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Intestinal Fibrosis in Inflammatory Bowel Disease and the Prospects of Mesenchymal Stem Cell Therapy

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Intestinal Fibrosis in Inflammatory Bowel Disease and the Prospects of Mesenchymal Stem Cell Therapy

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Intestinal fibrosis is an important complication of inflammatory bowel disease (IBD). In the course of the development of fibrosis, certain parts of the intestine become narrowed, significantly destroying the structure and function of the intestine and affecting the quality of life of patients. Chronic inflammation is an important initiating factor of fibrosis. Unfortunately, the existing anti-inflammatory drugs cannot effectively prevent and alleviate fibrosis, and there is no effective anti-fibrotic drug, which makes surgical treatment the mainstream treatment for intestinal fibrosis and stenosis. Mesenchymal stem cells (MSCs) are capable of tissue regeneration and repair through their self-differentiation, secretion of cytokines, and secretion of extracellular vesicles. MSCs have been shown to play an important therapeutic role in the fibrosis of many organs. However, the role of MSC in intestinal fibrosis largely remained unexplored. This review summarizes the mechanism of intestinal fibrosis, including the role of immune cells, TGF-β, and the gut microbiome and metabolites. Available treatment options for fibrosis, particularly, MSCs are also discussed.
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Intestinal Fibrosis in Inammatory
Bowel Disease and the Prospects of
Mesenchymal Stem Cell Therapy
Yifei Wang
1,2
, Bin Huang
1,3
, Tao Jin
4
, Dickson KoWiredu Ocansey
2,5
, Jiajia Jiang
1,2
*
and Fei Mao
1,2
*
1
Aoyang Institute of Cancer, Afliated Aoyang Hospital of Jiangsu University, Suzhou, China,
2
Key Laboratory of Medical
Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China,
3
General
Surgery Department, Afliated Aoyang Hospital of Jiangsu University, Suzhou, China,
4
Department of Gastrointestinal and
Endoscopy, The Afliated Yixing Hospital of Jiangsu University, Yixing, China,
5
Directorate of University Health Services,
University of Cape Coast, Cape Coast, Ghana
Intestinal brosis is an important complication of inammatory bowel disease (IBD). In the
course of the development of brosis, certain parts of the intestine become narrowed,
signicantly destroying the structure and function of the intestine and affecting the quality
of life of patients. Chronic inammation is an important initiating factor of brosis.
Unfortunately, the existing anti-inammatory drugs cannot effectively prevent and
alleviate brosis, and there is no effective anti-brotic drug, which makes surgical
treatment the mainstream treatment for intestinal brosis and stenosis. Mesenchymal
stem cells (MSCs) are capable of tissue regeneration and repair through their self-
differentiation, secretion of cytokines, and secretion of extracellular vesicles. MSCs have
been shown to play an important therapeutic role in the brosis of many organs. However,
the role of MSC in intestinal brosis largely remained unexplored. This review summarizes
the mechanism of intestinal brosis, including the role of immune cells, TGF-b, and the gut
microbiome and metabolites. Available treatment options for brosis, particularly, MSCs
are also discussed.
Keywords: intestinal brosis, IBD, mechanism, MSC, therapy, immune cells
INTRODUCTION
Intestinal brosis is a common complication of IBD and is usually dened as an excessive
accumulation of scar tissue in the intestinal wall. Intestinal brosis can occur in both forms of
IBD: ulcerative colitis (UC) and Crohns disease (CD), but mostly in CD (1). It represents a
challenge for both basic scientists and clinicians, with respect to diagnosis, pathogenic mechanisms,
and clinical management, owing to the lack of reliable and easily transferrable experimental models
of brosis, the lack of drugs targeting brosis, and the scarcity of predictive markers (2). In the past
years, researchers have intensely explored the mechanism of brosis. Similar to brosis of other
organs, intestinal brosis can activate an immune response, release cytokines, and act on various
cells of the intestine, including epithelial cells, broblasts, and smooth muscle cells, accelerating the
accumulation of extracellular matrix and depositing collagen. The common treatment for intestinal
brosis is always around anti-inammation but not directly anti-brosis. Although existing
Frontiers in Immunology | www.frontiersin.org March 2022 | Volume 13 | Article 8350051
Edited by:
Hongcui Cao,
Zhejiang University, China
Reviewed by:
Johan Dabrosin Söderholm,
Linköping University, Sweden
Shao-wei Li,
Taizhou Hospital of Zhejiang Province
Afliated to Wenzhou Medical
University, China
*Correspondence:
Jiajia Jiang
jiangjiajia_2001@163.com
Fei Mao
maofei2003@ujs.edu.cn
These authors have contributed
equally to this work
Specialty section:
This article was submitted to
Alloimmunity and Transplantation,
a section of the journal
Frontiers in Immunology
Received: 14 December 2021
Accepted: 26 January 2022
Published: 18 March 2022
Citation:
Wang Y, Huang B, Jin T,
Ocansey DKW, Jiang J and Mao F
(2022) Intestinal Fibrosis in
Inammatory Bowel
Disease and the Prospects of
Mesenchymal Stem Cell Therapy.
Front. Immunol. 13:835005.
doi: 10.3389/fimmu.2022.835005
REVIEW
published: 18 March 2022
doi: 10.3389/fimmu.2022.835005
treatment has some preventive effects on brosis, it still does not
prevent recurrence (3). In the existing clinical data, there is an
indication that many patients with IBD develop the later stage of
stenosis, and mostly experience unsatisfactory surgical
solutions (4).
In recent years, MSCs therapy has become a popular central
issue in anti-tumor and tissue regeneration because of their self-
differentiation ability, the release of regulatory factors, and
particularly, the secretion of extracellular vesicle (EV) (5).
Many studies have found that MSCs can play an important
role in the brosis of various organs. Notwithstanding, there has
not been much elaboration on the role of MSCs in intestinal
brosis. In addition, few studies have conrmed the role of MSCs
in the treatment of IBD (6). There is prospect and condence
that MSCs could be an effective therapeutic solution to intestinal
brosis. We, therefore, explore the mechanism of intestinal
brosis and discuss available treatment options, particularly
the prospects of MSCs in IBD treatment.
INTESTINAL FIBROSIS
IBD, a chronic inammatory disease that includes CD and UC,
severely affects the quality of life of the patient (7). A lot of factors
such as environment, genetic, gut microbiome, and immune
disorder can affect the occurrence and progression of IBD (8,9).
In addition to affecting the quality of life of patients, IBD also
increases the risk of colorectal cancer between 1.4 to 2.2 fold,
with decreased survival rate in patients with IBD (10).
As a crucial complication of IBD, intestinal brosis serves as a
common and great challenge for IBD therapeutic. It is
documented that brotic complications occur in more than
50% of patients with CD, mainly reected as stricture and
penetrate. Stricture is a serious problem with an 8% incidence
in UC, whereas brostenotic complications lead to stricture
formation (narrowing), intestinal obstruction, and a need for
surgical intervention, and as such, is one of the largest unresolved
clinical challenges in IBD (11). The development of intestinal
brosis is complex and the specic mechanism has not been
understood until today, however, researchers widely believe that
the progression of intestinal brosis includes the following steps:
cells injury, production of transforming growth factor (TGF-b1),
recruitment of inammatory cells, and activation of
myobroblasts and collagen-producing cells (1216).
