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Materials Express
2158-5849/2021/11/1339/008
Copyright © 2021 by American Scientific Publishers
All rights reserved. doi:10.1166/mex.2021.2043
Printed in the United States of America www.aspbs.com/mex
Treatment of ectomesenchymal stem
cells-conditional medium in ulcerative colitis
Wenjing Yang∗, † , Zhe Wang† , Yao Wang, Fei Mao, Chen Chen, Weijiang Wu, Xiaodong Lu, Qian Chen,
Jingjing Liu, Wentao Shi, Sucheng Cao, and Qianzhe Li
School of Medicine, Jiangsu University, Zhenjiang 212013, P. R. China
ABSTRACT
The experiments in this paper was to investigate the effect of ectomesenchymal stem cells-conditional medium
(EMSCs-CM) in DSS-induced ulcerative colitis (UC) which is expected to provide a therapeutic treatment for
DSS-induced UC. Herein, EMSCs were isolated from the nasal cavity of mice and its supernatants without FBS
Article
were collected as conditioned medium for EMSCs (EMCSs-CM). The concentrated EMCSs-CM was further
IP: 192.168.39.211
prepared by dissolving freeze-dried CM with PBS.On: Tue, 30 Nov
Depending 2021 19:06:36
on different treatments, C57 mice was classified
Copyright: American Scientific Publishers
into normal group, DSS model group and EMSCs-C group. To build model mice, DSS at 3% concentration
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was accepted. The effects of intervention were assessed on the basis of body weight changes, disease activity
index (DAI) score, colon length, pathological variations and colitis biomarkers. Results revealed that EMSCs-CM
could express TGF-, SHH and Laminin in vitro, respectively and significantly reduce the disease activity index
and alleviate the severity of mice in vivo. a low level of inflammatory cytokine expression was also monitored
in the EMSCs-CM group. In conclusion, EMSCs-CM is conducive to improve the DSS-induced UC, owing to
multiple factors secreted by EMSCs.
Keywords: Ectomesenchymal Stem Cells-Conditional Medium (EMSCs-CM), DSS-Induced Ulcerative Colitis,
Inflammatory Cytokines.
1. INTRODUCTION Mesenchymal stem cells (MSCs) are famous for their
Ulcerative colitis is a chronic multifactorial disorder of immunoregulation in the public eye [5–7]. Many attempts
the gastrointestinal tract affecting millions of people. in reducing the burdens of immunosuppression after allo-
Four basic clinical regimens: aminosalicylates (5-ASA), transplantation and promotion of durable graft tolerance
steroids, immunosuppressants and biologic therapies are has made a good progress [8, 9]. Even if MSCs ther-
available in current treatment for ulcerative colitis [1]. In apy achieved promising results in inflammatory disorders,
recent years, some papers have reported that the introduc- the source of MSCs remains a problem in the dimen-
tion of anti-TNF therapy was an important achievement in sion of morality and ethics [10]. A peculiar stem cell
the medical treatment of patients with UC [2, 3]. Although population emanating from neural crest was reported in
substantial progress in the past several decades brings us this paper [11]. These cells are easily collected from the
many therapeutics especially in the field of immunology, nasal cavity of mammals without any ethical or technical
a complete cure for this disease remains a problem [4]. issues [12–15]. Same with other types of MSCs, EMSC
Efficient and patient-friendly cures are then highly needed has also been shown to possess potent immunosuppres-
to replenish it. sive functions, which provides a new possibility in cur-
ing disorders [16–19]. Moreover, several studies reported
∗
Author to whom correspondence should be addressed. that EMSCs own a more excellent capacity for produc-
†
These two authors contributed equally to this work. ing NO, IL-10, TGF- and PD-L1 when compared with
Mater. Express, Vol. 11, No. 8, 2021 1339
Materials Express Treatment of EMSCs-conditional medium in ulcerative colitis
Yang et al.
bone marrow-derived MSCs (BM-MSCs) [20–22]. Among group was then treated daily by intragastric administration
these cytokines, IL-10 was considered to have a crucial of 1000 L prepared EMSCs-CM/mouse.
