
==== Front
Stem Cell Res Ther
Stem Cell Res Ther
Stem Cell Research & Therapy
1757-6512
BioMed Central London

39218946
3878
10.1186/s13287-024-03878-y
Research
Umbilical cord mesenchymal stem cells in ulcerative colitis treatment: efficacy and possible mechanisms
Jiang Xiaoke 1
Luo Xiaoying 12
Cai Conghui 12
Bai Yangqiu 1
Ding Hui 1
Yue Han 3
Li Yalong 3
Yang Zhiyu 12
Zhang Huimin 1
Liang Yuan 4
Peng Cong 5
Huang Huanrong 12
Liu Min 12
Li Zhenjuan 1
Shi Yujie 126
Han Shuangyin hansy007@zzu.edu.cn

1
Li Xiuling zzlixiuling@aliyun.com

1
http://orcid.org/0000-0003-3515-9954
Zhang Bingyong zhbingyong@sina.com

1
1 grid.414011.1 0000 0004 1808 090X Department of Gastroenterology, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, School of Clinical Medicine, Henan University, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province 450003 China
2 grid.414011.1 0000 0004 1808 090X Microbiome Laboratory, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province 450003 China
3 grid.414011.1 0000 0004 1808 090X Stem Cell Research Center, Henan Key Laboratory of Stem Cell Differentiation and Modification, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province 450003 China
4 https://ror.org/03hqvqf51 grid.440320.1 0000 0004 1758 0902 Department of Pulmonary and Critical Care Medicine, Xinyang Central Hospital, No.1, Siyi Road, Xinyang, Henan Province 464000 China
5 https://ror.org/0493m8x04 grid.459579.3 Department of Gastroenterology, Yunfu People’s Hospital, No. 120, Huanshi East Road, Yunfu, Guangdong Province 527300 China
6 grid.414011.1 0000 0004 1808 090X Department of Pathology, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, School of Clinical Medicine, Henan University, No.7 Weiwu Road, Jinshui District, Zhengzhou, Henan Province 450003 China
2 9 2024
2 9 2024
2024
15 27212 4 2024
1 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Background

Mesenchymal stem cells (MSCs) possess powerful immunomodulatory ability. This study aimed to assess the efficacy and safety of human umbilical cord-derived mesenchymal stem cells (UMSCs) in patients with ulcerative colitis (UC) and to explore the potential mechanisms.

Methods

This prospective, self-controlled clinical study was conducted at Henan Provincial People’s Hospital. Patients with moderate-to-severe active UC, unresponsive to traditional drugs were continuously enrolled from September 2018 to March 2023. UMSCs were administered intravenously monthly for two months at a cell dosage of 1 × 106 per kg. The primary outcome was a clinical response at 2 months. The levels of cytokines and progerin in the plasma of the patients were analyzed using enzyme-linked immunosorbent assay kits, and longitudinal data was analyzed using generalized estimation equation.

Results

Forty-one patients were enrolled and received UMSC therapy. At 2 months, 73.2% (30/41) of patients achieved a clinical response, and 41.5% (17/41) achieved a clinical remission. At 6 months, 2 patients were lost to follow-up; the corresponding figures were 70.0% (25/41) and 34.2% (14/41), respectively. After UMSC therapy, the Mayo score, Mayo endoscopy score, mean and maximum values of Ulcerative Colitis Endoscopic Index of Severity and Nancy index were significantly reduced compared with baseline values. Additionally, the levels of progerin and inflammatory markers, such as interleukin (IL)-1β, IL-6, IL-8, IL-12, and IL-17 A decreased, while hemoglobin, albumin, and IL-10/IL-17 A ratio increased, particularly in the response group. Multiple stepwise logistic regression analysis showed age was an independent risk factor affecting efficacy (odds ratio, 0.875 (95% confidence interval (0.787, 0.972)); the area under the receiver operating characteristic curve for age was 0.79. No serious adverse events were observed during or after UMSC therapy.

Conclusion

UMSCs are safe and effective for patients with UC, with age being an independent risk factor affecting efficacy. Mechanistically, UMSC treatment may ameliorate cell senescence and suppress the secretion of pro-inflammatory cytokines.

Trial registration

The study was retrospectively registered at www.chictr.org.cn/ (ChiCTR1900026035) on September 18, 2019.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13287-024-03878-y.

Keywords

Umbilical cord mesenchymal stem cells
Ulcerative colitis
Inflammation
Aging
medical science and technology project of Henan Province SBGJ202001002 Zhang Bingyong National Health Commission project CMR-20180615-1001 Luo Xiaoying Science and Technology Department of Henan Province212102310203 Yang Zhiyu issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcIntroduction

Ulcerative colitis (UC) is an inflammatory disease that primarily affects the intestine. UC is characterized by chronic and recurrent episodes and is caused by a combination of environmental, genetic, microbial, and immune-mediated factors [1]. The latest epidemiological data has shown a steady increase in both the incidence and prevalence of this disease, leading to a significant rise in disease burden. As the disease progresses, there is an elevated cumulative risk of colectomy and colorectal carcinoma [2, 3]. Treatment for inflammatory bowel disease (IBD) includes untargeted approaches, like 5-aminosalicylic acid (5-ASA) and glucocorticoids, and targeted approaches, such as anti-tumor necrosis factor (TNF) or anti-α4β7 integrin antibodies. However, not all patients respond adequately to the aforementioned treatments, and some may face intolerance [4]. Furthermore, colectomy, especially with the production of an ileoanal pouch, has the risk of pouchitis, pouch failure, and the decline of female fertility [5]. Consequently, new approaches are urgently needed.

Mesenchymal stem cells (MSCs) possess self-renewal, multidirectional differentiation, immune system regulation abilities, and low immunogenicity. They can inhibit inflammation and apoptosis, regulate immunity, and promote angiogenesis. Because of the aforementioned properties, stem cell therapy has become an attractive therapeutic strategy for intestinal injury in IBD [6]. MSCs have powerful immunomodulatory effects, which can affect both the innate immune response and the adaptive immune response [7, 8]. Numerous studies have verified the excellent therapeutic potential of MSCs in intestinal inflammation in colitis mice. Previous studies have shown that umbilical cord mesenchymal stem cells (UMSCs) significantly reduced the disease activity index (DAI) of the mice through the rebalancing of Th1/Th17/Treg cells, reducing the secretion of pro-inflammatory cytokines and regulating intestinal flora [6, 9]. Regarding the optimization of stem cell therapy, a 2023 review has highlighted recent advances, including culturing MSCs in 3D vectors, changing culture medium of MSCs to promote cell proliferation and differentiation, genetic modification of MSCs to increase the function and efficacy of MSCs, and introducing cellular markers to MSCs to improve the homing rate of MSCs to injured tissues. Furthermore, extracellular vesicles (EVs), especially exosomes, released by MSCs have been proven to possess powerful therapeutic potential in preclinical and clinical studies in inflammatory diseases [6]. However, there are some controversies in the field, such as the heterogeneity of stem cell therapy and the potential tumorigenicity of MSCs. Adipose-derived stem cells (Cx-601) have been reported to effectively induce and maintain fistula closure in patients with Crohn’s disease [10], but few clinical trials have used MSCs in the treatment of active UC.

Compared with MSCs derived from adipose and bone marrow, UMSCs are more attractive due to several specific advantages. For instance, UMSCs are easier to obtain, involve less ethical controversy, exhibit lower immunogenicity, and do not pose age-related senescence challenges [11]. Notably, a large number of UMSCs can be produced in vitro after several passages. Moreover, UMSCs exhibited more pronounced anti-inflammatory and immunoregulatory abilities than adipose- and bone marrow-derived MSCs [12–14]. Therefore, in this study, we investigated (Trial Registration No. ChiCTR1900026035) the safety and efficiency of UMSCs in the treatment of UC and the changes of cytokines and progerin in sera of the patients with UC pre- and post-UMSC transplantation to explore the possible mechanisms of UMSCs on UC.