Currently, there is no anti-inammation medicine that
effectively prevents the development of intestinal brosis.
Patients with IBD always undergo surgery under the help of
endoscopic when strictures occur (1719). Therefore, the
discovery of therapy targeting intestinal brosis reverse or
prevention will be a big breakthrough in medicine. One of the
keys focused in the study of colon brosis is the hope to detect
the appearance of brosis earlier in patients. Apart from the help
of colonoscopy and endoscope, researchers are probing at the
molecular level, including serum genetic markers (20),
extracellular matrix (ECM) components (21), growth factors
(22), and miRNAs (23)inbrosis.
It is normally considered that unhealed inammation triggers
the excessive accumulation of ECM and increased production of
collagen, indicating that the occurrence and severity of colon
brosis may show a positive correlation to an inammatory
condition Figure 1. A study found that several brosis mediators
including the TGF-bsignaling pathways, pro-brotic cytokines,
and other brosis-related factors were increased even in healed
mucosal of UC patients (24). Moreover, an earlier study also
FIGURE 1 | The progression of brosis in IBD. In the inammatory condition, tissue injury is stimulated by inammatory factors and cytokines, leading to the
proliferation and activation of broblasts in the intestine. In addition, epithelial cells and endothelial cells transition to mesenchymal cells. Fibroblasts and smooth
muscle cells also transition to myobroblasts. Myobroblasts and broblasts accumulate the product of ECM, leading to the development of brosis. ECM,
extracellular matrix; a-SMA, alpha-smooth muscle actin.
Wang et al. MSC Therapy in Intestinal Fibrosis
Frontiers in Immunology | www.frontiersin.org March 2022 | Volume 13 | Article 8350052
found that intestinal brosis develops despite the removal of an
inammatory stimulus and elimination of inammation. This
implicates that, early intervention ameliorates but does not
abolish subsequent brosis, suggesting that brosis, once
initiated, is self-propagating, therefore a very early top-down
interventional approach may have the most impact on
brostenosing diseases (25). Similarly, Hünerwadel and
colleagues found that severity of inammation does not affect
brosis, by using established animal models from IL10
-/-
mouse
(26). These observations clearly show the current situation,
whereby existing anti-inammation drugs exert an insufcient
anti-brotic effect in the therapeutic process. Otherwise, the use
of current drugs is hard to prevent the appearance of brosis and
stricture recurrence (27). Therefore, it is a great challenge to
understand the development of intestinal brosis and explore
effective therapeutic and diagnostic methods that could nally
help ease patientscare challenges.
MECHANISM OF INTESTINAL FIBROSIS
Role of MMPs and TIMPs
Intestinal brosis followed by chronic and recurrent
inammation leads to deposition of extracellular matrix (ECM)
in the mucosa, including collagen and bronectin. The
accumulation of ECM can be regulated by one pair of proteins,
matrix metalloproteinases (MMP) and their inhibitors, tissue
inhibitors metalloproteinases (TIMP) (28). MMPs regulate
brosis by degrading the ECM that is normally deposited as
the tissue renews. However, MMPsfunction is tightly regulated
by TIMPs, which inhibit MMP activity in a 1:1 ratio. Fibrotic
tissue resected from IBD patients and pre-clinical models of
intestinal brosis shows altered expression of MMP-2, MMP-3,
MMP-8, MMP-9, and TIMP-1 to varying degrees (28,29).
However, MMPs and TIMPs are also increased in inamed
intestinal tissue and it remains unclear how their expression is
altered in inamed relative to brotic tissue (30).
The Role of TGF-bSignaling
Transforming growth factor-b(TGF-b) plays an important role
in inammation, cell proliferation, and cancer. There are three
subtypes of TGF-b; TGF-b1, TGF-b2, and TGF-b3. It is known
to activate downstream mediators like Smad2, Smad3, and
Smad7 to play a positive or negative regulatory role. In vivo,it
does not only regulate proliferation to maintain homeostasis but
also promotes the development of cancer and brosis (31). A
clinical trial showed that the application of anti-TGF-bis able to
reduce bronectin and high molecular weight type IV collagen
production (32). The use of TNFaantagonists can decrease the
occurrence of brosis on patients after irradiating through lower
TGF-b(33). Moreover, an earlier study proved that urinary
TGF-bis a potential marker and predictor of hepatocellular
carcinoma (HCC) (34).
As a central cytokine in the development of intestinal brosis,
TGF-bcan play a role as an upstream molecule to activate
downstream signaling pathways. TGF-bbinds receptors to
activate the sphingosine kinase 1/sphingosine-1-phosphate/
mammalian target of rapamycin (SPHK1/S1P/mTOR) pathway
and accelerates the production of pro-brotic molecules, which
nally contribute to the occurrence of intestinal brosis (35). The
TGF-b/Smad signaling pathway is seen as a vital signaling
pathway in the development of brosis in a number of organs.
This pathway can regulate myobroblast proliferation, broblast
transition to myobroblast, and the process of epithelial-to-
mesenchymal transition (EMT). In addition to the canonical
TGF-b/Smad signaling pathway, TGF-bcan activate other
signaling pathways, including extracellular regulated protein
kinases (ERK) signaling pathway, Phosphatidylinositol-3-
kinase/protein kinase B (PI3K/AKT) signaling pathway, and
WNT signaling pathway Figure 2.
In addition to its target on cells through signaling pathways,
TGF-bseems to associate with other physiological changes in
intestinal brosis. Reactive oxygen species (ROS) can lead to the
development of intestinal brosis on the account of TGF-b
dependency. NF-E2-Related Factor 2 (Nrf2) is a nuclear
transcription factor that plays a role in defending against
oxidative stress in cells. A study found that Nrf2 could
suppress intestinal brosis in vivo and in vitro. In that study,
TNBS-induced-brosis mice were given Nrf2 agonist, which
resulted in a reduced degree of brosis compared with the no
agonist group. Similarly, the application of siNrf2 inhibited the
differentiation of TGF-b-induced CCD18Co cells (36).
Due to its critical role in the development of brosis, TGF-b
targeted inhibition has been seen as a worth considering therapy
approach in intestinal brosis. In exploring this option,
peroxisome proliferator-activated receptor g(PPARg), which is
a member of ligand-activated transcription factors of the nuclear
hormone receptor superfamily and involved in many diseases
including inammation has been tested. The result showed that
PPARgregulator GED-0507-34 Levo could ameliorate
inammation-related brosis in the colon. Oral gavage of the
TGF-binhibitor daily in DSS brotic mice effectively decreased
the expression of brosis markers in the colon. Similarly, in vitro,
GED could inhibit the differentiation of myobroblasts under the
stimulation of TGF-b, hence repressing the process of EMT of
HT29, a type of colon epithelial cells, and the expression of
brosis marker in human primary broblast (37).
