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Mesenchymal Stem Cell Therapy of Pulmonary Fibrosis: Improvement with Target Combination

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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 application 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 disease.
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Review Article
Mesenchymal Stem Cell Therapy
of Pulmonary Fibrosis: Improvement
with Target Combination
Hong-Meng Chuang
1,2
, Tina Emily Shih
1
, Kang-Yun Lu
1,3
,
Sheng-Feng Tsai
2,4
, Horng-Jyh Harn
1,4
, and Li-Ing Ho
5
Abstract
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
disease.
Keywords
pulmonology, pharmacology, stem cell therapy
Introduction
Idiopathic pulmonary fibrosis (IPF) is a specific form of
chronic and progressive fibrosing interstitial pneumonia of
unknown cause
1
. It occurs mainly in older adults (median
age at diagnosis 66 years, range 55–75 years)
2
, is limited to
the lungs, and is characterizedbyfibroblastproliferation
and extracellular matrix remodeling
3
, 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
3
. The majority of patients
demonstrate a slow and gradual progression over many
years, and some patients remain stable while others have
an accelerated decline
4
. A small minority of IPF patients
(approximately 5–10%) may suffer from acute exacerba-
tion annually
1
. 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
5
.
1
Buddhist Tzu Chi Bioinnovation Center, Tzu Chi Foundation, Hualien,
Taiwan
2
Department of Life Sciences, Agricultural Biotechnology Center, National
Chung Hsing University, Taichung, Taiwan
3
Graduate Institute of Basic Medical Science, China Medical University,
Taichung, Taiwan
4
Department of Pathology, Buddhist Tzu Chi General Hospital, Tzu Chi
University, Hualien, Taiwan
5
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.
Corresponding Authors:
Horng-Jyh Harn, Buddhist Tzu Chi Bioinnovation Center, Tzu Chi
Foundation, No. 707, Sec., 3 Chung Yang Road, Hualien 970, Taiwan.
Email: arthewduke@gmail.com
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.
Email: breathho@gmail.com
Cell Transplantation
1–7
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
6–8
. Recently, they
have been recommended conditionally in several guidelines
for the treatment of IPF
9
; 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
10
.Previous
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
toxic components
11
. Bleomycin (BLM) is commonly used to
induce symptoms of IPF in animal models, as it produces an
oxidative stress specific to alveolar epithelial cells
12
. 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
13
.Other
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
14
. 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
15
, 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
16
. 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
17
. 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
18
.
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.
0.00%
1.00%
2.00%
3.00%
4.00%
5.00%
6.00%
7.00%
8.00%
Percentage relative to total IPF studies
Years
Stem cells New drugs
Fig. 1. Publications of new drugs or stem cells development and each percentage of total IPF studies.
2Cell Transplantation
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
19
. 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
6
human BMSC
20
. 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
21
. 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
6
cells, and the cell fate
was traced by
99m
Tc-HMPAO
22
. 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-
plications.
23
. It has been well-established that management
of host rejection through HLA typing in placenta-derived
MSCs can be performed easily in clinical applications.
24
.
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
25
.
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
3
, 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,
respectively
26,27
. 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
28
.
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
p27
29
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
30
. Addition-
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/
Akt pathway
31
. The activation of the PI3K/Akt pathway is
another upstream regulator of EMT
32
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
33
, perhaps
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-
derived MSCs
34
. However, placenta-derived MSCs had a
suppressive effect in cytokine-stimulated natural killer lym-
phocytes
35
, 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
36
. 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
37
.
Stem cell therapy also benefits from secretion of isolated
exosomes that contain proteins and RNA from their own cell
origin
38
. These extracellular vesicles of between 10 and
100 nm in size, called exosomes, allow communication
between distal cells and their cargos
39
. The effects induced
by exosomes may be associated with the modulation of the
immune response and suppression of macrophage pheno-
type
40
. 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
41
. Moreover, the specific
delivery potential of exosomes has been reported to be due to
thepresenceofmembraneproteins
42
,makingtheuseof
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
43
. Unfortu-
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
44
; 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
TNF-a
45
. The anti-inflammatory molecule TSG-6 can be
secreted and homed to the injury site of myocardiocytes by
the embolized-MSCs in the lung
46
. Evidence of MSC differ-
entiation into lung epithelial cells was found in nude mice
engrafted with amnion-derived stem cells
47
,andthe
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
37
.It
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
points
48
. A double dosage of autologous stem cell transplan-
tation produced a two-fold better outcome (10%vs 20%)ina
study on humans
49
. 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-
ment
50
. 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
51
.