Methods

Trial design and patient recruitment

This was a prospective self-controlled before and after clinical study conducted at Henan Provincial People’s Hospital. Patients were continuously enrolled from September 2018 to March 2023. The study was approved by the Committee on the Ethics of Henan Provincial People’s Hospital (approval number: (2018) NO.03 − 01), and all patients provided written informed consent.

Inclusion criteria comprised (1) patients aged 18–65; (2) patients with moderate-to-severe active UC; and (3) those who failed to respond to conventional drugs, including 5-ASA or glucocorticoids. The diagnosis of UC in patients was based on the comprehensive judgment of experienced physicians. They exhibited active UC, with a Mayo score [15] ranging from 6 to 12 points, and moderate-to-severe active disease according to the “modified Truelove and Witts Disease Severity Scale” [16]. The range of colonic lesions was determined according to the “Montreal classification” [17]. None of the patients responded well to conventional treatments, including those inadequately responding to 5-ASA for at least 2–4 weeks and those resistant to hydrocortisone, steroid-dependent, or immunosuppressant resistance [18].

Patients with chronic colitis resulting from other causes (e.g., radiation- or drug-induced colitis, unexplained colitis), intestinal stenosis not passable by an endoscope, positive tuberculin skin tests, and a history of colectomy or malignant tumors were excluded. Moreover, patients with allergic constitution or allergies to UMSC treatment were also excluded. Patients exhibiting steroid dependence, steroid resistance, immunosuppressive resistance, or non-response to biologics constituted the refractory group, while others were categorized into the non-refractory group.

Screening and baseline studies

Assessments conducted before the first MSC infusion included demographic information, symptom questionnaires, physical examinations, blood tests, stool analysis, tuberculin tests, and chest radiography. Subsequently, an endoscopy was conducted, and the baseline Mayo score and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) value [19] were determined. All blood samples were processed and tested at Henan Provincial People’s Hospital.

Isolation, culture, and identification of UMSCs

Umbilical cord samples were taken from full-term healthy pregnant women with written informed consent obtained from all donors. Then, MSCs derived from the umbilical cords were isolated and identified according to our previous methods [20]. UMSCs were cultured in serum-free medium (#NC0106, Yocon, Beijing, China) in a cell incubator at 5% CO2 and 37℃ to eliminate potential interference from serum exosomes. Consistent with previous studies, UMSCs were identified based on the morphology and phenotype of the third generation and were used in subsequent experiments (Supplementary Fig. 1) [21]. Cell surface antigens of the expanded cells, including CD73, CD90, CD105, CD44, CD34, CD11b, CD19, CD45 and human leukocyte antigen-antigen D related (HLA-DR), were detected using the BD Stemflow Human MSCs Analysis kit (BD Biosciences, New Jersey, USA) and the data were analyzed using FlowJo software (version VX) [22].

UMSC therapy and procedures

UMSCs suspended in 100 mL of normal saline were administered intravenously each month for two consecutive months with a cell dosage of 1 × 106 per kg each time, based on a previous study in patients with Crohn’s disease [10]. After UMSC transplantation, the dose of prednisone was gradually reduced, initially by one tablet per week to a dose equivalent to 20 mg of prednisone per day, then by half a tablet per week until discontinuation. The doses of other related medications such as 5-ASA remained constant. Corticosteroids and biologics via intravenous or rectal administration were not permitted during stem cell therapy. The therapy was deemed unsuccessful if any of these events occurred.

Cytokines and progerin detection

Fasting blood samples of patients with UC and healthy controls (HC) were collected. The plasma Interleukin-1β (IL-1β), IL-6, IL-8, IL-10, IL-12, IL-17 A, and plasma progerin levels were detected using enzyme-linked immunosorbent assay (ELISA) kits (Quanzhou Ruixin Biological Technology Co., Ltd., Quanzhou, China) following the manufacturer’s instructions.

Follow-up

The final evaluation before the first UMSC infusion served as the baseline for all analyses. During the first 6 months, the patients were evaluated every month. Blood and stool samples were collected at 0, 2, and 6 months, and colonoscopies were performed simultaneously. The Mayo score (0 ~ 12) and UCEIS score (UCEIS average and maximum value) were calculated accordingly. The Nancy index (0 ~ 4; a higher grade indicates a more active disease) was employed to evaluate the histological disease activity of the biopsy samples obtained during colonoscopies [23]. Subsequently, patients were followed up by phone every 2 months until disease recurrence or a change in the treatment. Adverse events and concomitant treatments were recorded at each follow-up.

Outcomes

The primary outcome of our study was clinical response at 2 months, referred to a decline of ≥ 3 points and 30% in the total Mayo score from the scores before MSC therapy, and simultaneously a decline of ≥ 1 point or an absolute score of ≤ 1 point in rectal bleeding subscale. Secondary outcomes included clinical response at 6 months, clinical remission (referred to the total Mayo score of ≤ 2 points, accompanied by no subscore of ≥ 1 point) and mucosal healing (referred to an absolute endoscopy subscore of ≤ 1 point) at 2 and 6 months, sustained clinical response and remission (response/remission at both 2 and 6 months), and glucocorticoid-free remission at 6 months in patients treated with corticosteroids before UMSC therapy.

Patients who took prohibited medication, discontinued the study treatment due to poor efficacy, underwent intestinal surgery, or were lost to follow-up were all considered treatment failures in stem cell therapy, regardless of their Mayo scores. Relapse or aggravation refers to the recurrence or aggravation of the disease after complete symptom control with previous therapy [24]. Additionally, if the patient changed treatments or was readmitted to the hospital due to aggravating symptoms during follow-up, it was considered a relapse.

Statistical analysis

Measurement data is presented as mean (standard deviation (SD)) or median (interquartile range (IQR)), and enumeration data with numbers (percentages). The two independent sample t-test was applied to normally distributed measurement data, and the Wilcoxon (Mann–Whitney) test was applied to non-normally distributed measurement data to compare baseline characteristics between UC patients and HC or responders and non-responders. The generalized estimation equation was employed to compare baseline and results at 2 and 6 months of the longitudinal data. Single-factor binary logistic regression analysis was employed to identify factors affecting the treatment efficacy of UMSCs on UC patients, and the independent variable with p < 0.05 was included in the multivariate binary logistic regression model. In order to assess the accuracy of risk factors in predicting efficacy, the area under the receiver operating characteristic (ROC) curve (AUC) was calculated. A p-value < 0.05 was considered statistically significant.

Results

Demographics of the patients

Patients with moderate-to-severe active UC who were admitted to our hospital between September 2018 and March 2023 were accessed for eligibility. Among the evaluated patients, 46 met the inclusion criteria and expressed willingness to undergo UMSC treatment. However, five patients were excluded based on specific criteria. Finally, 41 patients were enrolled in the study (Fig. 1). Of these, 25 patients were male, and 16 patients were female; the longest duration of UC was 21 years. All patients had received a full dose of 5-ASA. Additionally, 53.7% (22/41) of patients had previously received glucocorticoids. Within this sub-group, five patients underwent a combined therapy of immunosuppressive agents (i.e., azathioprine), and one underwent anti-TNF antibody (i.e., infliximab) treatment. Among the 22 patients who had received glucocorticoids, 6 (27.3%) were steroid-dependent, 14 (63.7%) were steroid-resistant, and 2 (9.1%) were steroid-sensitive (Table 1).