The Contribution of Immune Cells
and Their Cytokines
T Cells
T cells are one of the most important immune cells in IBD.
Studies showed T cells can regulate brosis in different tissues
Table 1. The regulatory mechanism of T cells in intestinal cells
has not been well documented. Several pieces of research
demonstrate that T cells subsets such as Th1, Th2, Th9, Th17,
Th22, and regulatory T cells (Treg), and their expressed
cytokines could promote the development of intestinal brosis.
Th17 is one type of T helper cell that mainly produces
interleukin-17 (IL-17). The IL-17 produced by Th17 cells and
innate lymphoid cells has been conrmed to play an important
role in IBD (58,59). Recently, researchers found that it also
Wang et al. MSC Therapy in Intestinal Fibrosis
Frontiers in Immunology | www.frontiersin.org March 2022 | Volume 13 | Article 8350053
exhibits a crucial function in intestinal brosis by contributing to
its pathogenesis. Jian Li and colleagues investigated the level of
probrotic molecules and collagen in the blood of Balb/c mice
and found that the group treated with anti-IL-17 signicantly
decreased the quantity of collagen and expression of pro-
brogenic molecules, leading to alleviated intestinal brosis
(60). At the same time, as a member of IL-17, IL-17A is found
to increase intestinal epithelial cell-6 (IEC-6) and potentially
induce EMT through reducing E-cadherin expression and
increasing the expression of Vimentin (61). Contrary to these
reports, a study found that Tregs and IL-17 had no important
contributions in regulating the DSS-induced brosis model (62).
Most of the studies on the function of IL-17/Th17 have been
conducted using an animal model, which could not completely
imitate the real situation in humans, therefore, more studies are
needed to conrm these observations.
Th2 is another T helper cell that produces IL-4, IL-5. and IL-
13. IL-13 is able to inhibit MMP production, causing elevated
ECM deposition and induced TGF-bfunction (63). Interleukin-
10 (IL-10) is an anti-inammation cytokine and has been seen as
a potential and novel target in anti-brotic therapies. IL-10 is an
anti-inammation cytokine and has been seen as a potential and
novel target in anti-brotic therapies. IL-10 is rst found as the
product of Th2 cells in the process of inhibiting T helper 1 cell
and it has been conrmed to be produced by different immune
cells (macrophage, B cells, dendritic cells, mast cells, and others)
(64). IL-10 plays an important role in inhibiting brosis. A study
found that IL-10KO mice treated with IL-10 decreased the
expression of collagen I and TGF-b(65). In addition,
compared with wild-type mice, IL-10 mice showed higher
brosis scores under the treatment (66).
Tregs are a subset of T cells and secret IL-10 which functions
as an anti-inammatory agent. Contrary to other subtypes of T
cells, Tregs seem to be activated in the process of anti-brosis. A
study found that treatment that induces Tregs could effectively
ameliorate intestinal brosis in mice (67).
IL-12 is a product that affects the polarization of naïve T helper
cells to the Th1 phenotype, while IL-23 plays an important role in
stabilizing Th17. It is reported that the administration of p40,
which blocks IL12 and IL 23 in TNBS chronic colitis animals,
could efciently relieve the deposition of collagen (68). In another
study, the researchers used Th-related cytokine to induce colon
broblast and found that the cytokines could up-regulate or down-
regulate pro-brotic gene expression (69). This afrms the crucial
role of T cells and related cytokines in the development of
intestinal brosis. In addition, apart from the commonly used
chemical damage model, researchers usually use the T cells
transfer model to study T cell-related regulatory factors in
inammation (70). This model also serves as an appropriate
medium for discussing T cell-related effects on brosis.
Macrophages
Macrophages are a critical part of the immune response in IBD.
A recent study showed that macrophage in patientsblood has
the potential to differentiate IBD patients into different groups
with different phenotypes and may therefore help determine
response to therapy (71). In recent years, several studies have
focused on the role of macrophages in intestinal brosis.
Intestinal macrophages keep gut homeostasis through secreting
several cytokines, regulating molecules, and participating in
epithelial proliferation (72). The disorder of macrophage leads
to aberrant repair, abnormal inammatory mediator and growth
FIGURE 2 | TGF-bactivated signaling pathway in intestinal brosis. TGF-bpromotes brosis by regulating related cells through the activation of the canonical Smad
signaling pathway and noncanonical pathway including MAPK and WNT, which contribute to the development of EMT in epithelial cells, the proliferationof
broblasts, and transformation of broblasts and smooth muscle cells to myobroblasts. In effect, ECM is overexpressed, resulting in increased collagen deposition.
TGF-b, transforming growth factor b; Smad, drosophila mothers against decapentaplegic; Ras, rat sarcoma; MEK, methyl ethyl ketone; ERK, extracellular regulated
protein kinases; GSK3b, glycogen synthase kinase3b.
Wang et al. MSC Therapy in Intestinal Fibrosis
Frontiers in Immunology | www.frontiersin.org March 2022 | Volume 13 | Article 8350054
factor production, and altered communication between
macrophages and broblasts, epithelial cells, and endothelial
cells, nally promoting the progression of brosis (73).
Macrophages are divided into M1 macrophages and M2
macrophages. In the inammatory environment, M1 releases
pro-inammatory cytokines while M2 releases IL-10 and TGF-b,
which inhibit inammation (74). Although M2 macrophages
have anti-inammatory properties, it does not mean that they
automatically play an anti-brotic role. Both M1 and M2
macrophages are involved in the occurrence and development
of brosis (75). Notwithstanding, the different macrophage
phenotypes play different roles in brosis. Pedro Salvador and
colleagues found that CD16+ macrophages are increased in the
mucosa of CD patients and were mediated by signal transducer
and activator of transcription-6 (STAT6), where the deciency of
STAT6 elevated the population of CD16+ macrophages (76).
There are relatively few studies on the role of macrophages in
intestinal brosis, providing a research gap to be explored in
the future.
Mast Cells
Mast cells (MCs) are innate immune cells capable of responding to
different stimuli. They are fundamental elements of the intestinal
barrier as they regulate epithelial function and integrity, modulate
both innate and adaptive mucosal immunity, and maintain neuro-
immune interactions, which are closely linked to the functioning
of the gut (7779). Although the role of MCs, which are members
of the sentinel immune cell population, remains largely unknown
in intestinal brosis, there are reports of a large inux of MCs into
the muscularis externa of the small intestine in brosis (80), and
the promotion of intestinal brosis after the breakdown of the
mucosal barrier (81).
The role of MCs in intestinal inammation appears to own two
sides, i.e., anti-inammation and inammation. On the anti-
inammation side, a study showed that MCs alleviate colitis and
(82) protect against intestinal barrier injury in IL-10 decient
mouse models. Similarly, the inltration of MCs in the intestine
tissue is especiallyincreased at the DSS-induced experimentalcolitis
remission phase and deciency of MCs could lead to failed tissue
repair (83). On the contrary, other studies have demonstrated the
inammatory property, reporting that MCs accelerate the
development of intestinal inammation. For example, Musheng
Li and colleagues examined MCs-derived exosomes, which showed
that exosomal miR-223 from human mast cells-1 (HMCs-1) could
destroy intestinal epithelial function through inhibiting the
expression of CLDN8 (Claudin 8) in epithelial cells (84). These
ndings implicate that MCs may have a more important role in
chronic inammation, even in brosis development (85).
