Hindawi

Stem Cells International

Volume 2019, Article ID 4236973, 14 pages
https://doi.org/10.1155/2019/4236973

Review Article
Mesenchymal Stem Cell-Based Therapy of Inflammatory Lung
Diseases: Current Understanding and Future Perspectives

C. Randall Harrell,1 Ruxana Sadikot,2,3 Jose Pascual,4 Crissy Fellabaum,1

Marina Gazdic Jankovic,5 Nemanja Jovicic ,6 Valentin Djonov,7 Nebojsa Arsenijevic,6
and Vladislav Volarevic 6
1
Regenerative Processing Plant, LLC, 34176 UD Highway 19 N Palm Harbor, Palm Harbor, Florida, USA
2
Emory University School of Medicine, 648 Pierce Dr NE, Atlanta, GA, USA
3
Atlanta VA Medical Center, 1670 Clairmont Rd, Decatur, Atlanta, GA, USA
4
Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Serbia
5
Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar
Markovic Street, Kragujevac, Serbia
6
Institute of Anatomy, University of Bern, 2 Baltzerstrasse, Switzerland
7
West Pasco Pulmonary Associates, 7545 Medical Dr, Hudson, Florida, USA

Correspondence should be addressed to Vladislav Volarevic; [email protected]

Received 30 September 2018; Revised 6 February 2019; Accepted 14 February 2019; Published 2 May 2019

Academic Editor: Stan Gronthos

Copyright © 2019 C. Randall Harrell et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.

During acute or chronic lung injury, inappropriate immune response and/or aberrant repair process causes irreversible damage in
lung tissue and most usually results in the development of fibrosis followed by decline in lung function. Inhaled corticosteroids and
other anti-inflammatory drugs are very effective in patients with inflammatory lung disorders, but their long-term use is associated
with severe side effects. Accordingly, new therapeutic agents that will attenuate ongoing inflammation and, at the same time,
promote regeneration of injured alveolar epithelial cells are urgently needed. Mesenchymal stem cells (MSCs) are able to
modulate proliferation, activation, and effector function of all immune cells that play an important role in the pathogenesis of
acute and chronic inflammatory lung diseases. In addition to the suppression of lung-infiltrated immune cells, MSCs have
potential to differentiate into alveolar epithelial cells in vitro and, accordingly, represent new players in cell-based therapy of
inflammatory lung disorders. In this review article, we described molecular mechanisms involved in MSC-based therapy of
acute and chronic pulmonary diseases and emphasized current knowledge and future perspectives related to the therapeutic
application of MSCs in patients suffering from acute respiratory distress syndrome, pneumonia, asthma, chronic obstructive
pulmonary diseases, and idiopathic pulmonary fibrosis.

1. Introduction against invading microbes [1]. Accordingly, in the lungs,

inflammation is the result of the infection, trauma, and
The respiratory system is continuously exposed to various hypersensitivity caused by pathogens, airborne irritants, haz-
irritants such as inhaled toxins, carbon granules, pathogens, ardous pollutants, toxins, and allergens. Pathogen-associated
and their products. Pulmonary homeostasis is maintained molecular patterns (PAMPs) expressed on the lung infil-
by interaction between alveolar epithelial cells and lung- trated microbes, as well as damage-associated molecular pat-
resident immune cells that continually monitor the pulmo- terns (DAMPs) and alarmins, released from the injured lung
nary microenvironment, induce tolerance to innocuous parenchymal cells, activate residential macrophages which
inhaled particles, or provide efficient immune reactions produce a large amount of inflammatory chemokines and
2 Stem Cells International