Fig. 1 Trial procedure. UC: ulcerative colitis; UMSCs: umbilical cord mesenchymal stem cells

Table 1 Demographics of patients with UC treated with UMSCs

Variable	Case (n = 41)	
Male n (%)	25 (61.0)	
Age (in years, Mean ± SD)	45.0 ± 12.5	
Duration of UC (years, Mean ± SD)	5.5 ± 4.7	
Smoking n (%)		
Never smokers	30 (73.2)	
Former smokers	10 (24.4)	
Current smokers	1 (2.4)	
Clinical severity n (%)		
Moderate	24 (58.5)	
Severe	17 (41.5)	
The colonic area involved n (%)		
Left side of colon	26 (63.4)	
Extensive colon	15 (36.6)	
Previous treatment n (%)		
5-ASA alone	17 (41.5)	
5-ASA + Glucocorticoids	16 (39.0)	
5-ASA + Glucocorticoids + Immunosuppressant	5 (12.2)	
5-ASA + Glucocorticoids + Biological agents	1 (2.4)	
5-ASA + Biological agents	2 (7.3)	
Abbreviations UC: ulcerative colitis; UMSCs: umbilical cord mesenchymal stem cells; SD: standard deviation; 5-ASA: 5-Aminosalicylic acid

Clinical outcomes and safety

Efficacy

At 2 months, 73.2% (30/41) of patients undergoing UMSCs transplantation achieved a clinical response, 41.5% (17/41) exhibited a clinical remission, and 43.9% (18/41) experienced mucosal healing. At 6 months, 2 patients were lost to follow-up, 61.0% (25/41) achieved a clinical response, 34.2% (14/41) exhibited a clinical remission, 41.5% (17/41) experienced mucosal healing, and 30.0% (3/10) attained a glucocorticoid-free remission. Furthermore, 58.5% (24/41) and 26.8% (11/41) of patients attained sustained clinical response and remission at 6 months, respectively (Table 2).

Table 2 Outcome indicators of UMSCs on patients with UC (n = 41)

Variable	T2	T6	
Clinical response			
Total, n (%)	30 (73.2)	25 (61.0)	
Non-refractory group†, n/total n (%)	14/19 (73.7)	13/19 (68.4)	
Refractory group‡, n/total n (%)	16/22 (72.7)	12/22 (54.6)	
Clinical remission			
Total, n (%)	17 (41.5)	14 (34.2)	
Non-refractory group, n/total n (%)	10/19 (52.6)	7/19 (36.8)	
Refractory group, n/total n (%)	7/22 (31.8)	7/22 (31.8)	
Mucosal healing, n (%)	18(43.9)	17 (41.5)	
Sustained clinical response§, n (%)

n (%) {n (%)}

		24 (58.5)	
Sustained clinical remission¶, n (%)		11 (26.8)	
Glucocorticoid-free remission, n/total n (%)

{no./total no. (%) }

		3/10 (30.0)	
T2: 2 months after UMSC therapy; T6: 6 months after UMSC therapy

† Patients not belonging to refractory group constituted the non-refractory group;

‡ Patients exhibiting steroid dependence, steroid resistance, immunosuppressive resistance, non-response to biologics constituted the refractory group;

§ A sustained clinical response means that patients obtained clinical response at both 2 and 6 months;

¶ A sustained clinical remission means that patients obtained clinical remission at both 2 and 6 months

Abbreviations UC: ulcerative colitis; UMSCs: umbilical cord mesenchymal stem cells

Following UMSC treatment, patients experienced a gradual improvement in clinical symptoms, including reduced abdominal pain, decreased defecation frequency, and less bloody purulent stool. Endoscopy revealed a significant reduction in colonic inflammation and ulcer disappearance, and mucosal remission was gradually achieved. Histopathology showed decreased inflammatory cell infiltration and gradual normalization of glandular structure. Representative endoscopic images are shown in Fig. 2.

Fig. 2 Representative endoscopic images of patients with UC before and after UMSC therapy. A–B: Endoscopic presentation within the sigmoid colon and rectum before UMSC treatment. C–D: Endoscopic presentation within the sigmoid colon and rectum 2 months after UMSC treatment. E–F: Endoscopic presentation within the sigmoid colon and rectum 6 months after UMSC treatment. UC: ulcerative colitis; UMSC: umbilical cord mesenchymal stem cell

Compared with baseline, Mayo score, Mayo endoscopic score, UCEIS average and maximum values, and Nancy index decreased, while albumin (ALB) and hemoglobin (HB) increased in patients with UC following UMSC transplantation. These differences were statistically significant at 2 and 6 months (Table 3).

Table 3 The changes in clinical indicators of patients with UC treated with UMSCs

Variables	T0 (n = 41)	T2 (n = 41)	T6 (n = 39)	P †	
Mayo score (Mean ± SD)	10.6 ± 1.6	4.9 ± 3.9**	5.1 ± 4.0*	< 0.001	
Mayo endoscopic score, Median (IQR)	3.0 (3.0–3.0)	2.0 (1.0–2.5)**	2.0 (1.0–3.0)*	< 0.001	
UCEIS average value (Mean ± SD)	2.7 ± 1.0	1.8 ± 0.9**	1.6 ± 0.7*	< 0.001	
UCEIS maximum value (Mean ± SD)	4.9 ± 1.0	3.2 ± 1.3**	2.9 ± 1.4*	< 0.001	
Nancy index, Median (IQR)	4.0 (3.0–4.0)	2.0 (1.0–3.0)**	2.0 (1.0–3.0)*	< 0.001	
WBC (109/L, Mean ± SD)	6.9 ± 2.4	6.5 ± 2.3	6.6 ± 3.7	0.520	
HB (g/L, Mean ± SD)	111.5 ± 22.6	117.5 ± 25.1**	118.2 ± 25.2*	0.014	
ESR, Median (IQR)	21.0 (10.0–40.0)	23.0 (12.0–44.0)	22.0 (11.8–46.5)	0.458	
CRP, (mg/L, Median (IQR))	5.7 (1.9–18.7)	1.5 (0.0–7.2)	1.3 (0.0–7.7)	0.105	
ALB (g/L, Mean ± SD)	36.1 ± 5.7	40.4 ± 7.1**	39.6 ± 6.6*	< 0.001	
T0: before UMSC therapy; T2: 2 months after UMSC therapy; T6: 6 months after UMSC therapy

† The generalized estimation equation was employed to compare baseline and results at 2 and 6 months of the longitudinal data. **p < 0.01 T2 versus T0; *p < 0.05 T6 versus T0

Abbreviations UC: ulcerative colitis; UMSCs: umbilical cord mesenchymal stem cells; UCEIS: Ulcerative Colitis Endoscopic Index of Severity; SD: standard deviation; IQR: interquartile range; WBC: white blood cell; HB: hemoglobin; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; ALB: albumin

In order to explore the risk factors affecting the efficacy of UMSC transplantation, patients achieving clinical response at 2 months were divided into a response group (n = 30), while the other patients constituted a no-response group (n = 11). The baseline indicators of the response and no-response groups were not significantly different (Table S1). Compared with baseline, the response group displayed statistically significant decreases in Mayo score, Mayo endoscopic score, UCEIS average and maximum values, and Nancy index at 2 and 6 months, while ALB and HB levels increased significantly. In contrast to the no-response group, Mayo score, Mayo endoscopic score, UCEIS average and maximum values, and Nancy index were lower and ALB level was higher in response group at 2 and 6 months, and the difference was statistically significant (Fig. 3).