MCs are conrmed to play a signicant role in tissue brosis of
several organs, including liver, lung, pulmonary, and atrial (86,87).
MCs also regulate brosis in Chronic Graft-Versus-Host Disease.
Interestingly, MCs seem to show contradictory effects in different
conditions from differentresearches. Some studiesreport that when
brosis starts in the tissue, the MCs increase and are activated, as
shown by degranulation and secretion of cytokines including TGF-
band other tryptases, which accelerate the ECM production and
promote the progression ofbrosis (88). Bin Liu and colleagues also
documented the elevated presence of MCs in brotic intestinal
tissues, and MCs affected the development of brosis with the
release of tryptase. Unfortunately, researchers in this area are not
rich and await further exploration (89).
EMT, EndoMT, and Intestinal Fibrosis
EMT is an important pathophysiological process in the
occurrence and development of many conditions, including
intestinal brosis and cancer initiation, invasion, and
metastasis (90). EMT is an important hallmark of intestinal
brogenesis through which epithelial cells lose their polarity or
their epithelial phenotype and transform into mesenchymal cells
functionally and morphologically (91). EMT-associated
molecules were found in the brotic lesion of CD patients (77).
According to Dolores Ortiz-Masiáand colleagues, the process of
EMT is accompanied by stula development, which is an
abnormal tract between two epithelial cells and is associated
with brosis (92). Certain pro-inammatory cytokines such as
IL-17A have been shown to possess probrotic properties as they
are associated with brosis of multiple organs including the
intestine. IL-17A is found to participate in the initiation and
development of intestinal brosis through inducing EMT (61).
Other mechanisms involved in EMT induction that leads to
intestinal brosis include toll-like receptor 4 (TLR4) and succinate
stimulation. The absence of the TLR4 gene attenuated chronic
inammation and colonic macrophages inltration and
suppressed intestinal brosis and collagen deposition. Moreover,
suppression of TLR4 transcription affected myobroblasts
activity, collagen synthesis, and EMT in CCD-18Co cells, a
human cancer cell line (93). In another study, succinate and its
receptor UCNR1 were up-regulated around CD-stulas and
activated WNT signaling-mediated EMT in intestinal epithelial
cells (92). In addition to studies of EMT in intestinal brosis in cell
lines and animal models, manner-organoid, a novel 3D model in
colon studies has been shown to be more specic than animal
models and more complex than cell models. In this model,
Soojung Hahn and colleagues used TGF-bor TNF-ato
stimulate the organoid colon model and the result showed a
combination of the two cytokines could effectively promote the
expression of mesenchymal markers like N-cadherin and brotic-
related factors including a-SMA (94).
In recent years, in addition to EMT, endothelial-to-
mesenchymal transition (EndoMT) has also been reported as a
novel mechanism in brosis, where transcription factors involved
in the transformation process were conrmed in both inamed
human and murine intestine (95,96). Moreover, EndoMT has
been detected in experimental colonic brosis of Tie2- green
uorescent protein (GFP) reporter-expressing mice (97).
Involvement of the Gut Microbiome in
Intestinal Fibrosis
The gut microbiome inuences health and disease. Changes in the
composition of the gut microora, immune system, or intestinal
barrier function can upset the host-microbiome interaction and
lead to inammation and brosis (98). For instance, adherent-
invasiveEscherichia. coli(AIEC), a type of gut bacteria, is conrmed
to be involved in IBD, especially CD (99,100). A study discovered
Wang et al. MSC Therapy in Intestinal Fibrosis
Frontiers in Immunology | www.frontiersin.org March 2022 | Volume 13 | Article 8350055
that AIEC could colonize the intestine when acute inammation
occurs, leading to brosis via increased expression of ST2 -the
receptor of IL-33, under the mediation of Flagellin (101). The
microbial infection triggers a disorder of the immune
microenvironment, where the persistent infection of AIEC leads
to an active T-helper 17 response and increases the brotic growth
factors (102). Tumor necrosis factor-like cytokine 1A (TL1A,
TNFSF15) is associated with IBD, regulating the location and
severity of intestinal inammation and brosis. TL1A production
is elevated in the inamed gut mucosa, is linked with brostenosing
CD, and is well dependent on the gut microbiome. The authors
showed that pro-brotic and inammatory phenotype resulting
from TL1A-upregulation was abrogated in the absence of resident
microbiota (8).
Salmonella enterica serovar Typhimurium also plays a key role
in intestinal brogenesis. Katrin Ehrhardt and colleagues found
that mice develop intestinal brosis under persistent infection with
Salmonella enterica serovar Typhimurium through inducing
protease expression in macrophages and epithelial cells (103).
Microbial products such as cell wall components can be directly
pro-brogenic, while the administration of fecal material or
anaerobic bacteria into autologous animals could also trigger
intestinal brosis (98). Generally, the CD is associated with
shifts in the composition of the enteric microbiota, with overall
reduced bacteria diversity and signicantly depleted abundance of
the phyla Firmicutes and Bacteroidetes, while Proteobacteria and
Actinobacteria increase (104).
However, the gut microbe does not only contribute to the
induction but also the prevention of intestinal brosis. The gut
microbe and related proteins can protect the intestine from
brotic injury. For example, a study found heat-shock-protein
56 (HSP56) secreted by invasive Lactococcus lactis can reduce
the severity of brosis (105).
When the microbiome leads to dysregulation of the immune
response, the immune and non-immune cells sense the
pathogen-associated molecular patterns (PAMPs) from
microbe with the help of pattern recognition receptors (PRRs),
which consists of TLRs and Nod-like receptors (NLRs). MyD88
is an adaptor molecule that helps all TLRs except TLR3 to release
signals, hence, several researchers believe that MyD88 may have
a role in intestinal brosis. Shuai Zhao and colleagues conrmed
that intestinal brosis improves when the gene of MyD88 in a-
SMA positive cells is deleted (106). However, an earlier study
from C. Lutz et al. indicated that MyD88 shows no or little effect
in intestinal brosis (107). As a member of TLRs, TLR4 is
reported to participate in intestinal brosis. Studies show that
intestinal brosis and the deposition of collagen are suppressed
under the silence of the TLR4 gene in vivo and in vitro (93).
Autophagy and Intestinal Fibrosis
Autophagy is an evolutionarily conserved important process for the
turnover of intracellular substances in eukaryotes with cytoplasmic
cargo transferring to the lysosome and degradation (108).
Autophagy is considered to be widely involved in various
conditions such as intestinal brosis (109), cancer (110), kidney
diseases (111), and pulmonary diseases (112).In intestinal epithelial
cells of IBD subjects, autophagy could regulate programmed cell
death and limit the development of colitis (113).Atthesametime,
autophagy functions in regulating inammatory cytokines, such as
IL-1b(114). Under physiological conditions, the system of cellular
adaptation permits the intestinal mucosa to maintain the gut barrier
function and avoids excessive immune response to non-self-
antigens from commensal microbes or dietary origin (115,116).