cytokines, attract circulating immune cells in the lungs, and ini- role in the pathogenesis of inflammatory lung diseases,
tiate inflammation. Clinically, acute lung injury and inflamma- including professional antigen-presenting cells (dendritic
tion is seen in pneumonia and acute respiratory distress cells (DCs), macrophages, and B lymphocytes), neutrophils,
syndrome (ARDS), whereas chronic inflammation is repre- and effector and regulatory T cells. MSCs alter immune
sented by asthma and chronic obstructive pulmonary diseases response through juxtacrine or paracrine mechanisms [7].
(COPD) [2]. The repair of the airway epithelium after acute MSCs lack the surface expression of costimulatory molecules
or chronic injury is modulated by matrix metalloproteinases and are able to render Th1, Th2, and Th17 cells anergic.
(MMPs), cytokines, and growth factors produced by epithelial Additionally, interaction of the inhibitory molecule pro-
cells, lung-resident immune cells, fibroblasts, and chondrocytes grammed death 1 (PD-1) with its ligands PD-L1 and PD-
[1]. Inappropriate immune responses and/or aberrant repair L2 was responsible for MSC-mediated inhibition of T cell
process causes irreversible damage in lung tissue and most usu- proliferation [5]. Precisely, upregulation of the cyclin-
ally results in the development of fibrosis followed by decline in dependent kinase inhibitor p27kip1 and inhibition of
lung function [3]. Inhaled corticosteroids are very effective in cyclin-D2 were observed in T cells after a cross-talk with
patients with inflammatory lung disorders, but their long- MSCs. In this way, transplanted MSCs significantly reduce
term use is associated with an increased risk of pneumonia, oral the total number of effector T cells in the injured lungs and
candidiasis, osteoporosis, skin bruising, and tuberculosis [4]. attenuate Th1-, Th2-, or Th17-driven inflammation [5].
Accordingly, new therapeutic agents that will attenuate ongoing In addition to juxtacrine mechanisms, MSCs may sup-
inflammation and prevent accumulation of fibrous connective press ongoing T cell-dependent inflammation through the
tissue on one side and, at the same time, promote regeneration secretion of soluble, immunosuppressive factors (prostaglan-
of injured alveolar epithelial cells are urgently needed. din E2 (PGE2), transforming growth factor beta (TGF-β),
Due to their capacity to suppress detrimental immune indoleamine 2,3-dioxygenase (IDO), and nitric oxide (NO))
response and ability to differentiate into type II alveolar epithe- [8]. Through the production of PGE2, MSCs attenuate the
lial (ATII) cells in vitro, mesenchymal stem cells (MSCs) repre- expression of the interleukin- (IL-) 2 receptor and, accord-
sent new players in cell-based therapy of acute and chronic ingly, inhibit clonal expansion of activated T cells. TGF-β is
inflammatory lung disorders [5, 6]. Since these adult multipo- also a potent inhibitor of the IL-2 signaling pathway and is
tent stem cells can be readily isolated from numerous tissues involved in MSC-mediated G1 cell cycle arrest of activated
(bone marrow (BM), adipose tissue (AT), amniotic fluid (AF), T cells. In a similar manner, MSC-derived NO inhibits phos-
placenta (PL), umbilical cord (UC), peripheral blood, lungs, phorylation of signal transducer and activator of transcrip-
and deciduous teeth) and expanded with high efficiency, tion- (STAT-) 5 in T cells, leading to cell cycle arrest while
MSC-based therapy of lung diseases has rapidly progressed over MSC-derived IDO promotes the degradation of tryptophan
the past decade [5]. Accordingly, in this review article we sum- into kynurenine which suppresses proliferation or induce
marized findings obtained in preclinical and clinical studies that apoptosis of activated T cells [8].
demonstrated beneficent effects of MSCs in the treatment of In addition to the direct suppression of effector T cells,
lung diseases. An extensive literature review was carried out in MSCs are able to suppress the generation of Th1, Th2, and
July 2018 across several databases (MEDLINE, EMBASE, Goo- Th17 cells by modulating the antigen-presenting function
gle Scholar, and ClinicalTrials.gov), from 1990 to present. Key- of DCs in a PGE2-, IL-10-, and IL-6-dependent manner
words used in the selection were “mesenchymal stem cells,” [5]. After an interaction with MSCs, DCs became immature,
“inflammatory lung disease,” “ARDS,” “lung injury,” “COPD,” with a reduced capacity for antigen presentation, due to the
“asthma,” and “idiopathic pulmonary fibrosis (IPF).” Eligible reduced expression of the major histocompatibility complex
studies had to delineate molecular and cellular mechanisms (MHC) and costimulatory molecules. Additionally, MSCs
involved in the MSC-based therapy of acute and chronic can induce tolerogenic phenotype in DCs and may promote
inflammatory lung diseases, and their findings were analyzed polarization of inflammatory M1 macrophages towards
in this review. immunosuppressive M2 macrophages. In this way, MSCs
reduce the production of inflammatory cytokines (tumor
2. Main Text necrosis factor alpha (TNF-α), IL-1β, and IL-12) in DCs
and macrophages and promote the production of anti-
MSCs are self-renewable, multipotent cells capable of suppress- inflammatory IL-10 and TGF-β resulting in enhanced tissue
ing immune response and differentiating into ATII cells in vitro repair and regeneration [5, 9–13]. In an IL-10- and TGF-β-
[5, 6]. Accordingly, MSC-mediated suppression of inflamma- dependent manner, tolerogenic DCs and M2 macrophages
tion and, at the same time, MSC-dependent lung repair and induce enhanced production of immunosuppressive human
regeneration were responsible for their therapeutic effects in leucocyte antigen- (HLA-) G5 in MSCs and promote their
the treatment of ARDS, pneumonia, asthma, COPD, and IPF. capacity to stimulate generation and expansion of T regula-
tory cells (Tregs) [14], contributing to the creation of the
3. Molecular Mechanisms Responsible for MSC- anti-inflammatory microenvironment in the injured lungs.
Based Beneficial Effects in the Therapy of In addition to their interaction with lung-infiltrated
Lung Diseases immune cells, MSCs have potential to differentiate into
ATII-like cells in vitro. Ma and coworkers provided the first
MSCs are able to modulate proliferation, activation, and evidence that BM-derived MSCs (BM-MSCs) can be success-
effector function of all immune cells that play an important fully differentiated into ATII cells in vitro after coculturing
Stem Cells International 3