role in regulating inflammation by most of scholars [23–
25]. Based on this evidence, we examined whether the 2.5. Disease Activity Index (DAI) and Colon Length
treatment of conditional medium from (EMSCs-CM) could As mentioned earlier, a daily Disease Activity Index
induce beneficial effects in UC in this study, hoping to was performed including body weight changes, stool
develop an effective treatment for UC caused by DSS.
examination and general bleeding [29]. Also, the
length of colon was also measured for further
2. MATERIALS AND METHODS evaluation.
2.1. Isolation and Culture of EMSCs
EMSCs were isolated from the nasal cavity of mice as 2.6. Hematoxylin and Eosin (H&E) Staining
previously reported [26]. The nasal mucosae were cut into Entire colon fixed in 4% paraformaldehyde was stained
pieces which were then digested by Pancreatic enzyme (HE). The histopathological scores were calculated follow-
at 37 C for 10 min. After centrifugation removes the ing previous report [30].
trypsin, the cells cultivated in the Dulbecco’s modified
Eagle medium/HAM’S F12 (DMEM/F12) containing 15% 2.7. Western-Blot Analysis
foetal bovine serum (Gibco, Thermo Fisher Scientific).
Colon was extracted with RIPA buffer containing
The cells were digested and dilated after merging 80% in
PMSF and analyzed with Western-blot as previously
the petri dish.
described [31]. In short, the protein moved in an elec-
tric current via SDS-polyacrylamide gel and transmitted
2.2. Preparation of EMSCs-CM
to polyvinylidene fluoride (PVDF) membranes. The mem-
Briefly, when the culture dish was covered with EMSCs
brane was sealed with 5% BSA at 37 C for half an hour.
around 80%, the medium with less fetal bovine serum
Antibodies against IL-1, IL-10, MPO, TNF, Collagen II,
was gradually replaced in future days, avoiding the oxida-
Article
tive stress-related changes caused by serum-free medium. Villin, and Laminin, Actin (BOSTER Biological Technol-
The supernatant of EMSCs wasIP: 192.168.39.211
then On: Tue,ogy
collected as condi- 30 Co.
NovLtd)
2021were used to incubate membranes at 4 C
19:06:36
tional medium (CM) of EMSCs (EMCSs-CM) Copyright: and
American overnightPublishers
cen- Scientific and then HRP-conjugated secondary antibod-
Delivered
trifuged to purify it. To achieve a good efficiency of by Ingenta
ies combined (BOSTER Biological Technology Co. Ltd).
medium, 50 mL EMSCs-CM was made into freeze-dried Finally, the bands were detected by Fusion Solo S (Vilber
powder after being dialyzed with 3500 D dialysis mem- lourmat).
brane (Solarbio). To prepare the specimen, 50 mL EMSCs-
CM powder was dissolved with 3 ml of PBS prior to ani- 2.8. Immunohistochemistry Analysis
mal experiments and components analysis. Colon tissues were embedded by paraffin in a form of
5 m thick and. And then tissue sections were deac-
2.3. Analysis of EMSCs-CM tivated and rehydrated in xylene and graded alcohols.
A cocktail of protease inhibitors was added to protect spec- After the pretreatment with 3% of H2 O2 for 10 min at
imens. 12% acrylamide gel was used for effective sepa- 4 C, 10% normal goat serum was made to block sections
ration of SDS-polyacrylamide gel electrophoresis (PAGE). at room temperature for 30 minutes. Anti-IL-10 (Pro-
Following that, proteins were transferred into cellulosic teintech 20850-1-AP), Anti-TNF (Boster, BA0131) and
nitro membrane. According to antigen-antibody reaction, Anti-Mucin (Boster, A00187) were used to incubate the
primary antibody and secondary antibody bonded proteins samples. Following that, parts were stained with biotiny-
in order after blocking with 5% milk.
lated secondary antibody for one hour, and then treated
with streptavidin-peroxidase complex for another hour.