Interestingly, autophagy inhibits the pathogenic immune response
to dietary antigens in cystic brosis, an inherited disorder that
causes severe damage to the digestive system, lungs, and other
organs (115).
A study conrmed that autophagy played an important role in
regulating intestinal brosis in mice, where the administration of
autophagy inhibitor, resulted in the appearance of intestinal
brosis, implicating autophagy as a protective mechanism
against brosis generation (64). Moreover, autophagy is reported
to increase in the mice colitis model, which helps to ease
inammation (3). In another study, the antibrotic effects of
curcumin were demonstrated via its alleviation of IL-6-induced
endothelial-to-mesenchymal transition through promoting
autophagy in allografted organs and human umbilical vein
endothelial cells (HUVECs) (117). However, it is reported that
autophagyin immune cells could induce an immune response that
nally aggravates brosis. The autophagy in CX3Cr1+
mononuclear phagocytes could up-regulate IL-23/IL-22 axis (15).
The Link of the Renin-Angiotensin System
(RAS) to Intestinal Fibrosis
The renin-angiotensin system (RAS) is widely present in various
parts of the body including blood vessels, kidneys, and heart, and
is an important regulatory system for several disease conditions.
Recent researches conrm that the renin-angiotensin-
aldosterone system (RAAS) interacts with the TGF-bpathway,
participating in brosis development by regulating cells and
cytokines. Further exploration revealed that different pathways
of RAAS may lead to different outcomes; while some molecules
prevent brosis, others promote it (118).
Other studies show that the imbalance of RAS induces
inammation and brosis in the colon. For example, a recent
studybyGarget.al.,reportedthatAng(1-7)reducedthe
proliferation of myobroblasts and secretion of collagen, whereas
Ang II promoted these events. When the quantity of RAS
components in IBD patients was compared with healthy people,
circulating renin and alternative RAS components were high in IBD
patients. Interestingly, patients with CD had reduced the
requirement of hospitalization and surgery after treatment with
RAS blockers (119). These ndings indicate that drugs targeting the
RAS, besides being antihypertensive, also possess antibrotic and
anti-inammatory properties and could offer an inexpensive
alternative to control inammation and brosis in the gut.
The Role of Non-Coding RNAs in Fibrosis
In recent studies, the importance of non-coding RNAs (ncRNAs)
stands out in brotic diseases in that ncRNAs exhibit a remarkable
variety of biological functions in modulating brogenic responses.
The participation of ncRNAs in intestinal brogenesis makes them
potential therapeutic targets and diagnostic biomarkers in the
management of intestinal brosis (120). The overexpression of
Wang et al. MSC Therapy in Intestinal Fibrosis
Frontiers in Immunology | www.frontiersin.org March 2022 | Volume 13 | Article 8350056
certain microRNA(miRNAs) can inhibit the development of
brosis. For instance, studies on MiR-200 in intestinal brosis
show down-regulated expression of miR-200 family in intestine
tissuefromCDpatients(121,122). Moreover, treatment of IEC-6
with micro-vesicles carrying miR-200b induced by TGF-b
prevented the process of EMT and alleviated brosis (123). In
radiation-induced intestinal brosis, lncRNA WWC2-AS1
functions as a competing endogenous RNA in the regulation of
FGF2 expression via sponging miR-16. The resultant inhibition of
FGF2 function, prevents intestinal cell proliferation, migration,
invasion, and brosis (124). Contrary to these observations, other
studies have reported thebrosis-promoting effects of ncRNAs. For
example,it is documented that themiR-29 family enhancescollagen
deposition (125).
In addition to the intestine, several studies have demonstrated
ncRNAs to participate in the brotic diseases of multiple organs
including liver diseases, myocardial brosis, and renal brosis. The
ncRNAs involved in brotic diseases mainly consist of miRNAs,
long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs).
ncRNAs modulate the function of mesenchymal cells,
inammatory cascades, ECM, and microbiota via mechanisms of
endogenous RNA competition, RNA transcription regulation,
protein sponges, and translation regulation (126,127).
miRNA occupy advantages in the future for early non-
invasive diagnosis. Using serum from healthy people and CD
patients, an earlier study found miR-19 to have lower expression
in the serum of CD patients (23).
PRESENT TREATMENT OPTIONS FOR
INTESTINAL FIBROSIS AND STRICTURE
A variety of drugs and standardized treatment guidelines are
available for IBD, and these measures are conrmed to be
effective to relieve inammation in IBD. However, no anti-brotic
drug is currently approved, although some present popular anti-
inammation drugs appear effective against brosis. When IBD
patients develop severe intestinal brosis and stricture, the rst
treatment choice is surgery. However, surgery does not always
resolve brosis, thus, it persists and continues to develop, and new
strictures may appear (128). Therefore, the observation thatsome of
the anti-inammatory drugs can alleviate brosis and stricture to a
certain extent, is crucial. Table 2 shows the present treatment
measures in IBD-associated brosis and stricture in addition to
surgery for resection. Although these current therapeutic options
can alleviate the suffering of patients to a certain degree, the
preventive rate is low, and surgical methods also have a high or
low recurrence rate. This provides grounds to seek more effective
treatment options.
MSCs were discovered in the past few years and quickly
became a research hotspot in curative and regenerative medicine,
with an outstanding performance in tissue regeneration.
Considering the admirable therapeutic prospects of MSCs, its
application in intestinal brosis offers hope for future treatment.
THERAPEUTIC PROSPECTS OF MSCS IN
INTESTINAL FIBROSIS
Characteristics of MSCs
MSCs, which possess great self-renewal and multilineage
differentiation potential, have been certied to have a great
therapeutic effect, including tissue regeneration. Relying on
their low antigenicity, MSCs are an expectant hope as a
potential therapy in the future. In addition to their wonderful
self-renewal and multilineage differentiation abilities, MSCs also
possess multipotency with osteogenic, chondrogenic, and
adipogenic potentials. All MSCs express similar surface
TABLE 1 | Function of T cells subsets in different brosis.
Immune cells Organ Effects in brosis References
Th1 cells Lung Anti-brotic (38)
Heart Pro-brotic (39,40)
Liver Anti-brotic (41)
Th2 cells Skin Pro-brotic (42)
Liver Pro-brotic (41,43)
Kidney Pro-brotic (44)
Biliary Pro-brotic (45)
Th9 cells Liver Pro-brotic (46)
Th17 cells Liver Pro-brotic (41)
Lung Pro-brotic (38)
Heart Pro-brotic (47)
Th22 cells Liver Anti-brotic (48)
Treg cells Lung Anti-brotic (49)
Lung Pro-brotic (50)
Kidney Pro-brotic (51)
Cytotoxic T Cell Lung Pro-brotic (52)
Kidney Anti-brotic (53)
Thyroid Pro-brotic (54)
NKT cells Liver Anti-brotic (55)
Liver Pro-brotic (56)
Heart Anti-brotic (57)
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Frontiers in Immunology | www.frontiersin.org March 2022 | Volume 13 | Article 8350057
markers such as a cluster of differentiation CD73, CD90, and
CD105 and lack the expression of CD14, CD34, CD45, and
human leukocyte antigen-DR (HLA-DR) (142).
