Duan YL, Wen YH, Chen SA, Nie R, Pang MQ, Deng MJ, Wang ZX, Fan HN. Efficacy and safety of cell-based regenerative therapies for fistula-related diseases: An umbrella review of systematic reviews. World J Stem Cells 2026; 18(7): 122048 [DOI: 10.4252/wjsc.122048]
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Hai-Ning Fan, PhD, Chief Physician, Full Professor, Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, No. 29 Tongren Road, Xining 810001, Qinghai Province, China. fanhaining@medmail.com.cn
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Duan YL, Wen YH, Chen SA, Nie R, Pang MQ, Deng MJ, Wang ZX, Fan HN. Efficacy and safety of cell-based regenerative therapies for fistula-related diseases: An umbrella review of systematic reviews. World J Stem Cells 2026; 18(7): 122048 [DOI: 10.4252/wjsc.122048]
Yun-Long Duan, Yong-Hao Wen, Man-Jun Deng, Hai-Ning Fan, Stem Cell and Regenerative Medicine Laboratory, Affiliated Hospital of Qinghai University, Xining 810001, Qinghai Province, China
Yun-Long Duan, Yong-Hao Wen, Ru Nie, School of Clinical Medicine, Affiliated Hospital of Qinghai University, Xining 810001, Qinghai Province, China
Si-Ai Chen, Department of Basic Medical Sciences, Qinghai University Medical College, Xining 810001, Qinghai Province, China
Ru Nie, Stem Cell and Regenerative Medicine Laboratory, Qinghai University Medical College, Xining 810001, Qinghai Province, China
Ming-Quan Pang, Zhi-Xin Wang, Hai-Ning Fan, Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining 810001, Qinghai Province, China
Co-corresponding authors: Zhi-Xin Wang and Hai-Ning Fan.
Author contributions: Duan YL and Wen YH contributed to the conception and design of the study; Duan YL, Wen YH, Chen SA, and Nie R contributed to the literature search and data collection and analysis; Duan YL interpreted the findings and prepared the first draft of the manuscript; Pang MQ, Deng MJ, Wang ZX, and Fan HN contributed to the protocol development and reviewed the manuscript; Deng MJ, Wang ZX, and Fan HN had full access to all study data and took final responsibility for the decision to submit the manuscript for publication. Wang ZX and Fan HN are co-corresponding authors and contributed equally to this work. Wang ZX was primarily responsible for the academic guidance, data analysis, manuscript revision. Fan HN has taken on the primary role in the study conception, experimental design, and project administration. Both authors were involved in supervision, review & editing of the manuscript, and have approved the final version. They agreed to be jointly accountable for all aspects of the work.
AI contribution statement: AI tools (specifically ChatGPT) were used only for language editing and formatting support. It was not used to generate research data, analyze data, interpret results, or draw conclusions. All output was critically reviewed and revised by the authors.
Supported by the Fourth “Qinghai Scholar” Program, No. 2025-qhxz-fhn.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Corresponding author: Hai-Ning Fan, PhD, Chief Physician, Full Professor, Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, No. 29 Tongren Road, Xining 810001, Qinghai Province, China. fanhaining@medmail.com.cn
Received: April 8, 2026 Revised: May 13, 2026 Accepted: June 18, 2026 Published online: July 26, 2026 Processing time: 107 Days and 22.3 Hours
Abstract
BACKGROUND
Fistula-related diseases are characterized by a chronic course, high recurrence rates, and limited therapeutic benefits. Conventional treatments are associated with suboptimal healing rates and substantial complication risks. Cell-based regenerative therapies have attracted increasing attention due to their combined immunomodulatory and tissue-repair properties. However, evidence regarding their overall efficacy and safety remains fragmented and heterogeneous.
AIM
To determine the overall efficacy and safety of cell-based regenerative therapies for fistula-related diseases through a systematic review and meta-analysis.
METHODS
PubMed, EMBASE, Web of Science, and the Cochrane Library were searched from database inception through December 15, 2025 to identify systematic reviews and meta-analyses examining regenerative therapies for fistula-related diseases. Review quality was appraised with A Measurement Tool to Assess Systematic Reviews 2, certainty of evidence was evaluated according to Grading of Recommendations, Assessment, Development and Evaluation, overlap among primary studies was measured using the corrected covered area, and visual evidence maps were generated.