with MRC-5 cells (derived from normal fetal lung mesenchy- 4. MSC-Mediated Attenuation of ARDS
mal tissue) in a modified small airway growth medium and Pneumonia
(SAGM) that contained bovine serum albumin (BSA,
0.5 mg/ml), insulin (5 mg/ml), transferrin (10 mg/ml), bovine ARDS is a severe clinical syndrome triggered by the disrup-
pituitary extract (30 mg/ml), adrenaline (epinephrine, tion of the alveolar-epithelial barrier, accompanied with
0.5 mg/ml), fibroblast growth factor (FGF)10 (1ong/ml), cor- interstitial edema and infiltration of inflammatory cells
tisol (0.5 mg/ml), human EGF (epidermal growth factor, that resulted in progressive acute respiratory failure [21–
0.5 ng/ml), and antibiotics (gentamicin sulfate, 0.05 mg/ml; 24]. This “exudative phase” is followed by a fibrotic phase
amphotericin-B, 0.05 mg/ml) [15]. ATII-like cells became characterized by proliferation of type II pneumocytes, fibro-
dominant in culture two to three weeks after interaction of blasts, myofibroblasts, and matrix deposition [25]. Although
BM-MSCs with MRC-5, and at the same time point, surfac- numerous pharmacologic agents, including inhaled synthetic
tant protein (SP) C, a specific functional marker of human surfactants, ketoconazole, simvastatin, and ibuprofen, have
ATII cells, was detected in differentiated cells [15]. In a sim- been tested in the therapy of ARDS, none of them managed
ilar manner as BM-MSCs, AF-derived MSCs (AF-MSCs) and to significantly reduce a notably high mortality rate of ARDS
decidua-derived MSCs (D-MSCs) can be differentiated into which remains at 34-44 percent [26].
ATII cells in vitro [16, 17]. Li and coworkers demonstrated Several, recently conducted, preclinical studies demon-
that, with the use of the appropriate induction medium, strated that MSCs and their secretomes could be considered
including KnockOut™ serum replacement (KOSR), activin as new and effective therapeutic agents for the treatment of
A, and small airway basal medium, AF-MSCs differentiate ARDS (Figure 1). ARDS often develops as a complication
into SPC-expressing ATII-like cells in vitro [16]. Similar of severe sepsis, particularly after infection with Gram-
findings were reported by Cerrada and colleagues who dem- negative bacteria [27]. MSC treatment prevented the devel-
onstrated that D-MSCs cultured in the small airway epithelial opment of ARDS in an animal model of sepsis induced by
cell growth medium successfully generated functional ATII- Escherichia coli-derived lipopolysaccharide (LPS) [28, 29].
like cells which were able to exocytose lipid-rich assemblies Systemic application of MSCs in a mouse model of LPS–
with high surface-active capabilities [17]. induced ARDS significantly ameliorated alveolar injury and
Activation of canonical as well as noncanonical Wnt path- inflammation [30]. MSCs, in a paracrine, IL-10-dependent
ways is crucially important for differentiation of MSCs into manner, attenuated the influx of neutrophils in the lungs
ATII-like cells [18, 19]. Liu and associates used a modified and decreased the production of inflammatory TNF-α in
coculture system with murine lung epithelial-12 (MLE-12) cells lung-infiltrated immune cells [30, 31]. Additionally, through
and SAGM to demonstrate that Wnt3a-induced activation of the production of the keratinocyte growth factor (KGF), vas-
the canonical Wnt/β-catenin pathway resulted in differentia- cular endothelial growth factor (VEGF), and hepatocyte
tion of murine MSCs in functional ATII-like cells which growth factor (HGF), MSCs promoted the regeneration of
expressed specific markers: SPC, SPB, and SPD [18]. Members ATII cells, prevented the apoptosis of endothelial cells, and
of the same research group documented that Wnt5a-induced contributed to the enhanced repair of the alveolar-epithelial
activation of noncanonical Wnt/c-Jun N-terminal kinase barrier in the ARDS-injured lungs [32–34]. A diminished
(JNK) or Wnt/protein kinase C (PKC) pathways could also inflammatory injury in MSC-treated animals correlated with
result in the successful differentiation of MSCs into ATII-like reduced edema, improved oxygenation, and prolonged sur-
cells in vitro [19]. Furthermore, addition of dickkopf Wnt sig- vival [28, 29]. Additionally, MSCs protect from sepsis-
naling pathway inhibitor 1 (Dkk1) as well as JNK or PKC associated ARDS by increasing the capacity of macrophages
inhibitors to the SAGM suppressed the activation of canonical to produce anti-inflammatory IL-10 in a PGE2-dependent
and noncanonical Wnt pathways and completely abrogated the manner [35].
capacity of MSCs to generate ATII-like cells [18, 19]. In line In addition to their regenerative and immunosuppressive
with these results are findings reported by Shi and coworkers effects responsible for the attenuation of ARDS, MSCs are
who demonstrated that Wnt/β-catenin signaling may be an also able to promote resolution of ongoing inflammation by
essential mechanism underlying the regulation of epithelial dif- producing proresolving mediator lipoxin A4 (LXA4) which
ferentiation of lung residential MSCs [20]. Nevertheless, it has reduces pulmonary edema and promotes survival of mice
to be highlighted that differentiation of MSCs in ATII-like cells suffering from LPS-induced ARDS [36].
was mainly documented in vitro, while MSC-dependent bene- Several immunomodulatory factors, released during
ficial effects in attenuation of inflammatory lung diseases were ARDS, may reduce differentiation of MSCs into ATII-like
mainly based on the paracrine effects of transplanted MSCs. cells and consequently attenuate therapeutic potential of
Accordingly, future experimental studies must provide stron- MSCs in the treatment of ARDS. Overexpressed microRNA-
ger evidence about the capacity of MSCs to differentiate into 615-3p or microRNA-155-5p inhibits differentiation of
ATII-like cells in vivo. MSCs into ATII cells leading to the progression of ARDS
Having in mind that MSCs have the capacity to generate [37, 38]. Pathological changes in the microenvironment of
ATII cells and that injury of ATII cells and alveolar-epithelial ARDS-injured lungs, in turn, negatively affect the capacity
barrier represents the main pathological characteristic of MSCs to proliferate and differentiate into ATII cells [39].
observed in patients suffering from ARDS, several experi- In this way, a negative loop is created that attenuates thera-
mental studies investigated the therapeutic potential of MSCs peutic potential of MSCs and contributes to the further pro-
in the treatment of ARDS. gression of acute lung injury.
4 Stem Cells International

Figure 1: Molecular mechanisms responsible for MSC-based attenuation of ARDS. Intravenously injected MSCs engrafted in the ARDS-
injured lungs and, in a paracrine manner (through the production of KGF, VEGF, HGF), promoted proliferation of epithelial cells,
induced protection of vascular permeability, and prevented apoptosis of endothelial cells. Additionally, MSC-based therapy reduced the
presence of neutrophils in bronchoalveolar lavage fluid (BLF) and in a PGE2-dependent manner suppressed the production of
inflammatory cytokines (TNF-α and IL-6) and stimulated the secretion of immunosuppressive IL-10 in alveolar macrophages.