2.4. Induction of Colitis and Treatment
Immunohistochemical staining was carried out using a
Seven-week-old male C57 mice were purchased from Nan- DAB kit (Boster, AR1027). Between each of the steps
jing Qing Longshan company. Mice were kept at 23 ±2 C
above, PBS was taken to wash for 5 min three times.
degrees Celsius and humidity at 45–55%. All experimental
Finally, working solution of diamino biphenylamine as a
protocols on animals were approved by the regional com-
mittee for the study of animals and followed guidelines for chromogenic reagent was used.
the correct use of animals in biomedical research. Mice
was distributed randomly into three groups: Control group 2.9. Statistical Analysis
with a normal diet, DSS group without treatment, EMSCs- The statistic was analyzed based on Single factor ANOVA.
CM group with lavage therapy. Colitis was induced by (SPSS23.0 software, Chicago, IL, USA). All above data
3% DSS (molecular weight 36000–50000, MP Biomedi- shall be presented with a mean ± standard deviation. p <
cals, LLC) for 7 days as before [27, 28]. The EMSCs-CM 0.05 meant a statistically significant level.
1340 Mater. Express, Vol. 11, pp. 1339–1346, 2021
Treatment of EMSCs-conditional medium in ulcerative colitis
Yang et al.
Materials Express
3. RESULTS AND DISCUSSION
3.1. Morphological Characterization of EMSCs
As presented in Figure 1(A), EMSCs were isolated from
the substantia propria and after the cell passage cultiva-
tion, EMSCs spread into fusiform shape at high prolif-
eration rate (Fig. 1(B)). Moreover, Immunofluorescence
results showed that 90% of EMSCs expressed neural crest
marker Nestin (Fig. 1(C)) and mesenchymal stem cell
marker Vimentin (Fig. 1(D)).
3.2. Analysis of EMSCs-CM
We detected that the concentrated EMSCs-CM had a stable
expression of IL-10 and TGF-, which indicated their anti-
inflammatory capacity. Laminin was also detected, which Fig. 2. The components of EMSCs-CM were analyzed by Western-
was derived from cell-extracellular matrix and thought to blotting. Two types of important factors: SHH, Laminin and two anti-
be essential for storing small molecules for the distribu- inflammatory cytokines: IL-10, TGF- were tested.
tion, activation, and presentation to cells [32]. Further-
more, sonic hedgehog, one of nutritive factors that could significantly. (Figs. 3(A, B)). The average length of colon
promote the repair of injured tissues, was also verified in in the EMSCs-CM group was longest among all of the
EMSCs-CM (Fig. 2) [33]. groups. (∗∗ P < 0.05) (Figs. 3(C, D)).
3.3. EMSCs-CM Ameliorated DSS-Induced Acute 3.4. Histopathological Alteration
Colitis in Mice To determine whether the administration of EMSCs-CM
Serious colitis with progressive weight loss, diarrhea had a good effect on colitis, H&E staining was performed.
Article
and hematochezia occurred in mice after drinking 3% Mice given DSS alone sustained serious colonic damage,
IP: 192.168.39.211
DSS water. However, the EMSCs-CM group relievedOn:
the Tue,including
30 Nov large
2021 amounts
19:06:36of inflammatory cells immersion
Copyright:
symptoms of colitis and decreased disease American
activity index Scientific Publishers
and structural damage in Figure 4(A). Results also clearly
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Fig. 1. Morphology of EMSCs under the microscope. (A) Image of primary EMSCs grown on a cell culture dish; (B) EMSCs of passage 3 grown
on a cell culture dish; (C) Immunofluorescence staining shows the EMSCs marker Nestin; (D) Immunofluorescence staining shows the EMSCs marker
Vimentin. (Bar = 200 nm).
Mater. Express, Vol. 11, pp. 1339–1346, 2021 1341
Materials Express Treatment of EMSCs-conditional medium in ulcerative colitis
Yang et al.
Article
Fig. 3. EMSCs-CM prevented progression of ulcerative colitis effectively. (A) Body weight; (B) DAI scores in the EMSCs-CM group lower than
that in the DSS group (∗∗ P < 0.05) (C) The picture of colonic length; (D) The length of colon in EMSCs-CM group longer than that in DSS group.