RESULTS
Thirty-five eligible systematic reviews and meta-analyses were included, and most of the evidence concerned perianal fistulas (PF) and fistulizing Crohn’s disease (FCD). Mesenchymal stem cells (MSCs) were the most frequently evaluated intervention, whereas evidence for platelet-rich plasma (PRP), MSC-derived exosomes, and hematopoietic stem cells (HSCs) was limited. Across PF and FCD, MSC-based therapy was generally associated with higher rates of combined remission, clinical and/or radiological healing, clinical remission, and clinical response than comparator treatments, although the strength and consistency of evidence varied across outcomes and reviews. Some findings were supported by moderate-certainty evidence, but most included reviews were rated as low or critically low confidence. Treatment effects appeared to differ according to cell source and delivery strategy, with adipose-derived, allogeneic, and locally injected MSC more often associated with favorable outcomes. MSC therapy did not increase the overall risk of adverse events (AE), and low-certainty evidence suggested that it may be associated with a reduced risk of serious AEs. Evidence for PRP, exosomes, and HSCs remained sparse and insufficient for firm conclusions.
CONCLUSION
Thirty-five eligible systematic reviews and meta-analyses were included, and most of the evidence concerned PF and FCD. MSCs were the most frequently evaluated intervention, whereas evidence for PRP, MSC-derived exosomes, and HSCs was limited. Across PF and FCD, MSC-based therapy was generally associated with higher rates of combined remission, clinical and/or radiological healing, clinical remission, and clinical response than comparator treatments, although the strength and consistency of evidence varied across outcomes and reviews. Some findings were supported by moderate-certainty evidence, but most included reviews were rated as low or critically low confidence. Treatment effects appeared to differ according to cell source and delivery strategy, with adipose-derived, allogeneic, and locally injected MSC more often associated with favorable outcomes. MSC therapy did not increase the overall risk of AEs, and low-certainty evidence suggested that it may be associated with a reduced risk of serious adverse events. Evidence for PRP, exosomes, and HSCs remained sparse and insufficient for firm conclusions.
Core Tip: This umbrella review demonstrates that mesenchymal stem cells (MSCs) based regenerative therapy is associated with meaningful improvements in healing and remission in perianal fistulas and fistulizing Crohn’s disease. The most consistent benefits were observed with adipose-derived, allogeneic, and locally injected MSC. MSC therapy was generally well tolerated, with no increase in overall adverse events and potential reduction in serious adverse events. Among currently studied regenerative approaches, MSC appears to be the most promising option for fistula-related diseases.
Citation: Duan YL, Wen YH, Chen SA, Nie R, Pang MQ, Deng MJ, Wang ZX, Fan HN. Efficacy and safety of cell-based regenerative therapies for fistula-related diseases: An umbrella review of systematic reviews. World J Stem Cells 2026; 18(7): 122048
Fistula-related diseases comprise a group of chronic disorders that are difficult to manage therapeutically, with an estimated prevalence of about 6.7% in patients with inflammatory bowel disease and 0.8% in the general population[1]. Their shared pathological hallmark is the formation of an abnormal epithelialized tract connecting two anatomical structures, typically accompanied by persistent inflammation, infection, and impaired tissue repair. Clinically, fistulas manifest in various forms, including cryptoglandular anal fistulas, Crohn’s disease-associated fistulas, radiation- or surgery-related fistulas, and obstetric injury-related rectovaginal fistulas[2]. Patients often suffer from chronic pain, persistent discharge, recurrent infections, and abscess formation, leading to substantial functional impairment, reduced quality of life, and considerable psychological burden[3,4]. Current standard treatments for fistula-related diseases include pharmacological therapy, endoscopic interventions, and surgery. Pharmacological approaches - such as antibiotics, immunomodulators, and biologic agents - yield limited overall fistula closure rates: 21%-48% for antibiotics, 20%-40% for thiopurines, and approximately 36% for adalimumab[5], with recurrence rates reaching up to 40.9%[6]. Endoscopic treatments have a relatively narrow indication spectrum and are generally considered only when active inflammation around the fistula opening is minimal and drainage is adequate[7]. Surgical excision or drainage remains the mainstay for achieving fistula control or eradication, yet postoperative complication rates may reach 50%[8]. In systemic inflammatory conditions such as Crohn’s disease, local closure alone often fails to achieve durable remission[9]. Accordingly, there is a strong need for new therapeutic strategies that can provide both anti-inflammatory activity and regenerative potential while preserving an acceptable safety profile.