The therapeutic potential of MSCs in the treatment of (TLR-) dependent activation of the nuclear factor kappa B
ARDS has been evaluated in several, already completed, (NF-κB) pathway in alveolar macrophages leading to the
clinical trials [40, 41]. Wilson and coworkers demonstrated enhanced secretion of CXCL8 and CXCL11. An increased
that single intravenous infusion of allogeneic BM-MSCs concentration of these inflammatory chemokines in inflamed
(1, 5, or 10 million cells/kg of body weight (bw)) was well lungs attract interferon gamma- (IFN-γ-) producing neutro-
tolerated in nine patients with moderate to severe ARDS phils and CD4+Th1 cells which, in turn, enhance the secre-
(NCT01775774). Side events, clinical instability, or dose- tion of inflammatory cytokines and proteolytic enzymes in
limiting toxicity was not observed in any of the nine patients alveolar macrophages, creating a “positive inflammatory
that received allogeneic BM-MSCs [40]. Results obtained in loop” in the injured lungs [43]. Alveolar macrophages play
this study were used as an optimistic starting point for a a crucially important role in the bacterial clearance and
larger randomized, multicenter, phase 2 clinical trial that attenuation of bacterial pneumonia, the most common infec-
was conducted from 2014 to 2018 in the United States tious cause of death worldwide [44]. It was recently revealed
(NCT02097641). The trial enrolled 60 adult ARDS patients that MSCs produce microvesicles which may promote
who intravenously received either a single dose of allogeneic phagocytic activity of alveolar macrophages resulting in the
BM-MSCs (10 million cells/kg bw) or placebo (Plasma-Lyte alleviation of bacterial pneumonia induced by Gram-
A). Although this trial has been completed in February negative Escherichia coli [45]. Additionally, MSCs produce
2018, the obtained results are not published yet. antibacterial proteins and are able to directly suppress bacte-
In another clinical study, Zheng and colleagues reported rial growth in the inflamed lungs [46]. Intratracheal adminis-
that intravenous administration of allogeneic MSCs is a safe tration of MSCs significantly attenuated lung injury and
but not efficient therapeutic approach in the treatment of inflammation and improved the survival of experimental
ARDS patients (NCT01902082). Twelve adult patients with animals with bacterial pneumonia by promoting bacterial
ARDS safely received one intravenous dose of allogeneic clearance in a lipocalin-2-dependent manner [46]. LPS-
AT-MSCs (1 million cells/kg bw), but AT-MSC-based ther- induced activation of TLR-4 in MSCs enhances secretion of
apy did not significantly attenuate serum levels of inflamma- lipocalin-2 that binds bacterial ferric siderophores, reduces
tory cytokines (IL-6 and IL-8) and did not manage to the uptake of iron, and suppresses bacterial growth [47]. In
improve lung function in ARDS patients [41]. line with these findings are results recently reported by Gupta
ARDS and pneumonia are interrelated in critically ill and coworkers who found that mutation of TLR-4 in MSCs
patients. Pneumonia is considered as the main cause of significantly impaired their therapeutic efficacy in an experi-
ARDS while ARDS is usually complicated by nosocomial mental model of bacterial pneumonia [48]. Accordingly,
pneumonia [42]. Heat shock proteins or other DAMPs, intratracheal administration of TLR-4-primed MSCs should
released from injured lung parenchymal cells, as well as be explored in future experimental studies as a potentially
PAMPs of inhaled pathogens, induce Toll-like receptor- new cell-based therapeutic approach for the elimination of
Stem Cells International 5

antibiotic resistant Gram-negative bacterial strains in the that MSC-derived exosomes alleviated airway inflamma-
inflamed lungs. tion and asthma, enhanced proliferation and immunosup-
pressive properties of Tregs, and enhanced production of
5. MSC-Based Therapy of Asthma anti-inflammatory cytokines (IL-10 and TGF-β) in periph-
eral blood mononuclear cells obtained from asthmatic
Epidemiological data show that bronchial asthma affects patients [59].
approximately 300 million people worldwide [49]. In sus- In an allergic, Th2-dominant microenvironment, IL-4
ceptible individuals, chronic airway inflammation causes and/or IL-13 activate the STAT6 pathway in the transplanted
recurrent episodes of airflow obstruction and bronchial MSCs resulting in an increase in the production of TGF-β,
hyperresponsiveness, which may lead to permanent struc- which, together with Tregs (expanded by the MSCs-derived
tural changes. Thus, understanding the pathophysiology heme oxygenase-1), suppress ongoing Th2 cell-driven
of this chronic inflammatory lung disease is essential to inflammation in the lungs [56, 60]. Intravenously injected
determining the potential applications of MSCs as an anti- MSCs reduced eosinophil infiltration and mucus production
asthmatic therapy. in the lungs and downregulated the levels of Th2 cytokines
Patients suffering from atopic asthma have a genetic pre- (IL-4, IL-5, and IL-13) in bronchial lavage and serum levels
disposition for the development of an antigen-specific, of IgG1 and immunoglobulin (Ig)E [56] (Figure 2).
immunoglobulin (Ig) E-mediated response to common aero- Zeng and colleagues demonstrated that beneficial effects
allergens (pollen, house dust mite, and fungal spores) which of MSCs in a murine model of bronchial asthma were a con-
is mediated by innate (DCs, mast cells, basophils, and eosin- sequence of MSC-mediated suppression of lung myeloid DCs
ophils) and adaptive immunity cells (CD4+Th2 cells and B [61]. DCs obtained from MSC-treated asthmatic mice were
lymphocytes) [50]. Lung DCs capture aeroallergens, bring immature with attenuated capacity for antigen presentation
them to regional lymph nodes, present them to allergen- and activation of naïve T cells. Additionally, DCs from mice
specific naive CD4+T cells, and induce generation of IL-4-, that received MSCs were not able to optimally migrate to the
IL-5-, and IL-13-producing effector Th2 cells [51]. CD4 regional lymph nodes and were not able to produce an
+Th2 cells in a IL-4-dependent manner induce generation appropriate amount of chemokine ligand (CCL) 17 and
and secretion of allergen-specific IgE in plasma cells which CCL22 that are crucially involved in migration of effector
binds to its high-affinity receptor (FcεRI), expressed on baso- Th2 cell in the inflamed lungs. Consequently, reduced num-
phils and mast cells [52]. Re-exposure to the allergen causes ber of IL-4-, IL-5-, and IL-13-producing Th2 cells, accompa-
crosslinking of FcεRI resulting in the massive release of hista- nied with downregulated serum levels of IgE, lower number
mine, prostaglandins, and leukotrienes from activated mast of lung-infiltrated eosinophils, and reduced production of
cells and basophils, which induce contraction of airway mucus were observed in MSC-treated asthmatic mice. These
smooth muscle cells and airflow obstruction. Additionally, MSC-mediated effects resulted in significant attenuation of
activated mast cells and basophils release inflammatory cyto- pulmonary inflammation, reduction of bronchial hyperre-
kines (TNF-α, IL-1β, IL-4, and IL-6) and chemokines sponsiveness, and notably improved lung function of MSC-
enabling massive accumulation of circulating eosinophils, treated asthmatic mice [61].
neutrophils, and CD4+Th2 cells in the inflamed lungs [53]. Braza and coworkers described an additional mechanism
CD4+Th2 cells in an IL-5-dependent manner promote acti- involved in MSC-mediated attenuation of bronchial asthma
vation of eosinophils while in an IL-13-dependent manner that was relied on the interaction between MSCs and alveolar
induce goblet cell metaplasia and airway hyperresponsive- macrophages in the injured lungs [62]. In particular, they
ness [54]. Cytokines and matrix-degrading enzymes released suggested that alveolar macrophages become alternatively
from activated eosinophils and neutrophils lay the founda- activated and developed an anti-inflammatory and immuno-
tion for airway hyperresponsiveness and airway remodeling suppressive M2 phenotype after phagocytosis of transplanted
by causing damage to epithelial layers, promoting broncho- MSCs [62]. Consequently, M2 macrophage produces immu-
constriction and deposition of extracellular matrices [50]. nosuppressive factors that suppress ongoing inflammation
MSCs are able to suppress proliferation and effector func- and promote repair and regeneration in the asthmatic lungs.
tion of CD4+Th2 cells, IgE production in plasma cells, and In line with these findings, it was recently highlighted by
IgE-dependent activation of mast cells in vitro [5]. In line Kitoko and colleagues that a cross-talk between murine
with these findings, several research groups demonstrated BM-MSCs or AT-MSCs with alveolar macrophages is cru-
that MSCs managed to attenuate airway inflammation and cially important for reduced lung inflammation, airway
remodeling and improve lung function of asthmatic animals hyporesponsiveness, and mucus hyposecretion in MSC-
[55–58]. Anti-inflammatory effects elicited by MSCs were treated asthmatic mice and that BM-MSC or AT-MSC-
mostly mediated by MSC-derived soluble factors. Cruz and mediated expansion of Tregs is not an obligatory effect of
coworkers suggested that MSCs altered the phenotype of transplanted MSCs in asthmatic animals [63]. Kitoko and
antigen-specific CD4 T cells in a model of airway allergic coworkers also concluded that pretreatment of asthmatic
inflammation via MSC-derived exosomes: nanosized extra- mice with murine BM-MSCs or AT-MSCs can increase the
cellular vesicles that deliver proteins, lipids, DNA fragments, presence of Tregs in the lungs, while BM-MSCs and AT-
and microRNA to the target cells—immune cells, endothelial MSCs were not able to induce the expansion of Tregs when
cells, pericytes, and other tissue-resident cells [55]. Similar lymphocytes were already allergenically primed indicating
conclusions were made by Du and colleagues who confirmed that the MSC : Treg interaction was not crucially involved
6 Stem Cells International