Fig. 3 The changes in the clinical indicators of the response and no-response groups after UMSC treatment. (A) Mayo score. (B) Mayo endoscopic score. (C) Ulcerative Colitis Endoscopic Index of Severity (UCEIS) average value. (D) UCEIS maximum value. (E) Nancy Index. (F) Hemoglobin (HB) concentration. (G) Albumin (ALB) concentration. (Response group: n = 30, no-response group: n = 11; T0: before UMSC therapy, T2: 2 months after UMSC therapy, T6: 6 months after UMSC therapy; ***p < 0.001, **p < 0.01, *p < 0.05). UMSC: umbilical cord mesenchymal stem cell

Recurrence

A total of 30 patients achieved a clinical response at 2 months, and 2 patients were lost to follow-up by 6 months. Furthermore, 14 patients experienced no recurrence during the follow-up, with maintenance time ranging from 8 months to 5 years. Among them, 13 patients had a maintenance duration of over 1 year, 6 patients over 3 years (Table 4).

Table 4 Recurrence in patients with UC treated with UMSCs

	2–6 months	6–12 months	1 year or longer	No recurrence	
Total	4	6	4	14	
Non-refractory group†	1	5	1	6	
Refractory group ‡	3	1	3	8	
† Patients not belonging to refractory group constituted the non-refractory group

‡ Patients exhibiting steroid dependence, steroid resistance, immunosuppressive resistance, non-response to biologics constituted the refractory group

Abbreviations UC: ulcerative colitis; UMSCs: umbilical cord mesenchymal stem cells

Safety

The most common adverse reactions associated with the UMSC infusion were low fever and fatigue, resolved with symptomatic treatment and rest. One patient developed dizziness, nausea, and vomiting after the first transplantation, while the symptoms disappeared after symptomatic treatment, and no significant discomfort occurred during the second infusion. After the second infusion, the other patient developed headache and hand numbness. A magnetic resonance imaging examination of the head was performed, and no significant abnormalities were found. The patient’s discomfort resolved after symptomatic treatment. No serious adverse events, infections, or cancers were found during MSC treatment or subsequent follow-up (Table 5).

Table 5 Adverse events in UC patients treated with UMSCs

Event n (%)	n = 41	
Fever	4 (9.8)	
Dizziness	1 (2.4)	
Headache	1 (2.4)	
Nausea	1 (2.4)	
Emesis	1 (2.4)	
Abdominal pain	1 (2.4)	
Hand numbness	1 (2.4)	
General numbness	1 (2.4)	
Upper respiratory tract infection	3 (7.3)	
Fatigue	5 (12.2)	
Abbreviations UC: ulcerative colitis; UMSCs: umbilical cord mesenchymal stem cells

Critical role of senescence in the treatment of umscs in UC patients

Senescence includes biological aging and stress-induced premature senescence. In order to explore risk factors affecting the effect of UMSC treatment, factors such as age, sex, body mass index, course of disease, severity of disease, and previous treatments were included in the logistic regression analysis model. The results showed that age was an independent risk factor affecting the efficacy of UMSCs in patients with UC, with an odds ratio (OR) value of 0.875 (95% confidence interval [CI]: 0.787–0.972). Furthermore, a ROC curve was employed to analyze the prediction accuracy of age for efficacy. The results showed an AUC of 0.791, a maximum Youden index of 0.518, and a corresponding cut-off point value of 54. This suggests that age ≤ 54 could be used as a reference value for forecasting efficacy. The sensitivity and specificity were 70% and 81.82%, respectively (Fig. 4).

Fig. 4 ROC curve of age for predicting the efficacy of UMSC treatment in patients with UC. UC: ulcerative colitis; UMSC: umbilical cord mesenchymal stem cell

Progerin is a permanently mutated lamin A, which is an important biomarker of cell premature senescence [25]. Furthermore, we explored the change of progerin in the plasma of patients with UC pre- and post-UMSC therapy. The plasma progerin level of patients with UC was markedly high compared with that in HC; whereas, the level of progerin declined noticeably after UMSC treatment at 2 and 6 months, and the differences were statistically significant (Figs. 5A and 6A).

Fig. 5 The level of progerin and cytokines of HC and UC patients pre and post-UMSC treatment. (A) Plasma progerin concentration. (B) Plasma interleukin (IL)-1β. (C) Plasma IL-6 concentration. (D) Plasma IL-8 concentration. (E) Plasma IL-12 concentration. (F) Plasma IL-10 concentration. (G) Plasma IL-17 A concentration. (H) Ratio of IL-10/IL-17 A. (HC: n = 50, patients: n = 41; T0: before UMSC therapy, T2: 2 months after UMSC therapy, T6: 6 months after UMSC therapy; ***p < 0.001, **p < 0.01, *p < 0.05). HC: healthy controls; UC: ulcerative colitis; UMSC: umbilical cord mesenchymal stem cell

UMSC Treatment inhibits pro-inflammatory cytokine secretion

we explored the change of inflammation-associated factors in the plasma of patients with UC before and after UMSC transplantation.

Initially, we examined the plasma levels of cytokines of patients with UC and HC. Results revealed significantly elevated plasma levels of IL-1β, IL-6, IL-8, IL-12, IL-17 A, accompanied by a decreased ratio of IL-10/IL-17 A in patients with UC compared to HCs. However, no prominent difference was found in IL-10 levels between the two. Subsequently, we investigated the changes in cytokines in patients with UC pre- and post-UMSC transplantation. The data indicated remarkably declined levels of IL-1β, IL-6, IL-8, IL-12, IL-17 A, with a noteworthy rise in the IL-10/IL-17 A ratio after UMSC transplantation at 2 and 6 months. However, no significant change in IL-10 level was observed (Fig. 5B-H).

Furthermore, we analyzed the change of the aforementioned cytokines in the response and no-response groups pre- and post-UMSC transplantation. At baseline, no prominent differences were observed in the levels of the aforementioned cytokines between the two. The results revealed that the IL-1β, IL-6, IL-8, IL-12, IL-17 A levels all prominently decreased, while the IL-10/IL-17 A ratio markedly increased after UMSC transplantation at 2 and 6 months in the response group. However, in the no-response group, only the IL-6, IL-12 levels decreased at 2 and 6 months after the UMSC transplantation. At 6 months, compared with the no-response group, the IL-6 level in the response group was lower, and the IL-10/IL-17 A ratio was higher, with the difference being statistically significant. Additionally, compared with the no-response group, the IL-17 A, IL-1β levels in the response group at 2 and 6 months were lower, though with no statistically significant differences (Fig. 6B-H).

Fig. 6 The progerin and cytokine changes of the response and no-response groups after UMSC treatment. (A) Plasma progerin concentration. (B) Plasma interleukin (IL)-1β. (C) Plasma IL-6 concentration. (D) Plasma IL-8 concentration. (E) Plasma IL-12 concentration. (F) Plasma IL-10 concentration. (G) Plasma IL-17 A concentration. (H) Ratio of IL-10/IL-17 A. (Response group: n = 30, no-response group: n = 11; T0: before UMSC therapy, T2: 2 months after UMSC therapy, T6: 6 months after UMSC therapy; ***p < 0.001, **p < 0.01, *p < 0.05). UMSC: umbilical cord mesenchymal stem cell

Discussion

Our study’s findings indicate that UMSC transplantation is effective and safe for patients with moderate-to-severe UC. Premature senescence is observed in UC patients, and UMSC treatment may mitigate cell senescence in UC patients. Age is identified as an independent risk factor impacting the efficacy of UMSC treatment. Furthermore, UC patients exhibit significant pro-inflammatory secretion, and UMSC treatment may inhibit the secretion of such cytokines.