In recent years, cell-based regenerative therapies have become a promising research direction in fistula management. Among these, mesenchymal stem cells (MSC) have garnered particular interest due to their immunomodulatory properties, ability to suppress excessive inflammatory responses, promotion of angiogenesis and tissue remodeling, and improvement of the local microenvironment, all of which may enhance fistula healing while minimizing sphincter damage[10,11]. Importantly, MSC show low immunogenicity, partly because they express low levels of major histocompatibility complex class II and costimulatory molecules, which facilitates the clinical use of allogeneic cells without systemic immunosuppression[12]. Over the past decade, many studies have examined MSC therapy in different fistula-related conditions, using a range of cell sources and delivery routes, and have reported encouraging preliminary findings[13,14]. In parallel, platelet-rich plasma (PRP), exosomes, and other cell-derived bioactive products have been investigated as adjunctive or alternative regenerative strategies[15,16]. Despite these developments, considerable uncertainty remains regarding the clinical effectiveness and safety of regenerative therapies, which has limited their broader implementation in routine practice[17].
Therefore, this umbrella review was undertaken to integrate evidence from published systematic reviews and meta-analyses and to provide a comprehensive assessment of the efficacy and safety of regenerative therapies for fistula-related diseases. Compared with previous reviews focusing mainly on MSCs in Crohn’s disease, this study has several strengths. First, it examined a broader range of fistula-related diseases beyond Crohn’s disease. Second, it included multiple regenerative approaches, such as MSC, PRP, MSC-derived exosomes, and HSC. Third, it summarized a wider range of clinically relevant outcomes, including combined remission, clinical and/or radiological healing, clinical remission, clinical response, and adverse events (AEs). Fourth, visual evidence maps were constructed to enhance interpretability. Overall, this review provides a broader and more rigorous evidence overview than previous studies.
MATERIALS AND METHODS
This umbrella review was performed in line with established methodological recommendations[18,19]. The review protocol was prospectively registered in PROSPERO (CRD420261278496), and the reporting adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines[20].
Literature search strategy
A comprehensive literature search was conducted from database inception to December 15, 2025 to identify published systematic reviews and meta-analyses assessing the efficacy and safety of regenerative therapies for fistula-related diseases. The electronic databases searched were PubMed, Web of Science, EMBASE, and the Cochrane Library. The search strategy combined controlled vocabulary terms (such as Medical Subject Headings) and free-text keywords related to “fistula-related diseases”, “regenerative therapies”, “stem cells”, “platelet-rich plasma”, and “systematic reviews/meta-analyses”. The detailed search strategies for each database are provided in Supplementary Table 1. The literature search was independently conducted by two reviewers, and discrepancies were resolved through discussion. In addition, the reference lists of all eligible reviews were manually examined to capture potentially relevant studies not identified through the electronic search.
Eligibility criteria and study selection
Eligibility criteria were established in advance according to the PICO framework (Population, Intervention, Comparator, Outcomes, and study design), and the full details are presented in Supplementary Table 2.
Systematic reviews, with or without meta-analysis, were considered eligible if they: (1) Included patients with any type of fistula-related disease; (2) Evaluate the effects of different regenerative therapies on fistula diseases; (3) Comparisons with standard care or other intervention measures; and (4) Reported clinical efficacy outcomes and/or safety outcomes. We excluded narrative reviews, scoping reviews, commentaries, editorials, and conference abstracts. Study selection was performed independently by two reviewers in two stages: Title/abstract screening followed by full-text assessment. Any disagreements were resolved by consensus.
In this umbrella review, “cell-based regenerative therapies” refer to therapeutic strategies involving living cells or biologically active cell-derived products that aim to promote tissue repair, modulate inflammation, and facilitate fistula healing. These include MSC from different sources, PRP, or exosomes, and other living cell-based regenerative medicine approaches. In contrast, inert biomaterial-based interventions without active cellular or molecular regenerative effects were excluded.
Definitions of outcomes
The efficacy of cell-based therapy was assessed using the following outcome definitions. Clinical response was defined as a reduction of at least 50% in fistula discharge. Clinical remission was defined as the closure of all treated external openings without discharge. Combined remission was defined as clinical remission together with radiological healing, with radiological healing defined as the absence of collections larger than 2 cm on magnetic resonance imaging (MRI).
Given that some meta-analyses did not distinguish between clinical remission and combined remission, and reported remission outcomes irrespective of radiological assessment, an additional composite outcome was defined as clinical and/or radiological healing. This outcome referred to fistula healing assessed either clinically alone or in combination with radiological evaluation, depending on the definitions used in the original meta-analyses. For the purposes of this umbrella review, clinical and/or radiological healing was therefore used as a unified outcome to enable the synthesis of remission data across meta-analyses with heterogeneous outcome definitions.
Data extraction
From each included meta-analysis, the following data were independently extracted by two reviewers: First author and publication year, number of studies included, total sample size, type and source of regenerative therapy, type of fistula-related disease, and summary risk estimates (relative risk, hazard ratio, or odds ratio) with corresponding 95% confidence intervals. When multiple pooled estimates were reported for different outcomes or subgroups, all clinically relevant estimates were extracted. Discrepancies in data extraction were resolved through discussion and consensus.