Asthma
IL-4
IL-5
IL-13
M

EVs
SC
s

T cells

Eosinophil
infiltration
Mucus
MSC
Eosinophil production

IgG1 Collagen deposition

Lungs IgE Resistive pressure
Viscoelastic pressure
Bronchoconstriction index

M1 M
휑

MSC Phagocytosis M2 M
휑

Figure 2: Therapeutic effects of intravenously injected MSCs in an animal model of asthma. Reduced deposition of collagen and lower
bronchoconstrictive index accompanied with reduced resistive and viscoelastic pressures were noticed in MSC-treated asthmatic animals.
Transplanted MSCs altered the phenotype of antigen-specific CD4 T cells in asthmatic animals via MSC-derived extracellular vesicles
(EVs). Additionally, MSCs reduced eosinophil infiltration and mucus production in the lungs and downregulated levels of Th2 cytokines
(IL-4, IL-5, and IL-13) in bronchial lavage, as well as serum levels of IgG1 and IgE. Alveolar macrophages become alternatively activated
and developed an anti-inflammatory and immunosuppressive M2 phenotype after phagocytosis of transplanted MSCs.

in therapeutic effects of MSCs in asthma [63]. On the con- airway remodeling in asthmatic rats [67]. Reduced Notch-1,
trary, Li and associates noticed that human PL-derived MSCs Notch-2, and jagged-1 and increased Notch-3, Notch-4,
(PL-MSCs) improved airway hyperresponsiveness and and delta-like ligand (delta)-4 expression were observed in
inflammation in asthmatic rats primarily by increasing the lungs of asthmatic rats that received human PL-MSCs [68].
total number of IL-10-producing Tregs in the lungs which Alterations in the expression of the Notch signaling pathway
was followed by a reduced presence of lung infiltrated Th17 were accompanied by polarization of immune response
cells, macrophages, neutrophils, and eosinophils [64]. These, towards Th1 immunity as manifested by increased serum
on first sight, opposite findings regarding the importance of levels of IFN-γ and decreased serum levels of IL-4 and IgE.
the MSC : Treg interplay in MSC-dependent attenuation of Furthermore, decreased goblet cell hyperplasia and mucus
asthma could be explained by the fact that MSCs from differ- production were noticed in lung tissues of PL-MSC-treated
ent sources have differential effects on immune cells [65] and asthmatic rats, indicating that MSCs suppressed asthma
that murine and human MSCs use different molecular mech- symptoms by modulating Notch signaling [68].
anisms for generation and expansion of Tregs [5]. Currently, two ongoing clinical studies are planning to
In addition to anti-inflammatory effects, MSC treatment test the safety and efficacy of MSC-based therapy for the
prevents airway remodeling in asthmatic animals [57, 58]. treatment of asthmatic patients. A phase 1 investigation will
Significantly reduced deposition of collagen in lung paren- be performed at the University of Miami Miller School of
chyma and decreased resistive and viscoelastic pressure, Medicine with the aim of testing the safety of allogeneic
accompanied with a downregulated bronchoconstriction BM-MSCs in the therapy of mild asthma. BM-MSCs will be
index, were noticed in MSC-treated asthmatic mice com- delivered via peripheral intravenous infusion to 6 asthmatic
pared to asthmatic animals that did not receive MSCs [57, patients who will be randomized in two experimental groups
58]. Additionally, MSCs managed to reduce generation of and will receive either 20 million or 100 million of BM-
reactive oxygen and nitrogen species responsible for oxida- MSCs. Pulmonary function tests, lung volumes, and dyspnea
tive stress in asthma. Transplantation of human BM-MSCs questionnaires will be assessed every 4 weeks while unwanted
had a beneficial effect on oxidative stress, reduced the levels side effects will be monitored continuously until study com-
of nitrotyrosine and maintained the oxidative balance in pletion (NCT03137199).
asthmatic lungs of experimental animals [66]. Having in mind that MSC-based beneficial effects in
Phosphoinositide 3-kinase (PI3K) and Notch signaling asthma are mainly a consequence of MSC-derived factors,
were proposed as the main molecular targets of MSCs in researchers from the Punta Pacifica Hospital of Panama City
asthmatic lungs [67, 68]. Transplantation of MSCs affected decided to elucidate safety and efficacy of allogeneic UC-
PI3K signaling by preventing the expression of Akt phos- MSC-derived trophic factors (MTF) in adult asthmatic
phorylation resulting in suppressed lung inflammation and patients. Although the study is still recruiting patients, it is
Stem Cells International 7