Since the discovery of MSCs from bone marrow in 1968, a
variety of sources have also been conrmed to produce MSCs,
like adipose tissue (143), human umbilical cord (144), Whartons
Jelly (145), placenta (146), among others. These MSCs have been
conrmed to have therapeutic potential in both experimental
and clinical settings among many diseases including IBD,
cardiovascular conditions, Parkinsons disease, osteoarthritis,
diabetes, neurological conditions, wounds, and malignancies
(147). Some of the most classic cases of the application of
MSCs include certain clinically intractable diseases such as
spinal cord injury (148), autoimmune diseases (149), and liver
diseases (150). MSCs function not only in tissue regeneration but
also in drug delivery. They serve as anti-cancer drug delivery
vehicles by loading nanoparticles to be delivered to the tumor
microenvironment, producing high transport efciency (151).
The study of MSCs in IBD has been extensively explored,
where MSCs actively ease IBD. For example, umbilical cord
MSCs (ucMSCs) are commonly used in disease treatment and
their transplantation (from Kunming mice and humans) can
effectively protect mice from intestinal injury (152). In addition,
ucMSCs can also attenuate colitis through regulating immune
cells and associated cytokines. For instance, ucMSCs attenuate
IBD by releasing miR148b-5p to inhibit the expression of 15-lox-
1 in macrophages (153) and by inhibiting ERK phosphorylation
in neutrophils (154). Moreover, clinical trials of MSCs performed
on luminal IBD have been proven effective (155). However, there
are limitations as the safety and stability data are not absolute,
and the effective result is also accompanied by side effects (156).
Meanwhile, the number of patients participating in such trials
remains small, thus, larger trials are needed in the future.
Exosomes that are secreted by MSCs constitute the classical
functional mechanism behind the therapeutic properties of MSCs.
As a subtype of extracellular vesicles (EVs), exosomes are lipid vesicles
secreted by cells into extracellular space. The other types of EVs are
micro-vesicles (MVs)and apoptotic bodies (157). Exosomes are
typically 30150 nm in diameter and recognized through electron
microscopy, NTA, and surface markers such as CD9, CD81, and
HSP70. Exosomes are secreted by nearly all cells and have been found
in plasma, urine, semen, saliva, bronchial uid, cerebral spinal uid
(CSF), breast milk, serum, amniotic uid, synovial uid, tears, lymph,
etc (158). They carry different molecules including proteins, nucleic
acid, and lipid, which inuence their function. When exosomes are
transferred to recipient cells, they inuence the phenotype of
recipient cells, therefore, exosomes are recognized as an important
medium for cell-to-cell commutation (159). In the therapeutic
application in IBD, exosomal proteins, RNAs, and lipids capably
modulate IBD microenvironmental components such as cytokines,
chemokines, immune cells, the gut microbiota, and the intestinal
mucosal barrier, as part of the mechanism to repair damage and
restore intestinal mucosal functions as extensively reviewed by
Ocansey et al. (160).
Comparedto MSCs, exosomes derivedfrom MSCs or other cells
appear to have more desirable unique structural, compositional,
and morphological characteristicsaswellaspredominant
physiochemical stability and biocompatibility properties,
producing enhanced injury repair and disease resolution in
animal models (161). The regulatory effect of exosomes in IBD
has been extensively investigated in recent years, where MSCs-
derived exosomes alleviate colitis through targeting immune cells
such as macrophages (162), T cells (163,164), and neutrophils
(154). Exosomes from immune cells, such as macrophages, can also
attenuate DSS-induced colitis (165). It is worth noting that EVs
from food sources including bovine milk are conrmed to alleviate
CD by regulating the immune environment and microbiota (166).
This suggests that EVsderived from materials that areeasy to obtain
could serve as a more practical and useful research direction.
MSCs Therapy in Intestinal Fibrosis in IBD
Currently, available research on the function and mechanism of
MSCs in intestinal brosis is severely minimal. However, the few
availablestudies largely present a good prospect of MSCs therapy in
TABLE 2 | Present treatments in IBD-associated brosis.
Type Treatment
route
Effect Reference
Drugs Mesalazine Oral Lower endoscopic postoperative recurrences in Mesalazine group compared with placebo groups (129)
Azathioprine Oral 49% of patients are free of rehospitalization in 36 mouths (130)
Iniximab Intravenous
injection
No development of new small bowel stenosis; Part of stenosis completely regressed (27,131
134)
Adalimumab Subcutaneous
injection
Effectively prevent the occurrence of small bowel stenosis; keep patients being free of surgery (135,136)
Vedolizumab Intravenous
injection
The patient remains in clinical and endoscopic remission without need for surgical treatment. (137)
Thiopurines Oral Early use is associated with preventing surgery and the development of brostenosis (138)
Surgery Endoscopic
stricturotomy
(ESt)
Endoscopic Offers comparable surgery-free survival; Avoids a surgical resection for a stricture at a previous ileocolonic
anastomosis (ICA); Appears to be effective in treating short ICA strictures with no pre-stenotic proximal dilation
in CD patients
(139)
Stenting Endoscopic Effective treatment for strictures relapse; High technical success rate; Risk of adherence of the stent to the
mucus membrane of the bowel, perforation, and spontaneous distal migration of the stent
(140)
Endoscopic
balloon dilation
(EBD)
Endoscopic Complete through gastrointestinal endoscopy; Reduce the need for surgery for resection (141)
Wang et al. MSC Therapy in Intestinal Fibrosis
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intestinal brosis, a potential opportunity for both preventing and
treating brogenesis Figure 3. For example, Lei Lian and colleagues
found that bone marrow-derived MSCs reduced brotic associated
activities such as collagen deposition and EMT in the TNBS-
induced colitis mice model (167). In another study of colorectal
brosis, MSCs mediated the downregulation of brogenesis via
controlling ECM turnover. Further investigation revealed that
MSCs induced a decreased expression of probrotic genes and
proteins by releasing hepatocyte growth factor (HGF) and tumor
necrosis factor-stimulated gene 6 (TSG-6) (168). The anti-brotic
effects of MSCs through the release of HGF are reported in other
tissue injuries including liver brosis (169). and lung brosis (170).
Both allogeneic and autologous MSCs transplantation is safe and
consequently represents a treatment option for brosing diseases,
stulizing colitis like CD, and refractory connective tissue diseases, as
they are non-immunogenic (171,172). Moreover, systemic
administration of MSCs for the treatment of refractory irradiation-
induced colitis was safe and effective on pain, diarrhea, hemorrhage,
inammation, and stulization accompanied by regulation of the
lymphocyte subsets towards an elevated Tregs cell and a reduction of
activated effector T cells (173,174). A study revealed that both i.v.
infusion and i.m. injunction of MSCs after anal sphincter injury in
rats resulted in a marked decrease in brosis and scar tissue compared
with PBS-treated groups (175).