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
52
. 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
profibrotic genes
53
. 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
MSCs
19
, which is also found in bleomycin-induced lung
injury or infarcted myocardium
44,54,55
. 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
are reached.
Problems and Future Breakthroughs
The ethical issues in stem cell transplantation include the
potential of these cells to develop into a human being
56
.
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-
peutic potential
57
. 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
58
. Autologous
transplantation is performed once a culture and expansion
method, which is as similar to the natural niche as possible,
is formalized
59
. Considering the economic concerns, HLA-
matched banking for allogenic transplantation and mass pro-
duction is rational
60
. Although it is not necessary to evaluate
the effects of graft-versus-host disease, cases with
4Cell Transplantation
immunosuppressive agents should be evaluated with the
total adding effect.
Conclusion
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-
broblast apoptosis
61
, re-epithelization of mesenchymal type
cells (or mesenchymal to epithelial transition, MET)
62
, and
TGF-binhibition
63
. 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
IPF,bearinginmindthatbothamolecularapproachand
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
forward.
Acknowledgments
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
MOST 106-2320-B-303-002-MY3).
Author Contribution
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.
Funding
The authors received no financial support for the research, author-
ship, and/or publication of this article.
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Chuang et al 7
... Recent studies have shown that pulmonary fibrosis can be alleviated by altering the inflammatory Milieu [33]. MSCs have potent anti-inflammatory, immunomodulatory properties and reduce tissue damage through paracrine release of multiple types of cytokines [34,35]. A common observation is that MSC treatment reduced the expression of pro-inflammatory cytokines (including IL-1α, IL-1β, IL-6, IFN-γ and TNF-α), pro-fibrotic factors (TGF-β) and chemokines (MIP, MCP) and increased the expression of anti-inflammatory cytokines (e.g. ...
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Background Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. Whether extracellular vesicles are effective in treating IPF and what is the optimal administrative route is not clear. Our previous studies have shown that immunity and matrix regulatory cells (IMRCs) derived from human embryonic stem cells can safely treat lung injury and fibrosis in mouse models, and its mechanism of action is related to the paracrine effect. In this study, we investigated the therapeutic effects of IMRC-derived extracellular vesicles (IMRC-EVs) on a bleomycin-induced pulmonary fibrosis mouse model and explored the optimal route of administration. Methods To study the biodistribution of IMRC-EVs after administration via different routes, NIR labeled-IMRC-EVs were delivered by intratracheal (IT) or intravenous (IV) route, and in vivo imaging was acquired at different time points. The therapeutic effects of IMRC-EVs delivered by different routes were analyzed by assessing histology, lung function, cytokines levels, and transcriptome profiling. RNA-seq of lung tissues was performed to investigate the mechanisms of EV treatment through IT or IV administrations. Results IMRC-EVs mainly reserved in the liver and spleen when administrated via IV route; and mainly retained in the lungs via the IT route. IMRC-EVs administrated via both routes demonstrated a therapeutic effect as attenuated pulmonary fibrosis, improved lung function, and histological parameters. Based on our RNA-seq results, different pathways may be affected by IMRC-EVs administrated via IT or IV routes. In addition, in vitro experiments showed that IMRC-EVs inhibited epithelial-to-mesenchymal transition induced by TGF-β. Conclusion IMRC-EVs administrated via IT or IV routes generate different biodistributions, but are both effective for the treatment of bleomycin-induced pulmonary fibrosis. The therapeutic mechanisms of IMRC-EVs administrated via different routes may be different.