IP: 192.168.39.211 On: Tue, 30 Nov 2021 19:06:36
Copyright: American Scientific Publishers
showed that there was a vast improvement that Delivered
occurred by3.5.
Ingenta
EMSCs-CM Decreased Occurrence of
in mice under the treatment of EMSCs-CM. A scoresheet Inflammatory Cytokines and Enhanced
was prepared in accordance with the evaluation criteria for Intestinal Regeneration
the evaluation criteria [30]. Obviously, EMSCs-CM group The effects of EMSCs-CM on expression of cytokines
decreased the colonic inflammation score of mice promi- were detected by Western-blotting. We observed that the
nently. (∗∗ P < 0.05) (Fig. 4(B)). colon from DSS group had highest expression of IL-1,
Fig. 4. Microscopic findings of colonic inflammation. (A) Images of microscopic colon (bar = 200 nm); (B) Histological scores. (∗∗ p < 0.05).
1342 Mater. Express, Vol. 11, pp. 1339–1346, 2021
Treatment of EMSCs-conditional medium in ulcerative colitis
Yang et al.
Materials Express
IL-6, TNF-, and MPO among all the groups. Interest- However, the mechanism for MSCs in colonic tissues
ingly, the expression of these inflammatory cytokines sig- remains largely uncertain. Ample studies reported that
nificantly decreased in the group treated with EMSCs-CM. MSCs owned potent immunosuppressive function and
However, there was enhanced expression of IL-10 promi- a good capacity to release trophic factors favor tissue
nently as compared to DSS group (Figs. 5(A–B)) (∗∗ P < repair [21, 37]. Therefore, many scholars believed that the
0.05). IL-10 is an important anti-inflammatory factor that therapeutic effects of MSCs depend largely on its paracrine
was available in large quantities in colon from the EMSCs- effect. Based on the above findings, recent studies princi-
CM group. Moreover, the EMSCs-CM group had better pally focused on the factors secreted by MSCs, especially
regeneration than DSS group by analysis of villin, laminin on exosomes or microvesicles [38, 39]. These are nano-
and collagen II. (Figs. 5(C–D)) (∗∗ P < 0.05). sized extracellular vesicle that contain MSC-derived bioac-
tive molecules to modulate immune function and regulate
3.6. EMSCs-CM Against DSS-Induced Colitis survival and proliferation of cells [40]. In a word, the fac-
tors secreted by MSCs could play a major beneficial effect
Immunohistochemistry staining was used to further
on experimental colitis.
explore the efficiency of EMSCs-CM. As expected, the
IL-10, as an essential regulatory cytokine in the
EMSCs-CM had satisfactory effect on DSS-induced colitis
mucosal immune system [41, 42], was reported that pro-
through analysis of IL-10 and Mucin (Fig. 6). Except for
inflammatory cytokines like TNF-a IL-1b, IL-6 and IL-
the high expression of IL-10, the EMSCs-CM group had
8 can be largely suppressed [43]. Moreover, mediating
a high term of mucin. At the same time, the expression of
mucosal repair is another important function [44]. Inter-
TNF was also identified. Excitedly, a low level expression
estingly, we found that both EMSCs-CM and the mice
of TNF in the EMSCs-CM group caught our sight. These
treated with EMSCs-CM had high expression of IL-10,
results indicated that there was impressive improvement in
while proinflammatory factors in the EMSCs-CM group
the EMSCs-CM group.
decreased significantly. Many papers reported that TGF-
could contribute to an immunosuppressive Milieu [45, 46].