The EVs derived from MSCs affect the development of intestinal
brosis through their cargoes, including proteins and RNAs. A
study by Jia Yang and colleagues demonstrated that micro-vesicles
containing miR-200b attenuate colitis-associated brosis by
preventing EMT (27). A recent study of experimental CD
examined the effect of MSCs engineered to overexpress hypoxia-
inducible factor 1-alpha and telomerase (MSC-T-HIF) and
conditioned with pro-inammatory stimuli to release EVs
(EVMSC-T-HIFC) on brosis and inammatory response of
activated endothelium. The authors found that in addition to
dampening inammation, the EVMSC-T-HIFC prevented
myobroblast differentiation of TGF-b-treated broblasts (176).
In a similar study, paracrine factors derived from MSCs were
shown to protect against lung brosis in terms of brotic scores,
collagen deposition, inammation, and cell apoptosis (177). It is also
exciting that MSC treatment is conrmed to be effective and safe in
a clinical trial on idiopathic pulmonary brosis patients (178). The
administration of culture supernatant of MSCs signicantly reduced
the degree of luminal stricture in the rectum and attenuated
myobroblast activation and hypertrophy of the muscularis
propria in pigs (179). In clinical trial, autologous bone marrow-
derived MSCs was conrmed to control the inammation in IBD,
especially in inhibiting TNF-aproduction (171). In a phase 2 study,
administration of allogeneic MSCs reduced CD activity index and
CD endoscopic index of severity scores in patients with luminal CD
refractory to biologic therapy (180). Although these clinical trials did
not examine brotic proliferation and stenosis, the results provide
an important proof-of-principal and intention of follow-up research
on brosis, considering the relationship between inammation
and brosis.
In addition, an anal stula is a common complication of CD
which mainly occurs around the anal rather than intestinal lumen.
However, the developmentof the stula is closely related to brosis.
Studies show that MSCs are an optional treatment for stula.
Allogeneic adipose-derived MSCs can reduce the occurrence of
stula in CD patients (181). Moreover, injection of autologous
adipose-derived MSCs is safe and could completely heal 57% of
patients with stulas and reduce secretion in part of remaining
patients (182). Furthermore, allogeneic and autologous adipose-
derived MSCs have shown advantageous results for stula
treatment in long-term clinical trials, and are proven to be safe
(183,184).
FIGURE 3 | The regulatory effect of MSCs in the progression of brosis in IBD. MSCs regulate intestinal brosis. MSCs regulate cells in the process of brosis by
producing cytokines and growth factors or by secreting EVs. MSCs inhibit the proliferation and activation of pro-brotic immune cells, like Th17 cells, Th2 cells, M1
macrophages, and mast cells, and promote the production of M2 macrophages and Tregs which inhibit brosis. In addition, MSCs inhibit the EMT process and the
production of myobroblasts. EVs, extracellular vesicles; Th, T helper; Treg, Regulatory cells.
Wang et al. MSC Therapy in Intestinal Fibrosis
Frontiers in Immunology | www.frontiersin.org March 2022 | Volume 13 | Article 8350059
As expected of every research eld, the hope of MSCs and
related EVs therapy in intestinal brosis is to translate the
outcome into clinical application. Although some clues have
been shown regarding the possibility of MSCs application in
intestinal brosis, the evidence is far from enough. There is still a
long way to go for laboratory research to transform into clinical
applications, as several questions remain unanswered and
mechanisms largely unclear.
Concerning other challenges in this eld of study, previous
research on brosis used different animal models, usually mice or
rats, which are confronted with many limitations. For better
experimental outcomes and subsequent clinical application, there
is the needto use models closerto the details of thedisease. Intestinal
organoids have been widely used in intestinal research recently and
have also been reported in the research of intestinal brosis (94). As
a more three-dimensional and more specic experimental model, it
can also be used in future research.
The Function of MSCs in Other
Tissue Fibrosis
Liver Fibrosis
Liver brosis which is triggered by viral or metabolic chronic
liver diseases is one of the common brosis in the clinical setting
and has the risk of transition to cancer (185). Due to the
admirable effect of MSCs on other diseases, researchers have
set to explore the function of liver brosis. Concerning immune
cells, macrophage has been proven to play a signicant role in the
progression of liver brosis. Xiao-Yu Luo et al. reported that the
transplanted BM-MSC can increase the M2/M1 macrophage
ratio through migrating to injury liver location, and the action,
in turn, affects hepatic stellate cells (HSCs) apoptosis (186).
Ly6Chi/lo macrophages are two different types of macrophages
in the liver. Ly6Chi is highly inammatory and brotic while
Ly6Clo could alternatively decrease liver inammation and
brosis through secreting certain cytokines. A study conrmed
that BM-MSCs ameliorate liver brosis by regulating Ly6Chi/
Ly6Clo conversion and preventing Ly6Chi recruitment (187).
Apart from macrophage, MSCs also promote liver regeneration
through regulating neutrophils (188) and T cells (189). The
cross-talk between MSCs and Tregs is crucially important for
the attenuation of acute liver injury.
Engineered MSC possesses an enhanced regulatory effect in
inhibiting and reversing liver brosis. IC-2 engineered BM-MSC
was proven to have the potential to relieve liver brosis (190).
Just as indicated earlier, MSCs functionally alleviate liver brosis
by producing cytokines or factors, directly acting on target cells,
and secreting EVs. Earlier research shows that BM-MSC-derived
exosomes could potently relieve brotic change in the CCI4 rat
model and protect the function of the liver. It is worth noting
that many comparative studies report that the effect of BM-MSC
exosomes is better than BM-MSC itself (191). Li yang Dong and
colleagues conrmed that hucMSC-EV was able to effectively
ameliorate liver brosis in rat models by inhibiting HSC
activation (192). In CCI4 rat models, EVs from amnion-
derived MSCs were also capable of targeting HSCs activation
to relieve liver brosis (193). In recent research, the authors
combined MSCs with Kampo medicine Juzentaihoto (JTT),
which is dried and powdered from 10 crude drugs, and used it
for liver brosis therapy in animal models. The results showed
that the combination therapy attenuated liver brosis by the JTT
increasing the CD4+/CD8+ratio while MSCs promoted the
transition of inammatory macrophages to anti-inammatory
macrophages (194).
Kidney Fibrosis
Kidney brosis is the nal outcome in the progression of certain
kidney diseases, especially chronic kidney diseases (CKD). Recent
reports show that hucMSCs effectively ameliorate renal brosis in
DN rats, including decreasing brotic molecules expression and
restoring tissue integrity. Meanwhile, hucMSCs would depress
FIGURE 4 | MSCs studies on different tissue brosis in recent 5 years. Using the keywords brosisand mesenchymal stem cells, as well as specic organs, a
search was conducted on the PubMed online library. Results were restricted to studies published from 2017 to 2021.