... Overwhelming in vitro and in vivo studies revealed that the MSCs suppress the over-activated inflammatory response, release factors including cytokines and extracellular vesicles, which promote neighbouring cell survival and growth and possess differentiation potential. In terms of lung regeneration, mainly, the immunomodulatory function of MSCs shown to help in the recovery of lung function and reduce pulmonary fibrosis [106]. According to the International Clinical Trials Registry Platform at World Health Organization, over twelve thousand clinical trials are undertaken on COVID-19 as of December 2021, where 131 studies are using stem cells to attenuate the detrimental effect caused by the SARS-CoV2. ...
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The unprecedented COVID-19 pandemic situation forced the scientific community to explore all the possibilities from various fields, and so far we have seen a lot of surprises, eureka moments and disappointments. One of the approaches from the cellular therapists was exploiting the immunomodulatory and regenerative potential of mesenchymal stromal cells (MSCs), more so of MSC-derived extracellular vesicles (EVs)-particularly exosomes, in order to alleviate the cytokine storm and regenerate the damaged lung tissues. Unlike MSCs, the EVs are easier to store, deliver, and are previously shown to be as effective as MSCs, yet less immunogenic. These features attracted the attention of many and thus led to a tremendous increase in publications, clinical trials and patent applications. This review presents the current landscape of the field and highlights some interesting findings on MSC-derived EVs in the context of COVID-19, including in silico, in vitro, in vivo and case reports. The data strongly suggests the potential of MSC-derived EVs as a therapeutic regime for the management of acute lung injury and associated complications in COVID-19 and beyond.
... Stem cell therapies are emerging as promising treatment modalities that can reduce inflammation and restore lung damage caused by corona virus disease of 2019 (COVID- 19), alone or in combination with existing therapy regimens [1,2]. An increasing body of research indicates that mesenchymal stem cell (MSC)-based treatment can help manage acute respiratory distress syndrome (ARDS) due to the ability of MSCs to produce anti-inflammatory, antifibrosis, and anti-apoptosis cytokines [3][4][5], promote recovery of lung function, and potentially influence the progression of pulmonary fibrosis [6,7]. As a result, MSC therapies may help in treating pneumonia, inflammation, and sepsis, which are among the leading causes of morbidity and death in patients with For different disorders such as lung diseases [2,8], bronchopulmonary dysplasia [9], cardiovascular diseases [10], diabetes mellitus [11,12], and spinal cord injury [13], the safety profile and efficacy of MSCs are relatively well established. ...
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Background Due to their immunomodulatory properties, mesenchymal stem cells (MSCs) have been proposed to have therapeutic potential to improve clinical outcomes in COVID-19. However, the safety and efficacy profile of MSC infusion therapy in patients with non-severe COVID-19 infection has not been completely established; there is, in particular, a substantial void in the literature on dose-dependent studies of MSC infusion in patients with low clinical risk COVID-19 infection. Methods This phase 1 double-blind, placebo-controlled, randomized clinical trial examines the safety, feasibility, and tolerability of 2 doses (high and low) of DW-MSC in patients with low clinical risk COVID-19. A total of 9 patients were enrolled in this study and randomized into low-dose (TL), high-dose (TH), and placebo (C) groups. Subjects in the TL and TH groups received single intravenous infusions of 5.0 × 10 ⁷ cells and 1.0 × 10 ⁸ cells, respectively. The main outcome was the occurrence of treatment-emergent adverse events (TEAE) during the 28-day study period. Vital signs and various inflammatory markers were also monitored weekly during the observation period. Results There were no apparent differences in clinical characteristics between study groups (TL, TH, and C) at baseline. All patients did not show the progression of severity during the study period. During the course of the study, 6 episodes of TEAE were observed in 5 subjects; however, none of the TEAEs were severe. During the follow-up period, 8 subjects recovered and were discharged from the hospital without complications. A subject exhibited abnormal liver function biomarkers at the end of the study period. Changes in inflammatory markers throughout the clinical course were not vastly different across study groups. Conclusions Our clinical trial has provided reliable results regarding the safety of MSCs in low clinical risk COVID-19 subjects treated with MSCs. However, further confirmation of the therapeutic efficacy aspects of MSC will require large-scale randomized controlled trials in subjects with varying severity profiles for COVID-19. Trial registration ClinicalTrials.gov, NCT04535856. Registered 2 September 2020, https://clinicaltrials.gov/ct2/show/NCT04535856
... MSCs feature the pluripotent capacity of and their ability to differentiate to important lineages that can modulate on immunity, impair inflammatory reactions, and promote epithelial tissue repair (247); the clinical application of MSC therapy has been shown to be feasible and safe in humans with IPF (www.clinicaltrial.gov) and several data have been already published (248)(249)(250)(251)(252). A schematic representation of the application of MSCs in lung fibrosis is reported in Figure 3. ...