3.7. Discussion
Article
Supporting by the analysis of EMSCs-CM, TGF- was
Recently, the effectiveness of bone marrow stromal stem proven to exist in the EMSCs-CM group. Some proteins
cells (BM-MSCs), adipose-derived IP: 192.168.39.211
MSCs (AD-MSCs) On: Tue, 30 Nov 2021 19:06:36
such as SHH
Copyright: American Scientific and Laminin, supporting the regeneration
Publishers
and umbilical cord-derived MSCs (UC-MSCs) has been byofIngenta
Delivered cells and promoting the recovery of colitis, were also
reported in animal models for colitis. The therapy of tested and detected in the EMSCs-CM group. As expected,
stem cells in colitis brought an active effect on weight the EMSCs-CM group relieved colonic tissue destruction
loss, inflammatory response, survival rate, etc. [34–36]. in the DSS models, and also decreased the DAI scores
Fig. 5. The expression of inflammatory factors and associated proteins in colitis. (A–B) Compared with that in the DSS group, the EMSCs-CM group
had lower expressions of IL-1, MPO, TNF. (∗∗ P < 0.05) (C–D) Expression of IL-10, Laminin, Collagen II, and Villin 1 was increased significantly
in EMSCs-CM group. (∗∗ P < 0.05).
Mater. Express, Vol. 11, pp. 1339–1346, 2021 1343
Materials Express Treatment of EMSCs-conditional medium in ulcerative colitis
Yang et al.
Fig. 6. Immunohistochemistry staining. These images showed that the IL-10 and Mucin in EMSCs-CM group were highly expressed but TNF kept
a low level expression.
Article
IP: 192.168.39.211 On: Tue, 30 Nov 2021 19:06:36
and preserved intestinal microstructure to a largeAmerican
Copyright: 4. CONCLUSION
extent. Scientific Publishers
Western-blotting and immunohistochemistry analysis also byIn
Delivered Ingenta
this paper, we assessed the effects of EMSCs-CM on
revealed intuitively that the EMSCs-CM group had low DSS-induced colitis in mouse model with some funda-
expression of inflammatory cytokines. Collectively, the mental experiments. Our findings indicated that a great
EMSCs-CM had a compound effect in improving the improvement of clinical symptoms and positive histo-
ulcerative colitis through multiple factors secreted by the logical changes occurred with treatment of colitis using
EMSCs. EMSCs-CM. As far as we known, this is the first study
Although EMSCs-CM have positive effect on ulcera- to examine the effects of EMSCs-CM on DSS-induced
tive colitis, we still face many challenges and confusions. UC in mice. However, the use of EMSCs-CM active con-
To relieve pain of patients, oral gavage was performed. stituents with different dosages and times will provide a
Whereas, we noted that the dose of EMSCs-CM required better understanding of the effects of this substance, and
to achieve the therapeutic effects was significantly large in the mechanism for IL-10 in colitis will be a great chal-
this study because of gastrointestinal wastage. Without any lenge for us to overcome in the future research.
protective measures to resist gastric acid, the EMSCs-CM
accounted for 500 g concentration was used once a day Ethical Compliance
against DSS-induced colitis. It will therefore be necessary Animals or humans mentioned in this paper were approved
in the future to focus on improvement in bioavailability by the medical ethics board of School of Medicine of
of therapeutic EMSCs-CM. Moreover, we only verified Jiangsu University and the authorized department, experi-
the improvement of EMSCs-CM on experimental colitis ments followed all guidelines, regulations, laws, and ethics
in this research. The details on mechanism of EMSCs-CM standards as required.
were still unclear. Accordingly, the findings from study
showed that the EMSCs-CM increased IL-10 production Conflicts of Interest
and suppressed secretion of inflammatory factors in coli- There are no conflicts to declare.
tis. We can speculate that IL-10 may play a crucial role on
intestinal tract by reducing the levels of inflammatory fac- Acknowledgments: This study was done by finan-
tors. Nevertheless, this conjecture needs further confirma- cial supports from National Science Foundation of China
tion and the mechanism for IL-10 remains to be invested (51403086), Jiangsu natural science foundation of China
in the following study. (BK20140544), Youth Talent Cultivation Program of
1344 Mater. Express, Vol. 11, pp. 1339–1346, 2021Treatment of EMSCs-conditional medium in ulcerative colitis
Yang et al.
Materials Express
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Received: 8 March 2021. Accepted: 11 May 2021.
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