MSC-based therapy has become a hopeful treatment strategy for chronic inflammatory diseases in recent years, including IBD [26, 27]. A mounting animal experiments have confirmed the remarkable role of MSC in colitis mice [28], but clinical trials of MSCs in IBD, especially in UC were few, and most of the previous studies were small sample case reports with low quality [6]. The therapeutic effects of MSC in UC deserves further study. Our results indicate that UMSC therapy is effective in patients who are unresponsive to traditional therapeutic approaches. At 2 months, 73.2% of patients achieved a clinical response, and 41.5% obtained clinical remission. In comparison, the clinical response and remission proportion for infliximab were 61.5–69.4% and 27.5–38.8%, respectively, and for vedolizumab, the corresponding figures were 47.1% and 16.9%, respectively, according to previous studies [15, 29]. Furthermore, among the 30 patients obtaining a clinical response at 2 months, 13 remained recurrence-free for over 1 year, and 6 remained recurrence-free for over 3 years. Importantly, these patients only underwent stem cell transplantation twice and did not receive maintenance therapy. MSCs possess powerful self-renewal, multilineage differentiation and immunomodulatory and tissue repair properties, possibly accounting for the remarkable effects of UMSCs in patients with UC. MSCs can modulate various immune cells and secrete numerous immune mediators to create an environment with immune tolerance properties [30, 31]. MSC-derived EVs were demonstrated have the abilities of anti-inflammation, anti-apoptosis, promotion of angiogenesis [26].

There are a few points worth noting. First, 53.7% of patients enrolled in the study had been treated with glucocorticoids alone or in combination with immunosuppressants. As is well known, prolonged application of glucocorticoids and immunosuppressants leads to various side effects [32, 33]. MSC therapy demonstrated promising efficacy in patients with refractory UC in our study. Second, in addition to the Mayo score, UCEIS was also used to more comprehensively and accurately evaluate the mucosal conditions in endoscopy and Nancy index was used to examine the histological disease activity of the biopsy samples in our study.

Senescence occurs in patients with IBD, as evidenced by upregulated expression of the cellular senescence markers p16 and p21, telomere shortening, and expression of the DNA damage response pathways [34]. Improving senescence has been shown to reduce colon inflammation [34–36]. Progerin is an important biomarker of premature cell senescence. Our results showed plasma progerin level in patients with UC was high compared with HC, and progerin level declined after UMSC treatment. EVs derived from MSCs were demonstrated could alleviate endothelial cells senescence in vitro and in vivo mouse wound-healing models though regulation of miR-146a/Src [37]. In addition, multiple progressive logistic regression analysis showed that age was an important risk factor affecting the efficacy of UMSCs in UC patients. The transplantation of bone marrow-derived MSCs in elderly patients with UC was less effective than in patients of young and middle age, which is consistent with our study [38]. As patients age, the mechanical barrier of the intestinal mucosa is impaired, intestinal flora and metabolites become disturbed, and the immune system and intestinal epithelial stem cells experience senescence. These factors can promote the development of IBD and influence the efficacy of MSC treatment [35, 39, 40].

Th17 cell-mediated abnormal immune response plays a crucial part in the pathophysiology of IBD and IL-17 A is the main effector cytokine of Th17 cells. IL-1β located at the upstream of the inflammatory response can aggravate the secretion of various pro-inflammatory cytokines including IL-6 and IL-8 [26, 41, 42]. High levels of IL-17 A and IL-1β were detected in colitis animal models and in the serum and colonic mucosa of patients with active UC. Neutralizing these cytokines reduces colonic inflammation in mice models [26, 27, 43–45]. IL-12 is a main Th1 cell-stimulating factor, and remarkably raised secretion of IL-12 was observed in IBD patients [46]. Our results showed there is elevation secretion of pro-inflammatory factors in UC patients. After UMSC treatment, the secretion of such cytokines declined, which was more obvious in the response group than in the no-response group. MSCs restrain the differentiation and activation of Th1 and Th17 cells directly or indirectly, thus inhibiting effector cytokine expression, such as IL-1β, interferon IFN‐γ, and IL-17 A. The expression of IL‐12 is downregulated by MSCs through inducing the production of prostaglandin E2 or suppressing the activation of macrophages. EVs derived from MSCs have been shown could effectively suppress expression of inflammatory markers in colitis models, such as IL-1β, IL-6, IL-8 and oxidative stress markers [26, 31].

Although MSC transplantation demonstrated a high level of efficacy in patients with UC in our study, not all patients respond well to MSC therapy. There are several possible reasons for this. Our results have indicated that age may be an important factor affecting the efficacy of stem cell treatment, a theory supported by previous research [40]. Additionally, the heterogeneity of MSC may also affect the efficacy of MSC therapy, resulting in significant individual differences [6, 26].

There are some limitations in our study. First, this was a single-center, non-randomized, single-arm clinical study. A larger sample size and multicenter randomized controlled trial is required. Moreover, patients in this study received weight-based doses of UMSCs (1 × 106 cells /kg body weight) according to previous research in patients with Crohn’s disease [10]. Clinically, we may need to establish different dose subgroups to explore the most suitable dose of UMSCs for UC patients. Finally, each patient received only two stem cell infusions and no maintenance therapy. Approximately 50% of the patients achieving a clinical response at 2 months relapsed at the subsequent follow-up, suggesting that repeated MSC therapy is of great significance. Notably, six patients maintained a 3-year relapse-free status. Therefore, patients who need maintenance therapy and the factors leading to relapse warrant further investigation.

Conclusion

In conclusion, our preliminary study demonstrated that intravenous infusion of UMSCs in patients with moderate-to-severe UC was safe and effective and age was an independent risk factor affecting the efficacy of UMSC treatment. UMSC transplantation may ameliorate cell senescence and suppress pro-inflammatory cytokine secretion.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 2

Acknowledgements

Not applicable.

Author contributions

XKJ, BYZ, SYH, XLL and HY contributed to the conception and design of the study. XKJ, XYL, YQB, HD, HY, and YLL provided study materials and completed patient enrollment. YL, CP, HRH, ML, HMZ, ZYY, ZJL and XYL collected clinical samples, performed experiments, and completed patient follow-up. YJS evaluated the histological disease activity of the biopsy samples. CHC conduced data analysis. XKJ interpreted the data. XKJ and XYL drafted the manuscript, and all authors approved the final manuscript.

Funding

This study was supported by the medical science and technology project of Henan Province (Grant number SBGJ202001002) and National Health Commission project (Grant number CMR-20180615-1001), Science and Technology Department of Henan Province (Grant number 212102310203).

Data availability

Datasets are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

The study was authorized by the Ethics Committee of Henan Provincial People’s Hospital (project title: Clinical study of mesenchymal stem cells in the treatment of moderately refractory ulcerative colitis; Approval number: (2018) NO.03 − 01; date of approval: 25 January 2018). All patients provided written informed consent.

Consent for publication

Not applicable.

Competing interests

All authors declare there are no conflicts of interest.

