
however, MSCs neither act as an inhibitor of signaling path-
ways, nor as an agonist of receptors. To counter this disad-
vantage, a combination of drugs and MSCs might be of
benefit. MSC treatment lacks the ability to improve myofi-
, re-epithelization of mesenchymal type
cells (or mesenchymal to epithelial transition, MET)
. MSC-derived MV or exosomes might
provide another option. Neutralizing antibodies or drugs
approved for marketing can support such limitations. Rather
than applying for new drug development trial approval at the
Institutional Review Board (IRB), which can be both time-
consuming and cost inefficient, use of approved drugs
proves to be a better strategy. These suggestions provide
more options for physicians and patients.
In summary, we concluded that current MSC therapies
have observed positive results in clinical and animal stud-
ies. Moreover, molecular targets involved in the process of
fibrogenesis, such as cytokines or growth factors, can work
alongside MSCs with synergistic effect. Here we discussed
some of the known mechanisms involved and studies based
on these mechanisms. Exploring possible combinations for
making the best therapeutic strategies should be the next
step in the pursuit of better outcomes in the treatment of
cell therapy have their own disadvantages. However, two
heads are better than one as they say, so selecting the pos-
itive features from each approach might be the best way
This study was funded by Buddhist Tzu Chi Bioinnovation Center,
Tzu Chi Foundation, Hualien, Taiwan; and Ministry of Science and
Technology, Taiwan (MOST 106-2320-B-303-001-MY3 and
Horng-Jyh Harn and Li-Ing Ho contributed equally to this study.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
The authors received no financial support for the research, author-
ship, and/or publication of this article.
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