planned that each of the 20 patients will intranasally receive suppressed cyclooxygenase-2 (COX2) expression and PGE2
MTF once per week for a period of 4 weeks. Side effects as production in alveolar macrophages [75]. MSC-mediated
well as alterations of lung function will be monitored during downregulation of the COX2/PGE2 pathway in inflamma-
the one-month follow-up (NCT02192736). tory M1 macrophages occurs via the p38 mitogen-activated
protein kinases (MAPKs) and extracellular signal-regulated
6. Usage of MSCs in Cell-Based kinase (ERK) and resulted in macrophage polarization
Therapy of COPD toward an anti-inflammatory M2 phenotype [75, 82].
Accordingly, a lower expression of M1 macrophage-derived
COPD is characterized by persistent respiratory symptoms inflammatory mediators (TNF-α, IL-1β, IL-6, and monocyte
and airflow limitation consequent to destruction of terminal chemoattractant protein 1 (MCP-1)) and a higher expression
bronchioles (obstructive bronchiolitis) and lung parenchyma of M2 macrophage-derived anti-inflammatory IL-10 and
(emphysema), usually caused by significant exposure to nox- TGF-β cytokines were observed in COPD animals that
ious particles or gases [69]. The main risk factors for the received MSCs [72, 75, 82]. Furthermore, transplantation of
development of this serious public health issue are cigarette MSCs significantly improved lung architecture of COPD ani-
smoking, airway hyperresponsiveness, a family history of mals by decreasing the production of macrophage-derived
asthma, and respiratory infections in childhood [70]. An MMP-2, MMP-9, and MMP-12 that mediated the degrada-
altered function of lung-infiltrated immune cells, oxidative tion of elastin connective fibers in lung parenchyma and
stress, and imbalance in activity of proteases and their inhib- caused tissue remodeling [79].
itors are responsible for the development of main pathologi- The beneficial effect of MSCs in COPD has been also
cal changes observed in COPD patients: progressive and attributed to the inhibition of alveolar cell apoptosis. An inhi-
persistent airflow limitation associated with an enhanced bition of ATII cell apoptosis in MSC-treated COPD mice was
chronic inflammatory response in the airways and the lungs a consequence of a significantly reduced expression of proa-
[71]. Due to their capacity to suppress detrimental immune poptotic Bax and enhanced expression of the antiapoptotic
response, maintain oxidative balance, and regulate activity Bcl-2 gene [83]. A decrease in the number of apoptotic cells
of matrix-degrading enzymes, MSCs are considered as prom- was also associated with MSC-induced suppression of cas-
ising tools for cell-based therapy of COPD. Several experi- pase 3, a crucial mediator of programmed cell death in ATII
mental and clinical studies demonstrated beneficial effects cells [84].
of MSCs in the treatment of COPD [72, 73]. Beneficial effects of MSCs in COPD are mainly due to
Intravenous, intratracheal, and intrabronchial adminis- paracrine effects involved in the suppression of inflammation
tration of BM-MSCs and AT-MSCs (in a minimum number and apoptosis in the lung tissue but also may be a conse-
of 5 × 104 cells/animal) was a safe therapeutic approach that quence of their differentiation into the structural cells of the
showed beneficial effects in both structural and functional alveolar unit (Figure 3) [83, 85, 86]. Liu and colleagues dem-
outcomes in the COPD animal models, which were prepared onstrated that transplanted MSCs successfully engrafted into
either by elastase instillation or by cigarette smoke exposure emphysematous lung tissue and were able to differentiate
[72]. The best effects were noticed after intratracheal injec- in vitro into functional, SPC-expressing ATII-like cells
tion of BM-MSCs which were even superior than lung through the activation of the canonical Wnt/β-catenin path-
tissue-derived MSCs (LT-MSCs). Interestingly, intravenous way [85]. In line with these results, Zheng and coworkers
injection of LT-MSCs resulted in immediate death of the demonstrated that transplanted MSCs successfully engrafted
recipient mice, a phenomenon that was not observed after in the lungs, differentiate in ATII-like cells, and protected
intravenous administration of BM-MSC or AT-MSCs [73]. against pulmonary emphysema [83]. Additionally, MSC-
Intravenous and intratracheal injected MSCs migrated based therapy of COPD mice resulted in proliferation of lung
and successfully engrafted into the COPD-injured lungs of resident stem cells that represent a valuable cellular source
experimental animals within 24 hours after administra- for the replacement of injured ATII cells. The total number
tion [74–77]. MSC transplantation significantly attenuated of endogenous stem cells (CD45-/CD31-/Sca-1+ cells) and
emphysematous changes in experimental animals as demon- significantly improved lung function were noticed in MSC-
strated by reduced alveolar damage and reduced alveoli treated COPD mice [87]. Although these results are encour-
number loss [78, 79]. A statistically improved pulmonary aging, it has to be emphasized that MSC-based attenuation of
function (determined by the analysis of vital capacity (VC), COPD was mainly based on the effects of MSC-derived solu-
forced expiratory volumen at 100 milliseconds (FEV100), ble factors and that signaling pathways responsible for differ-
dynamic compliance (Cdyn), and mean forced expiratory entiation of MSCs in functional ATII-like cells in vivo need to
flow) was noticed in MSC-treated COPD animal models be defined in future studies.
[72]. Improvement in histological outcomes and pulmonary The only completed clinical trial which investigated the
function were accompanied by reduced presence of inflam- therapeutic effects of MSCs in COPD was performed in the
matory cells in the alveolar septa and peribronchiolar and United States (NCT00683722). Sixty-two patients with mod-
perivascular interstitium [79, 80]. erate to severe COPD were randomized to intravenously
Among lung-infiltrated immune cells, the main cellular receive either infusion of ex vivo cultured allogeneic human
targets of transplanted MSCs in COPD animals were macro- MSCs (Prochymal, Osiris Therapeutics Inc.) or vehicle con-
phages [75, 81] (Figure 3). MSCs, in a paracrine manner, trol. Patients received four monthly infusions (100 million
through the production of IL-10, TGF-β, and HGF, MSCs/infusion) and were subsequently followed for 2 years
8 Stem Cells International