Abbreviations

ALB Albumin

AUC Area Under the Curve

CI Confidence Interval

CRP C-reactive Protein

DAI Disease Activity Index

ESR Erythrocyte Sedimentation Rate

EVs Extracellular Vesicles

HB Hemoglobin

HC Healthy Controls

HLA-DR Human Leukocyte Antigen-Antigen D Related

IBD Inflammatory Bowel Disease

IL Interleukin

IQR Interquartile Range

MSCs Mesenchymal Stem Cells

OR Odds Ratio

ROC Receiver Operating Characteristic

SD Standard Deviation

Th1 T Helper 1

Th17 T Helper 17

TNF Tumor Necrosis Factor

UCEIS Ulcerative Colitis Endoscopic Index of Severity

UC Ulcerative Colitis

UMSCs Umbilical Cord Mesenchymal Stem Cells

WBC White Blood Cell

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Xiaoke Jiang, Xiaoying Luo and Conghui Cai contributed equally to this work.
==== Refs
References

1. Glassner KL Abraham BP Quigley EMM The microbiome and inflammatory bowel disease J Allergy Clin Immunol 2020 145 16 27 10.1016/j.jaci.2019.11.003 31910984
Glassner KL, Abraham BP, Quigley EMM. The microbiome and inflammatory bowel disease. J Allergy Clin Immunol. 2020;145:16–27.31910984 10.1016/j.jaci.2019.11.003
2. Agrawal M Jess T Implications of the changing epidemiology of inflammatory bowel disease in a changing world United Eur Gastroenterol J 2022 10 1113 20 10.1002/ueg2.12317
Agrawal M, Jess T. Implications of the changing epidemiology of inflammatory bowel disease in a changing world. United Eur Gastroenterol J. 2022;10:1113–20.10.1002/ueg2.12317
3. Fumery M, Singh S, Dulai PS, Gower-Rousseau C, Peyrin-Biroulet L, Sandborn WJ et al. Natural history of adult ulcerative colitis in population-based cohorts: a systematic review. Clin Gastroenterol Hepatol. 2018;16:343 – 56.e3.
4. Chang JT Pathophysiology of inflammatory bowel diseases N Engl J Med 2020 383 2652 64 10.1056/NEJMra2002697 33382932
Chang JT. Pathophysiology of inflammatory bowel diseases. N Engl J Med. 2020;383:2652–64.33382932 10.1056/NEJMra2002697
5. Shen B Kochhar GS Kariv R Ileal Pouch Consortium Diagnosis and classification of ileal pouch disorders: consensus guidelines from the International Ileal Pouch Consortium Lancet Gastroenterol Hepatol 2021 6 826 49 10.1016/S2468-1253(21)00101-1 34416186
Shen B, Kochhar GS, Kariv R, Ileal Pouch Consortium. Diagnosis and classification of ileal pouch disorders: consensus guidelines from the International Ileal Pouch Consortium. Lancet Gastroenterol Hepatol. 2021;6:826–49.34416186 10.1016/S2468-1253(21)00101-1
6. Tian CM Zhang Y Yang MF Yu M Chen L Li H Stem cell therapy in inflammatory bowel disease: a review of achievements and challenges J Inflamm Res 2023 16 2089 119 10.2147/JIR.S400447 37215379
Tian CM, Zhang Y, Yang MF, Yu M, Chen L, Li H, et al. Stem cell therapy in inflammatory bowel disease: a review of achievements and challenges. J Inflamm Res. 2023;16:2089–119.37215379 10.2147/JIR.S400447
7. Dabrowska S Andrzejewska A Janowski M Walczak P Lukomska B Drela K Immunomodulatory and regenerative effects of mesenchymal stem cells and extracellular vesicles: therapeutic outlook for inflammatory and degenerative diseases Front Immunol 2020 11 591065 10.3389/fimmu.2020.591065 33613514
Dabrowska S, Andrzejewska A, Janowski M, Walczak P, Lukomska B, Drela K, et al. Immunomodulatory and regenerative effects of mesenchymal stem cells and extracellular vesicles: therapeutic outlook for inflammatory and degenerative diseases. Front Immunol. 2020;11:591065.33613514 10.3389/fimmu.2020.591065
8. Kasoju N Wang H Zhang B Greenaway T Chan HK Hu W Transcriptomics of human multipotent mesenchymal stromal cells: retrospective analysis and future prospects Biotechnol Adv 2017 35 407 18 10.1016/j.biotechadv.2017.04.005 28450077
Kasoju N, Wang H, Zhang B, Greenaway T, Chan HK, Hu W, et al. Transcriptomics of human multipotent mesenchymal stromal cells: retrospective analysis and future prospects. Biotechnol Adv. 2017;35:407–18.28450077 10.1016/j.biotechadv.2017.04.005
9. Fu Y Zhang C Xie H He H Zhang Q Liu J Human umbilical cord mesenchymal stem cells alleviated TNBS-induced colitis in mice by restoring the balance of intestinal microbes and immunoregulation Life Sci 2023 334 122189 10.1016/j.lfs.2023.122189 37865178
Fu Y, Zhang C, Xie H, He H, Zhang Q, Liu J, et al. Human umbilical cord mesenchymal stem cells alleviated TNBS-induced colitis in mice by restoring the balance of intestinal microbes and immunoregulation. Life Sci. 2023;334:122189.37865178 10.1016/j.lfs.2023.122189
10. Panés J García-Olmo D Van Assche G Colombel JF Reinisch W Baumgart DC Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomized, double-blind controlled trial Lancet 2016 388 1281 90 10.1016/S0140-6736(16)31203-X 27477896
Panés J, García-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, et al. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomized, double-blind controlled trial. Lancet. 2016;388:1281–90.27477896 10.1016/S0140-6736(16)31203-X
11. Charron D Allogenicity & immunogenicity in regenerative stem cell therapy Indian J Med Res 2013 138 749 54 24434327
Charron D. Allogenicity & immunogenicity in regenerative stem cell therapy. Indian J Med Res. 2013;138:749–54.24434327
12. Romanov YA Volgina NE Vtorushina VV Romanov AY Romanov PA Smirnov VN Comparative analysis of the secretome of human umbilical cord- and bone marrow-derived multipotent mesenchymal stromal cells Bull Exp Biol Med 2019 166 535 40 10.1007/s10517-019-04388-1 30793233
Romanov YA, Volgina NE, Vtorushina VV, Romanov AY, Romanov PA, Smirnov VN, et al. Comparative analysis of the secretome of human umbilical cord- and bone marrow-derived multipotent mesenchymal stromal cells. Bull Exp Biol Med. 2019;166:535–40.30793233 10.1007/s10517-019-04388-1
13. Li X Bai J Ji X Li J Zhang J Bai H Comprehensive characterization of four different populations of human mesenchymal stem cells as regards their immune properties, proliferation, and differentiation Int J Mol Med 2014 34 695 704 10.3892/ijmm.2014.1821 24970492
Li X, Bai J, Ji X, Li J, Zhang J, Bai H, et al. Comprehensive characterization of four different populations of human mesenchymal stem cells as regards their immune properties, proliferation, and differentiation. Int J Mol Med. 2014;34:695–704.24970492 10.3892/ijmm.2014.1821
14. Wang Q Yang Q Wang Z He Q Xu Y Li H Comparative analysis of human mesenchymal stem cells from fetal bone marrow, adipose tissue, and Warton’s jelly as sources of cell immunomodulatory therapy Hum Vaccin Immunother 2016 12 85 96 10.1080/21645515.2015.1030549 26186552
Wang Q, Yang Q, Wang Z, He Q, Xu Y, Li H, et al. Comparative analysis of human mesenchymal stem cells from fetal bone marrow, adipose tissue, and Warton’s jelly as sources of cell immunomodulatory therapy. Hum Vaccin Immunother. 2016;12:85–96.26186552 10.1080/21645515.2015.1030549