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Background and objective: Translational research is a source of continuous innovation in medicine, more particularly for clinical research on new treatment modalities in idiopathic pulmonary fibrosis (IPF) patients. However, the heterogeneity of the disease is well recognized, and different pathological and molecular settings have been identified. The molecular mechanisms by which IPF proceeds in time and space remains poorly understood. Although some IPF features are reminiscent of cancer, the dynamics of malignant divergent clonal selective pressure and heterogeneity clearly differ from those occurring in IPF. This is reflected in the absence of patient proper selection and stratification to biological agents (pirfenidone, nintedanib) which limit therapeutic efficacy. Consequently, increased costs are related to the clinical management of advanced IPF patients. Steady collaboration and fluid communication between pneumo-oncologists, radiologists and molecular biologists is a clear priority for the correct interpretation of tests and the definition of effective personalized strategies against this orphan disease. The present work aims at providing the most relevant hints shared by cancer and IPF. Methods: A systematic literature review was performed to identify all relevant data. The examined databases were Scopus, Web of Science, Cochrane, Google Scholar, and PubMed. The last search was run on January 5, 2022. We have primarily conducted separated research for lung cancer, IPF, genetics, epigenetics, surgery in IPF and cancer. Key content and findings: The data here presented mainly focus on gene mutations, epigenetics and novel therapeutic approaches. Moreover, epidemiology, prognostic variables and in new treatment strategies adopted in patients with IPF and lung cancer are discussed as well. Conclusions: Overall, the findings of this narrative review will be of help in defining the key molecular features that could applied in IPF setting with promising rationale to improve therapy and to better manage those cases carrying IPF and cancer concomitantly.
... These mechanisms include several biological pathways, including targeted transplantation into affected areas, differentiation of stem cells into lung epithelial cells, the ability of the immune system to modulate, secretion of antiinflammatory and anti-fibrotic factors, and the ability of the lung to repair endogenously [76]. Fibroblast activation processes through the epithelium and unfavorable response to anti-inflammatory medications are involved in developing idiopathic pulmonary fibrosis [77]. This process is associated with immune responses including the PGE2 pathway and epithelial mesenchymal transport (EMT) regulators of WISP-1 and BMP4, which are involved in the differentiation of fibroblasts and collagen [78][79][80]. ...
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Pulmonary fibrosis is a devastating disease that eventually leads to death and respiratory failure. Despite the wide range of drugs, including corticosteroids, endothelin antagonist, and pirfenidone, there is no effective treatment, and the only main goal of treatment is to alleviate the symptoms as much as possible to slow down the progression of the disease and improve the quality of life. Lung transplantation may be a treatment option for a few people if pulmonary fibrosis develops and there is no established treatment. Pulmonary fibrosis caused by the COVID19 virus is another problem that we face in most patients despite the efforts of the international medical communities. Therefore, achieving alternative treatment for patients is a great success. Today, basic research using stem cells on pulmonary fibrosis has published promising results. New stem cell-based therapies can be helpful in patients with pulmonary fibrosis. Wharton jelly-derived mesenchymal stem cells are easily isolated in large quantities and made available for clinical trials without causing ethical problems. These cells have higher flexibility and proliferation potential than other cells isolated from different sources and differentiated into various cells in laboratory environments. More clinical trials are needed to determine the safety and efficacy of these cells. This study will investigate the cellular and molecular mechanisms and possible effects of Wharton jelly-derived mesenchymal stem cells in pulmonary fibrosis.
... These beneficial outcomes were mediated by VEGF released from the transplanted MSCs. Moreover, Jung et al [63] reported that injecting MSCs in a LPSinduced ARDS mouse model resulted in the diminution of neutrophil infiltration, collagen deposition and lung fibrosis. MSCs have specific cytokines counteracting potentials to oppose the viral infection and reduce the spread of pulmonary fibrosis. ...