Figure 3: Molecular and cellular mechanisms responsible for beneficial effects of MSCs in the therapy of COPD. Reduced emphysematous
changes and alveolar damage, accompanied with increased FEVs, were noticed in MSC-treated COPD animals. MSC-dependent
downregulation of the COX2/PGE2 pathway in inflammatory M1 macrophages occurs via the p38 MAPKs and ERK pathways and
resulted in macrophage polarization toward an anti-inflammatory M2 phenotype. Transplantation of MSCs significantly improved the
lung architecture of COPD animals by decreasing the production of macrophage-derived MMP-2, MMP-9, and MMP-12. Additionally,
transplanted MSCs either directly (through the differentiation into ATII-like cells) or indirectly (by inducing proliferation and
differentiation of lung resident (CD45-/CD31-/Sca-1+) stem cells) regenerated injured lungs.

after the first infusion [88]. Serious adverse events, increased cells, several experimental and clinical studies investigated
frequency of COPD exacerbations, or worsening of disease therapeutic effects of MSCs in the treatment of IPF [97–103].
were not observed in COPD patients treated with MSCs sug- Administration of MSCs prevented irradiation-induced
gesting that systemic application of allogeneic MSCs was a lung fibrosis [97]. A diminished inflammatory injury in
safe procedure. Although downregulated serum levels of C- MSC-treated animals correlated with the attenuated produc-
reactive protein in the MSC-treated group of COPD patients tion of inflammatory cytokines, impaired proliferation of
indicated that MSC-based therapy managed to, at least par- fibroblasts, and reduced accumulation of collagen [97].
tially, suppress ongoing inflammation, pulmonary function In a similar manner, transplantation of MSCs (with a
testing as well as quality of life indicators were not signifi- dosage ranging between 0 1 × 106 and 4 × 106 cells) protects
cantly different between MSC-treated and nontreated COPD against bleomycin-induced lung injury and fibrosis as
patients [88]. Despite the fact that obtained results were dis- manifested by substantial improvement in histopathology,
couraging, the most important conclusion of this study was attenuated lung inflammation, reduced pulmonary edema,
that allogeneic MSCs could be safely intravenously adminis- diminished collagen deposition, impaired MMP-2, MMP-9,
trated in patients with moderate to severe COPD [88]. and MMP-13 activation, and notably decreased mortality of
MSC-treated animals [98]. MSCs managed to successfully
7. MSC-Based Therapy of IPF engraft in bleomycin-injured lungs within 4 hours after injec-
tion. Transplanted MSCs suppressed production of nitric
An initiating trigger of IPF is still unclear. Recurrent oxide, inflammatory cytokines (TNF-α, IL-1β, and IL-6),
lung injury, an increased apoptosis of ATII cells, aberrant and profibrotic TGF-β in lung infiltrated immune cells and
epithelial-mesenchymal interactions, altered coagulation resident macrophages [99, 100]. Ortiz and coworkers man-
and detrimental immune response associated with enhanced aged to characterize a specific subpopulation of MSCs that
fibroblast proliferation, and excessive deposition of the extra- express interleukin 1 receptor antagonist (IL-1Ra). These
cellular matrix are the main pathological changes observed in MSCs were able to, in an IL-1Ra-dependent manner,
patients suffering from IPF [89–95]. Destruction of normal completely attenuate inflammation and pulmonary fibrosis
lung architecture leads to the development of progressive in bleomycin-injured mice [101]. When MSC-derived IL-
fibrosis which results in reduced pulmonary function, mani- 1Ra was bound to the IL-1 receptor (IL-1R), various proin-
fested by dry cough, dyspnea, and fatigue [96]. flammatory events, initiated by IL-1 : IL-1R binding, become
Since MSCs may differentiate into ATII cells in vitro, inhibited (including the synthesis and releases of inflamma-
suppress production of degrading enzymes, and inhibit tory cytokines and chemokines accompanied with enhanced
secretion of profibrotic factors in lung-infiltrated immune influx of neutrophils, macrophages, and lymphocytes in
Stem Cells International 9