15. Rutgeerts P Sandborn WJ Feagan BG Reinisch W Olson A Johanns J Infliximab for induction and maintenance therapy for ulcerative colitis N Engl J Med 2005 353 2462 76 10.1056/NEJMoa050516 16339095
Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462–76.16339095 10.1056/NEJMoa050516
16. Truelove SC Witts LJ Cortisone in ulcerative colitis: final report on a therapeutic trial Br Med J 1955 2 1041 8 10.1136/bmj.2.4947.1041 13260656
Truelove SC, Witts LJ. Cortisone in ulcerative colitis: final report on a therapeutic trial. Br Med J. 1955;2:1041–8.13260656 10.1136/bmj.2.4947.1041
17. Satsangi J Silverberg MS Vermeire S Colombel JF Rook M Miller N The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications Gut 2006 55 749 53 10.1136/gut.2005.082909 16698746
Satsangi J, Silverberg MS, Vermeire S, Colombel JF, Rook M, Miller N, et al. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut. 2006;55:749–53.16698746 10.1136/gut.2005.082909
18. Eliadou E Day AS Thompson-Fawcett MW Gearry RB Bissett IP Collett JA New Zealand Society of Gastroenterology Guidelines for the management of Refractory Ulcerative Colitis N Z Med J 2015 128 63 76 26645757
Eliadou E, Day AS, Thompson-Fawcett MW, Gearry RB, Bissett IP, Collett JA, et al. New Zealand Society of Gastroenterology Guidelines for the management of Refractory Ulcerative Colitis. N Z Med J. 2015;128:63–76.26645757
19. Travis SP Schnell D Krzeski P Toth GT D’Haens G Ding N Reliability and initial validation of the ulcerative colitis endoscopic index of severity Gastroenterology 2013 145 987 95 10.1053/j.gastro.2013.07.024 23891974
Travis SP, Schnell D, Krzeski P, Toth GT, D’Haens G, Ding N, et al. Reliability and initial validation of the ulcerative colitis endoscopic index of severity. Gastroenterology. 2013;145:987–95.23891974 10.1053/j.gastro.2013.07.024
20. Zhang Y Lv P Li Y Liu Y Pan L Song Y Comparison of the biological characteristics of umbilical cord mesenchymal stem cells derived from the human heterosexual twins Differentiation 2020 114 1 12 10.1016/j.diff.2020.05.005 32460139
Zhang Y, Lv P, Li Y, Liu Y, Pan L, Song Y, et al. Comparison of the biological characteristics of umbilical cord mesenchymal stem cells derived from the human heterosexual twins. Differentiation. 2020;114:1–12.32460139 10.1016/j.diff.2020.05.005
21. Wu M Zhang R Zou Q Hu C Lu L Zhu W Comparison of the biological characteristics of mesenchymal stem cells derived from the human placenta and umbilical cord Sci Rep 2018 8 5014 10.1038/s41598-018-23396-1 29568084
Wu M, Zhang R, Zou Q, Hu C, Lu L, Zhu W, et al. Comparison of the biological characteristics of mesenchymal stem cells derived from the human placenta and umbilical cord. Sci Rep. 2018;8:5014.29568084 10.1038/s41598-018-23396-1
22. Dabrowski FA Burdzinska A Kulesza A Mieczkowski B Mieczkowska A Nowosielska D Comparison of the paracrine activity of mesenchymal stem cells derived from the human umbilical cord, amniotic membrane, and adipose tissue J Obstet Gynaecol Res 2017 43 1758 68 10.1111/jog.13432 28707770
Dabrowski FA, Burdzinska A, Kulesza A, Mieczkowski B, Mieczkowska A, Nowosielska D, et al. Comparison of the paracrine activity of mesenchymal stem cells derived from the human umbilical cord, amniotic membrane, and adipose tissue. J Obstet Gynaecol Res. 2017;43:1758–68.28707770 10.1111/jog.13432
23. Marchal-Bressenot A Salleron J Boulagnon-Rombi C Bastien C Cahn V Calabrese E Development and validation of the Nancy histological index for UC Gut 2017 66 1 43 9 10.1136/gutjnl-2015-310187 26464414
Marchal-Bressenot A, Salleron J, Boulagnon-Rombi C, Bastien C, Cahn V, Calabrese E, et al. Development and validation of the Nancy histological index for UC. Gut. 2017;66(1):43–9.26464414 10.1136/gutjnl-2015-310187
24. Inflammatory Bowel Disease Group, Chinese Society of Gastroenterology, Chinese Medical Association Chinese consensus on diagnosis and treatment in inflammatory bowel disease (2018, Beijing) Zhonghua Xiao Hua Za Zhi 2018 38 5 292 311
Inflammatory Bowel Disease Group, Chinese Society of Gastroenterology, Chinese Medical Association. Chinese consensus on diagnosis and treatment in inflammatory bowel disease (2018, Beijing). Zhonghua Xiao Hua Za Zhi. 2018;38(5):292–311.
25. Wheaton K Campuzano D Ma W Sheinis M Ho B Brown GW Progerin-induced replication stress facilitates premature senescence in Hutchinson-Gilford progeria syndrome Mol Cell Biol 2017 37 e00659 16 10.1128/MCB.00659-16 28483909
Wheaton K, Campuzano D, Ma W, Sheinis M, Ho B, Brown GW, et al. Progerin-induced replication stress facilitates premature senescence in Hutchinson-Gilford progeria syndrome. Mol Cell Biol. 2017;37:e00659–16.28483909 10.1128/MCB.00659-16
26. Che Z Ye Z Zhang X Ma Z Yan Y Yu D Mesenchymal stem/stromal cells in the pathogenesis and regenerative therapy of inflammatory bowel diseases Front Immunol 2022 13 952071 10.3389/fimmu.2022.952071 35990688
Che Z, Ye Z, Zhang X, Ma Z, Yan Y, Yu D, et al. Mesenchymal stem/stromal cells in the pathogenesis and regenerative therapy of inflammatory bowel diseases. Front Immunol. 2022;13:952071.35990688 10.3389/fimmu.2022.952071
27. Eiro N Fraile M González-Jubete A Costa L Monteiro J Veiga F Mesenchymal (stem) stromal cells based as a new therapeutic alternative in inflammatory bowel disease: basic mechanisms, experimental and clinical evidence, and challenges Int J Mol Sci 2022 23 8905 10.3390/ijms23168905 36012170
Eiro N, Fraile M, González-Jubete A, Costa L, Monteiro J, Veiga F, et al. Mesenchymal (stem) stromal cells based as a new therapeutic alternative in inflammatory bowel disease: basic mechanisms, experimental and clinical evidence, and challenges. Int J Mol Sci. 2022;23:8905.36012170 10.3390/ijms23168905
28. Hosseini-Asl SK Mehrabani D Karimi-Busheri F Therapeutic effect of mesenchymal stem cells in Ulcerative Colitis: A Review on achievements and challenges J Clin Med 2020 9 12 3922 10.3390/jcm9123922 33287220
Hosseini-Asl SK, Mehrabani D, Karimi-Busheri F. Therapeutic effect of mesenchymal stem cells in Ulcerative Colitis: A Review on achievements and challenges. J Clin Med. 2020;9(12):3922.33287220 10.3390/jcm9123922
29. Feagan BG Rutgeerts P Sands BE Hanauer SB Colombel JF Sandborn WJ Vedolizumab as induction and maintenance therapy for ulcerative colitis N Engl J Med 2013 369 699 710 10.1056/NEJMoa1215734 23964932
Feagan BG, Rutgeerts P, Sands BE, Hanauer SB, Colombel JF, Sandborn WJ, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369:699–710.23964932 10.1056/NEJMoa1215734
30. Najar M Raicevic G Fayyad-Kazan H Bron D Toungouz M Lagneaux L Mesenchymal stromal cells and immunomodulation: a gathering of regulatory immune cells Cytotherapy 2016 18 160 71 10.1016/j.jcyt.2015.10.011 26794710