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Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or coronavirus disease 2019 (COVID-19) pandemic has exhausted the health systems in many countries with thousands cases diagnosed daily. The currently used treatment guideline is to manage the common symptoms like fever and cough, but doesn’t target the virus itself or halts serious complications arising from this viral infection. Currently, SARS-CoV-2 exhibits many genetic modulations which have been associated with the appearance of highly contagious strains. The number of critical cases of COVID-19 increases markedly, and many of the infected people die as a result of respiratory failure and multiple organ dysfunction. The regenerative potential of mesenchymal stem cells (MSCs) has been extensively studied and confirmed. The impressive immunomodulation and anti-inflammatory activity of MSCs have been recognized as a golden opportunity for the treatment of COVID-19 and its associated complications. Moreover, MSCs regenerative and repairing abilities have been corroborated by many studies with positive outcomes and high recovery rates. Based on that, MSCs infusion could be an effective mechanism in managing and stemming the serious complications and multiple organ failure associated with COVID-19. In the present review, we discuss the commonly reported complications of COVID-19 viral infection and the established and anticipated role of MSCs in managing these complications Abu-El-Rub E, Khasawneh RR, Almahasneh F, Altaany Z, Bataineh N, Zegallai H, Sekaran S. Mesenchymal stem cells and COVID-19: What they do and what they can do. World J Stem Cells 2021; 13(9): 1318-1337 [DOI: 10.4252/wjsc.v13.i9.1318]
... These beneficial outcomes were mediated by VEGF released from the transplanted MSCs. Moreover, Jung et al [63] reported that injecting MSCs in a LPSinduced ARDS mouse model resulted in the diminution of neutrophil infiltration, collagen deposition and lung fibrosis. MSCs have specific cytokines counteracting potentials to oppose the viral infection and reduce the spread of pulmonary fibrosis. ...
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Full-text available
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or coronavirus disease 2019 (COVID-19) pandemic has exhausted the health systems in many countries with thousands cases diagnosed daily. The currently used treatment guideline is to manage the common symptoms like fever and cough, but doesn’t target the virus itself or halts serious complications arising from this viral infection. Currently, SARS-CoV-2 exhibits many genetic modulations which have been associated with the appearance of highly contagious strains. The number of critical cases of COVID-19 increases markedly, and many of the infected people die as a result of respiratory failure and multiple organ dysfunction. The regenerative potential of mesenchymal stem cells (MSCs) has been extensively studied and confirmed. The impressive immunomodulation and anti-inflammatory activity of MSCs have been recognized as a golden opportunity for the treatment of COVID-19 and its associated complications. Moreover, MSCs regenerative and repairing abilities have been corroborated by many studies with positive outcomes and high recovery rates. Based on that, MSCs infusion could be an effective mechanism in managing and stemming the serious complications and multiple organ failure associated with COVID-19. In the present review, we discuss the commonly reported complications of COVID-19 viral infection and the established and anticipated role of MSCs in managing these complications Abu-El-Rub E, Khasawneh RR, Almahasneh F, Altaany Z, Bataineh N, Zegallai H, Sekaran S. Mesenchymal stem cells and COVID-19: What they do and what they can do. World J Stem Cells 2021; 13(9): 1318-1337 [DOI: 10.4252/wjsc.v13.i9.1318]
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Mesenchymal stromal cells (MSCs) have been proposed as a potential therapy to treat congenital and acquired lung diseases. Due to their tissue-regenerative, anti-fibrotic, and immunomodulatory properties, MSCs combined with other therapy or alone could be considered as a new approach for repair and regeneration of the lung during disease progression and/or after post- surgical injury. Children interstitial lung disease (chILD) represent highly heterogeneous rare respiratory diseases, with a wild range of age of onset and disease expression. The chILD is characterized by inflammatory and fibrotic changes of the pulmonary parenchyma, leading to gas exchange impairment and chronic respiratory failure associated with high morbidity and mortality. The therapeutic strategy is mainly based on the use of corticosteroids, hydroxychloroquine, azithromycin, and supportive care; however, the efficacy is variable, and their long-term use is associated with severe toxicity. The role of MSCs as treatment has been proposed in clinical and pre-clinical studies. In this narrative review, we report on the currently available on MSCs treatment as therapeutical strategy in chILD. The progress into the therapy of respiratory disease in children is mandatory to ameliorate the prognosis and to prevent the progression in adult age. Cell therapy may be a future therapy from both a pediatric and pediatric surgeon’s point of view.