Wang et al. MSC Therapy in Intestinal Fibrosis
Frontiers in Immunology | www.frontiersin.org March 2022 | Volume 13 | Article 83500510
TGF-bexpression, which has been widely conrmed to be a key
cytokine in tissue brosis and secret anti-brotic molecule in the
tubular epithelial cells (195). Another research reported that the
transplantation of BM-MSCs induced anti-brotic events in rats by
decreasing collagen production and myobroblast accumulation.
Besides, BM-MSCs could also regulate non-coding RNAs, such as
miRNAs to inuence downstream proteins for easing brosis (196).
Pulmonary Fibrosis
Pulmonary brosis is a type of lung chronic diseases complication,
with a high global incidence. Studies show that the incidence of
pulmonary brosis in Europe and North America is estimated to
range between 2.8 and 18 cases per 100000 people per year (196).
However, the major health and safety incidents- the epidemic of
COVID-19pushed it to become a more meaningful needfor nding
anti-brotic therapy (197). In experimental models, MSCs can act
on immune cells to regulate lung brosis. In a clinical trial,
idiopathic pulmonary brosis patients who received doses of
allogeneic MSCs showed greater performance in lung function
examinations compared with patients with placebo (178). In
addition, MSCs-EVs have also shown positive implications in
lung brosis. Studies show EVs from human BM-MSCs could
preventand alleviate pulmonary brosisby changing the phenotype
of monocyte (198). Regardless, MSCs may have a probrogenic
function. As a type of stem cell which owns multilineage
differentiation, MSCs might have the chance to differentiate to
myobroblast under certain stimuli on the process of brosis
prevention and therapy. For example, a study found that BM-
MSC could accelerate lung brosis through a transform to
myobroblast (199). This calls for more investigations in
establishing a stable condition in which MSCs and their secretory
products could induce and sustain anti-brotic effect to a period
necessary to produce the desired outcome.
Apart from the three tissues above, MSCs could have a
probrogenic function in other tissues. Figure 4 shows MSCs-
related studies on different tissuesin recent 5 years, from 2017 to 2021.
CONCLUSION
Intestinal brosis has a high incidence rate in the course of IBD
and there is no ideal treatment solution currently. Fortunately,
studies have conrmed that MSCs and their secretory products
such as exosomes can alleviate brosis by inhibiting the EMT
process and reducing collagen deposition. Although studies on
MSCs application in intestinal brosis in IBD are woefully low,
by considering the promising role of MSCs in collective studies
on brosis of organs, we have reasons to believe that it can also
play an effective role in intestinal brosis. The mechanisms
involved still need further exploration.
AUTHOR CONTRIBUTIONS
YW and BH determined the topic of the article, proposed a
program, and wrote the article. TJ summarized and drew diagram
of the mechanism. DO modied the language of the article. JJ and
FM collectedliterature and guided the article and gave opinions. All
authors have read and approved the nal manuscript.
FUNDING
This work was supported by the Science and Technology Innovation
Fund Project of Zhenjiang City (grant no. SH2021066) and the
Technology Project of Zhangjiagang (ZKCXY2106).
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Wang et al. MSC Therapy in Intestinal Fibrosis
Frontiers in Immunology | www.frontiersin.org March 2022 | Volume 13 | Article 83500517
... However, most evidence indicates that gastrointestinal tract fibrosis occurs only in previously or actively inflamed regions, implying that persisting inflammation is a necessary condition for developing fibrosis. In physiological conditions, acute inflammation is normally followed by healing with tissue restoration and functional recovery; in pathological conditions, the fibrotic process is established by the persistence of the inflammatory stimulus [4][5][6][7][8][9]. Many studies have demonstrated that TGF-β stimulates the activation and proliferation of fibroblasts, resulting in extracellular matrix deposition and fibrosis in several organs, including lungs, kidneys, liver, skin, and gut [9][10][11][12][13][14]. Actually, inflammation causes the release of TGFβ, with the consequent activation of fibroblasts that differentiate into myofibroblasts, a cell type that has an intermediate phenotype between smooth muscle cells and fibroblasts. ...
... In physiological conditions, acute inflammation is normally followed by healing with tissue restoration and functional recovery; in pathological conditions, the fibrotic process is established by the persistence of the inflammatory stimulus [4][5][6][7][8][9]. Many studies have demonstrated that TGF-β stimulates the activation and proliferation of fibroblasts, resulting in extracellular matrix deposition and fibrosis in several organs, including lungs, kidneys, liver, skin, and gut [9][10][11][12][13][14]. Actually, inflammation causes the release of TGFβ, with the consequent activation of fibroblasts that differentiate into myofibroblasts, a cell type that has an intermediate phenotype between smooth muscle cells and fibroblasts. ...
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Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract. Chronic inflammation is the main factor leading to intestinal fibrosis, resulting in recurrent stenosis, especially in CD patients. Currently, the underlying molecular mechanisms of fibrosis are still unclear. ZNF281 is a zinc-finger transcriptional regulator that has been characterized as an epithelial-to-mesenchymal transition (EMT)-inducing transcription factor, suggesting its involvement in the regulation of pluripotency, stemness, and cancer. The aim of this study is to investigate in vivo and in vitro the role of ZNF281 in intestinal fibrogenesis. Intestinal fibrosis was studied in vivo in C57BL/6J mice with chronic colitis induced by two or three cycles of administration of dextran sulfate sodium (DSS). The contribution of ZNF281 to gut fibrosis was studied in vitro in the human colon fibroblast cell line CCD-18Co, activated by the pro-fibrotic cytokine TGFβ1. ZNF281 was downregulated by siRNA transfection, and RNA-sequencing was performed to identify genes regulated by TGFβ1 in activated colon fibroblasts via ZNF281. Results showed a marked increase of ZNF281 in in vivo murine fibrotic colon as well as in in vitro human colon fibroblasts activated by TGFβ1. Moreover, abrogation of ZNF281 in TGFβ1-treated fibroblasts affected the expression of genes belonging to specific pathways linked to fibroblast activation and differentiation into myofibroblasts. We demonstrated that ZNF281 is a key regulator of colon fibroblast activation and myofibroblast differentiation upon fibrotic stimuli by transcriptionally controlling extracellular matrix (ECM) composition, remodeling, and cell contraction, highlighting a new role in the onset and progression of gut fibrosis.
... Leading edge genes that contributed most to the enrichment score were presented in heatmaps (Figure 6 B and 6D). It is known that patients with inflammatory bowel disease usually develop intestinal fibrosis, which is marked by the activated epithelial-to-mesenchymal transition process [44]. Reactome GSEA showed the activation of pathways in the extracellular matrix organization, hemostasis and complement cascade (Table 1). ...
... Intestinal function was apparently disrupted in the xmrk fish, based on the deregulation of genes involved in digestion and absorption of nutrients from food, downregulation of genes maintaining epithelial cell barrier integrity, as well as downregulation of genes involved in general intestinal homeostasis. The activation of pathways in inflammation, ECM organization, EMT and hemostasis, which were found in the intestine of the xmrk fish, have also been reported in the inflammatory bowel disease in human patients [44,46,79]. Our GSEA analysis suggested common gene signatures between the xmrk intestine and human inflammatory bowel disease. ...
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