injured lungs), which consequently resulted with the attenu- most frequently recorded were bronchitis (in 3 patients)
ation of inflammation and fibrosis [101]. In line with these and common cold (in 2 patients)) [108].
results are our findings related to the therapeutic potential More optimistic results were obtained in another phase
of “Exosomes d-MAPPS,” whose activity was based on 1b clinical study that noticed a notable improvement in
PL-MSC-derived exosomes containing IL-1Ra and several quality-of-life parameters after endobronchial administra-
other imunomodulatory cytokines and chemokines (IL-27, tion of AT-MSCs in 14 IPF patients [109]. Importantly, the
CXCL14, and CXCL16) which are involved in immunomo- recently published longitudinal outcomes of this study dem-
dulation of the immune response in the injured lungs [102]. onstrated that endobronchial transplantation of AT-MSCs
Results, obtained in a pilot trial with a small number of was a safe therapeutic approach since no serious side effects
patients, revealed notably attenuated lung inflammation and (including exacerbation of IPF) were noticed in MSC-
significantly improved pulmonary function parameters in exo- treated patients, two years after the first administration of
some d-MAPPS-treated patients with chronic lung inflamma- MSCs [110]. Nevertheless, a significant functional decline
tion [102]. Similar results, related to the efficacy of MSC- occurred at 24 months after the first administration of AT-
derived exosomes in the therapy of lung injury and fibrosis, MSCs, indicating that new therapeutic strategies are urgently
were obtained by Tan and coworkers who found that AF- needed in order to prolong the therapeutic effects of trans-
MSC-derived exosomes attenuated fibrosis, recovered pulmo- planted MSCs.
nary function, and enhanced endogenous lung repair [103].
Importantly, despite the fact that MSCs can be used for 8. Strategies to Enhance the Survival of
the attenuation of chronic lung inflammation and fibrosis, Transplanted MSCs in the Injured Lungs
plenty of evidence suggests that aberrant activation of
Wnt/β-catenin and TGF-β signaling pathways in lung- The beneficial effects of MSCs are relied on their capacity to
resident MSCs might induce their differentiation towards home, engraft, and survive in the injured lung tissue [111].
myofibroblasts and could, consequently, contribute to the Accordingly, optimization of MSC culture conditions has
development of IPF [104]. In line with these findings, a phar- been used as an important strategy for the enhanced engraft-
macological inhibitor of Wnt/β-catenin signaling (ICG-001) ment and prolonged survival of MSCs within the inflamma-
managed to prevent MSC-myofibroblst transition and pro- tory microenvironment of the lungs. Several research groups
tected from bleomycin-induced fibrosis [105]. In a similar highlighted that induction of autophagy as well as overex-
manner, under hypoxic conditions, microRNA-145- (miR- pression of growth factors and their receptors in MSCs may
145-) dependent inhibition of TGF-β receptor II (TGF-βRII) increase survival and therapeutic potential of MSCs [112–
managed to prevent unwanted TGF-β-driven differentiation 117]. It was well documented that hypoxia could induce
of MSCs into fibroblast-like cells [106]. autophagy in MSCs allowing them better survival in the
Safety and efficacy of MSC-based therapy of IPF patients inflammatory microenvironment [112]. Overexpression of
have been evaluated in several, already completed, clinical hypoxia-inducible factor-1 alpha (HIF-1α) in MSCs signifi-
trials [107–110]. A phase 1b single-centre, nonrandomized cantly enhanced survival of engrafted MSCs and remarkably
study, which was conducted in Australia, investigated thera- increased their therapeutic effects in the Escherichia coli
peutic potential of PL-MSCs that were intravenously injected model of bacterial pneumonia [113]. Since hypoxia increases
in IPF patients (NCT01385644). From a total number of 8 production of anti-inflammatory and antifibrotic factors in
PL-MSC-treated patients, half of them received 1 million PL- MSCs, hypoxia-preconditioned MSCs managed to efficiently
MSCs/kg bw while 4 others received 2 million PL-MSCs/kg attenuate bleomycin-induced pulmonary fibrosis [114].
bw. Although both doses of PL-MSCs were well tolerated, Additionally, Chen and coworkers found that ischemic post-
with only minor and transient alterations in peri-infusion conditioning pretreatment significantly increased VEGF pro-
hemodynamics and gas exchange, PL-MSC-based therapy did duction in MSCs enhancing their beneficial effects in
not result in attenuation of IPF. MSC-treated patients were ischemia/reperfusion- (I/R-) induced lung injury [115].
followed for six months, and none of the monitored parameters It is well known that the interaction between growth
(forced vital capacity (FVC), diffusing lung capacity for carbon factors and their receptors promotes activation of antia-
monoxide (DLCO), six-minute walk test (6MWT), or com- poptotic pathways enabling cell survival and proliferation.
puted tomography (CT) fibrosis score) were significantly chan- Preconditioning of MSCs with TGF-β1 or oncostatin M
ged by intravenous infusion of PL-MSCs [107]. (OSM) significantly increased the expression of prosurvival
Safety issues related to the MSC-based therapy of IPF and antiapoptotic genes in MSCs [116, 117]. Accordingly,
were also analyzed in another phase 1 clinical trial in which compared to OSM-nonprimed MSCs, OSM-preconditioned
9 patients with mild to moderate IPF intravenously received MSCs better survived and more efficiently improved the
20, 100, or 200 million allogeneic MSCs (NCT02013700). respiratory function in bleomycin-induced lung fibrotic
None of treatment-emergent serious side effects (nonfatal mice [117].
pulmonary embolism, stroke, hospitalization for worsening
dyspnea, and clinically significant laboratory test abnormali- 9. Challenges towards Clinical Use of MSCs in
ties) were reported. Nevertheless, during the 60 weeks of fol- the Therapy of Inflammatory Lung Diseases
low-up, two MSC-treated patients died because of IPF
progression (disease worsening and/or acute exacerbation) The safety and efficacy of transplanted MSCs in the attenua-
and a total number of 21 adverse effects were reported (the tion of inflammatory lung diseases seem to be reasonably
10 Stem Cells International

proven in experimental models. However, results obtained in Conflicts of Interest

already conducted clinical trials pointed at several challenges
which have to be addressed before MSCs will be routinely The authors declare that there is no conflict of interest
used in clinical settings. regarding the publication of this article.
First, some of the patients who received MSCs within
a short time frame developed infection and reported
respiratory symptoms indicating that MSC-based treat- Acknowledgments
ment resulted in excessive suppression of immune response This work was supported by the Novartis Foundation for
in the injured lungs [108]. Accordingly, an optimal num- Medical-Biological Research (Grant No. 16C197), Serbian
ber of transplanted MSCs should be clearly defined with Ministry of Science (ON175069, ON175103) and Faculty of
the aim of finding the right balance between their benefi- Medical Sciences, University of Kragujevac (MP01/18).
cial and undesired effects which could happen due to
immunosuppression.
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