Najar M, Raicevic G, Fayyad-Kazan H, Bron D, Toungouz M, Lagneaux L, et al. Mesenchymal stromal cells and immunomodulation: a gathering of regulatory immune cells. Cytotherapy. 2016;18:160–71.26794710 10.1016/j.jcyt.2015.10.011
31. Jiang W Xu J Immune modulation by mesenchymal stem cells Cell Prolif 2020 53 e12712 10.1111/cpr.12712 31730279
Jiang W, Xu J. Immune modulation by mesenchymal stem cells. Cell Prolif. 2020;53:e12712.31730279 10.1111/cpr.12712
32. Ali S Paul S Yakkali S Hussain S Khan S Shaik S Glucocorticoids-induced neuropsychiatric disorders in patients with inflammatory bowel disease: a systematic review Cureus 2022 14 e28981 36225410
Ali S, Paul S, Yakkali S, Hussain S, Khan S, Shaik S, et al. Glucocorticoids-induced neuropsychiatric disorders in patients with inflammatory bowel disease: a systematic review. Cureus. 2022;14:e28981.36225410
33. Sattler L Hanauer SB Malter L Immunomodulatory agents for the treatment of patients with inflammatory bowel disease (review the safety of anti-TNF, anti-integrin, anti IL-12/23, JAK inhibition, sphingosine 1-phosphate receptor modulator, azathioprine / 6-MP, and methotrexate) Curr Gastroenterol Rep 2021 23 30 10.1007/s11894-021-00829-y 34913108
Sattler L, Hanauer SB, Malter L. Immunomodulatory agents for the treatment of patients with inflammatory bowel disease (review the safety of anti-TNF, anti-integrin, anti IL-12/23, JAK inhibition, sphingosine 1-phosphate receptor modulator, azathioprine / 6-MP, and methotrexate). Curr Gastroenterol Rep. 2021;23:30.34913108 10.1007/s11894-021-00829-y
34. Faye AS Colombel JF Aging and IBD: a new challenge for clinicians and researchers Inflamm Bowel Dis 2022 28 126 32 10.1093/ibd/izab039 33904578
Faye AS, Colombel JF. Aging and IBD: a new challenge for clinicians and researchers. Inflamm Bowel Dis. 2022;28:126–32.33904578 10.1093/ibd/izab039
35. Cai Y Song W Li J Jing Y Liang C Zhang L The landscape of aging Sci China Life Sci 2022 65 2354 454 10.1007/s11427-022-2161-3 36066811
Cai Y, Song W, Li J, Jing Y, Liang C, Zhang L, et al. The landscape of aging. Sci China Life Sci. 2022;65:2354–454.36066811 10.1007/s11427-022-2161-3
36. Fantini MC Onali S Gasbarrini A Lopetuso LR Immune system and gut microbiota senescence in elderly patients with IBD Minerva Gastroenterol (Torino) 2021 70 1 59 67 10.23736/S2724-5985.21.02934-X 34278753
Fantini MC, Onali S, Gasbarrini A, Lopetuso LR. Immune system and gut microbiota senescence in elderly patients with IBD. Minerva Gastroenterol (Torino). 2021;70(1):59–67. 10.23736/S2724-5985.21.02934-X.34278753 10.23736/S2724-5985.21.02934-X
37. Xiao X Xu M Yu H Wang L Li X Rak J Wang S Zhao RC Mesenchymal stem cell-derived small extracellular vesicles mitigate oxidative stress-induced senescence in endothelial cells via regulation of miR-146a/Src Signal Transduct Target Ther 2021 6 1 354 10.1038/s41392-021-00765-3 34675187
Xiao X, Xu M, Yu H, Wang L, Li X, Rak J, Wang S, Zhao RC. Mesenchymal stem cell-derived small extracellular vesicles mitigate oxidative stress-induced senescence in endothelial cells via regulation of miR-146a/Src. Signal Transduct Target Ther. 2021;6(1):354.34675187 10.1038/s41392-021-00765-3
38. Lazebnik LB, Kniazev OV, Parfenov AI, Konopliannikov AG, Sagynbaeva VÉ, Ruchkina IN, Efremov LI, Shcherbakov PL. Age as a prognostic factor in the treatment effectiveness of patients with ulcerative colitis with help of mesenchymal stromal cells. Eksp Klin Gastroenterol. 2010;(12):3–9. Russian.
39. Zheng H Zhang C Wang Q Feng S Fang Y Zhang S The impact of aging on intestinal mucosal immune function and clinical applications Front Immunol 2022 13 1029948 10.3389/fimmu.2022.1029948 36524122
Zheng H, Zhang C, Wang Q, Feng S, Fang Y, Zhang S. The impact of aging on intestinal mucosal immune function and clinical applications. Front Immunol. 2022;13:1029948.36524122 10.3389/fimmu.2022.1029948
40. Ghosh TS Shanahan F O’Toole PW The gut microbiome as a modulator of healthy ageing Nat Rev Gastroenterol Hepatol 2022 19 9 565 84 10.1038/s41575-022-00605-x 35468952
Ghosh TS, Shanahan F, O’Toole PW. The gut microbiome as a modulator of healthy ageing. Nat Rev Gastroenterol Hepatol. 2022;19(9):565–84.35468952 10.1038/s41575-022-00605-x
41. Chen L Ruan G Cheng Y Yi A Chen D Wei Y The role of Th17 cells in inflammatory bowel disease and the research progress Front Immunol 2023 13 1055914 10.3389/fimmu.2022.1055914 36700221
Chen L, Ruan G, Cheng Y, Yi A, Chen D, Wei Y. The role of Th17 cells in inflammatory bowel disease and the research progress. Front Immunol. 2023;13:1055914.36700221 10.3389/fimmu.2022.1055914
42. Martinon F Burns K Tschopp J The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta Mol Cell 2002 10 417 26 10.1016/S1097-2765(02)00599-3 12191486
Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10:417–26.12191486 10.1016/S1097-2765(02)00599-3
43. Ohman L Dahlén R Isaksson S Sjoling A Wick MJ Sjovall H Serum IL-17A in newly diagnosed treatment-naive patients with ulcerative colitis reflects clinical disease severity and predicts the course of disease Inflamm Bowel Dis 2013 19 2433 9 10.1097/MIB.0b013e3182a563cb 23966065
Ohman L, Dahlén R, Isaksson S, Sjoling A, Wick MJ, Sjovall H, et al. Serum IL-17A in newly diagnosed treatment-naive patients with ulcerative colitis reflects clinical disease severity and predicts the course of disease. Inflamm Bowel Dis. 2013;19:2433–9.23966065 10.1097/MIB.0b013e3182a563cb
44. Schmidt EGW Larsen HL Kristensen NN Poulsen SS Pederson AML Claesson MH TH17 cell induction and effects of IL-17A and IL-17F blockade in experimental colitis Inflamm Bowel Dis 2013 19 1567 76 10.1097/MIB.0b013e318286fa1c 23689808
Schmidt EGW, Larsen HL, Kristensen NN, Poulsen SS, Pederson AML, Claesson MH, et al. TH17 cell induction and effects of IL-17A and IL-17F blockade in experimental colitis. Inflamm Bowel Dis. 2013;19:1567–76.23689808 10.1097/MIB.0b013e318286fa1c
45. Ali Mohammed S Elbaramawy A Abd-Allah SH Elkholy A Elsayed NI Hussein S Therapeutic potentials of mesenchymal stem cells in treating inflammatory bowel disease in rats J Biochem Mol Toxicol 2024 38 e23532 10.1002/jbt.23532 37676835
Ali Mohammed S, Elbaramawy A, Abd-Allah SH, Elkholy A, Elsayed NI, Hussein S. Therapeutic potentials of mesenchymal stem cells in treating inflammatory bowel disease in rats. J Biochem Mol Toxicol. 2024;38:e23532.37676835 10.1002/jbt.23532
46. Sandborn WJ Feagan BG Rutgeerts P Hanauer S Colombel JF Sands BE Vedolizumab as induction and maintenance therapy for Crohn’s disease N Engl J Med 2013 369 711 21 10.1056/NEJMoa1215739 23964933
Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369:711–21.23964933 10.1056/NEJMoa1215739