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Renal interstitial fibrosis (RIF) is an incurable pathological lesion in chronic kidney diseases. Pericyte activation is the major pathological characteristic of RIF. Besides, fibroblast and macrophage activation are also involved in RIF. Studies have revealed that core fucosylation (CF), an important post-translational modification of proteins, plays a key role in pericyte activation and RIF by regulating multiple profibrotic signaling pathways as a “hub-like” target. Here, we reveal that mesenchymal stem cell (MSC)-derived exosomes reside specifically in the injured kidney and deliver microRNA (miR)-34c-5p to reduce cellular activation and RIF by inhibiting CF. Furthermore, we showed that the CD81–EGFR ligand–receptor complex aids the entry of exosomal miR-34c-5p into pericytes, fibroblasts, and macrophages. Altogether, our findings reveal a novel role of MSC-derived exosomes in inhibiting multicellular activation via CF and provide a potential intervention strategy for renal fibrosis.
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Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and no curative therapies. SCF-Skp2 E3 ligase is a target for cancer therapy, but there have been no reports about Skp2 as a target for IPF. Here we demonstrate that Skp2 is a promising therapeutic target for IPF. We examined whether disrupting Skp2 suppressed pulmonary fibrosis in a bleomycin (BLM)-induced mouse model and found that pulmonary fibrosis was significantly suppressed in Skp2-deficient mice compared with controls. The pulmonary accumulation of fibrotic markers such as collagen type 1 and fibronectin in BLM-infused mice was decreased in Skp2-deficient mice. Moreover, the number of bronchoalveolar lavage fluid cells accompanied with pulmonary fibrosis was significantly diminished. Levels of the Skp2 target p27 were significantly decreased by BLM-administration in wild-type mice, but recovered in Skp2−/− mice. In vimentin-positive mesenchymal fibroblasts, the decrease of p27-positive cells and increase of Ki67-positive cells by BLM-administration was suppressed by Skp2-deficency. As these results suggested that inhibiting Skp2 might be effective for BLM-induced pulmonary fibrosis, we next performed a treatment experiment using the Skp2 inhibitor SZL-P1-41. As expected, BLM-induced pulmonary fibrosis was significantly inhibited by SZL-P1-41. Moreover, p27 levels were increased by the SZL-P1-41 treatment, suggesting p27 may be an important Skp2 target for BLM-induced pulmonary fibrosis. Our study suggests that Skp2 is a potential molecular target for human pulmonary fibrosis including IPF.
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Results obtained from completed and on-going clinical studies indicate huge therapeutic potential of stem cell-based therapy in the treatment of degenerative, autoimmune and genetic disorders. However, clinical application of stem cells raises numerous ethical and safety concerns. In this review, we provide an overview of the most important ethical issues in stem cell therapy, as a contribution to the controversial debate about their clinical usage in regenerative and transplantation medicine. We describe ethical challenges regarding human embryonic stem cell (hESC) research, emphasizing that ethical dilemma involving the destruction of a human embryo is a major factor that may have limited the development of hESC-based clinical therapies. With previous derivation of induced pluripotent stem cells (iPSCs) this problem has been overcome, however current perspectives regarding clinical translation of iPSCs still remain. Unlimited differentiation potential of iPSCs which can be used in human reproductive cloning, as a risk for generation of genetically engineered human embryos and human-animal chimeras, is major ethical issue, while undesired differentiation and malignant transformation are major safety issues. Although clinical application of mesenchymal stem cells (MSCs) has shown beneficial effects in the therapy of autoimmune and chronic inflammatory diseases, the ability to promote tumor growth and metastasis and overestimated therapeutic potential of MSCs still provide concerns for the field of regenerative medicine. This review offers stem cell scientists, clinicians and patient's useful information and could be used as a starting point for more in-depth analysis of ethical and safety issues related to clinical application of stem cells.
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