Assessment of review quality
The methodological quality of all included systematic reviews and meta-analyses was assessed using A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2)[21]. This instrument includes 16 items, of which seven are considered critical domains that determine the overall confidence in the results of a review. Based on AMSTAR 2 guidance, the overall methodological quality of each review was categorized as high, moderate, low, or critically low. Quality assessment was conducted independently by two reviewers, with disagreements resolved by consensus.
Data synthesis and evidence mapping
Findings from the included reviews were synthesized narratively due to heterogeneity in intervention types, fistula etiologies, and outcome measures. Stratified analyses were conducted according to: Type of regenerative therapy, source of regenerative cells or biologic products, and type of fistula-related disease. Evidence tables were constructed to summarize the key characteristics and findings of each included review. In addition, an evidence map was created to visualize the volume, direction, and consistency of the evidence. To assess the certainty of evidence, we applied the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework, following the approach outlined in a previously published umbrella review by Pollock et al[22] (Supplementary Table 3). Specifically, we applied the seven AMSTAR-2 critical domains to inform review-level risk of bias (rather than the four domains originally used by Pollock et al[22]). Prespecified downgrading criteria were applied for imprecision (based on sample size), review-level and study-level risk of bias, and inconsistency (I2 > 75%). The certainty for each outcome was graded as high, moderate, low, or very low. As recommended, we used the corrected covered area to assess the degree of overlap among the main studies included in the systematic review and adopted the standard interpretive benchmarks[23]. All graphical visualizations, including bubble plots and forest plots, were constructed using R software, utilizing the ggplot2 and forestplot packages for visualization implementation.
RESULTS
Search results
The database search identified 569 potentially relevant records across the electronic sources. After duplicate records were removed, titles and abstracts were screened, and 59 articles were assessed in full text for eligibility. Ultimately, 35 systematic reviews and/or meta-analyses[6,24-57] satisfied the inclusion criteria and were included in the evidence synthesis. The study selection process is presented in Figure 1.
Table 1 summarizes the main characteristics of the included systematic reviews and meta-analyses. Among the 35 included reviews, 6 were systematic reviews and 29 were systematic reviews with meta-analyses. The earliest publication dated back to 2005, and the most recent was published in 2025. Regarding disease categories, 19 reviews focused primarily on fistulizing Crohn’s disease (FCD)[6,24-41], while 12 reviews evaluated perianal fistulas (PF)[42-53]. In addition, a small number of reviews addressed other fistula-related conditions, including cryptoglandular fistula[57], fistula after cleft palate repair[56], oroantral communication and fistulas[55], and vesicovaginal fistula[54], with one review for each condition. In terms of interventions, MSC were the most extensively investigated therapy, reported in 24 reviews. PRP was evaluated in 8 reviews[24,42-44,54-57], while Darvadstrocel was systematically assessed in 2 reviews[35,38]. In addition, hematopoietic stem cells (HSCs) and MSC-derived exosomes were reported in 3[26,27,40] and 1[45] review(s), respectively. The control group was based on the original definitions of each systematic review. The main formulations were fibrin glue or normal saline/placebo. A few cases involved surgical intervention, and some were not clearly specified (Supplementary Table 4). Based on the corrected covered area, the degree of overlap among the included reviews was estimated to be 5.4% (n = 372 total citations, r = 131 unique primary studies, c = 35 systematic reviews), indicating a low level of overlap. The detailed process is presented in Supplementary Figure 1.
Table 1 Characteristics of included studies in the current review.
Based on the AMSTAR 2 assessment, 1 review was judged as high confidence[29], 1 as moderate confidence[26], 12 as low confidence, and 21 as critically low confidence (Supplementary Figure 2). The most frequent methodological shortcomings were failure to provide a list of excluded studies with reasons for exclusion (item 7), insufficient reporting of funding sources for the included studies (item 10), and lack of information on the possible influence of publication bias on the meta-analyses (item 15).
Summary of findings
The primary efficacy outcomes included combined remission, clinical and/or radiological healing, clinical remission, and clinical response, while safety outcomes mainly focused on AEs and serious AEs (SAEs). For comparative (two-arm) meta-analyses, evidence maps were constructed to illustrate both the direction and certainty of treatment effects (Figure 2). Color coding represents the therapeutic effect, while Bubble size reflects the certainty of evidence according to GRADE criteria. When multiple single-arm meta-analyses evaluated the same outcome, only the meta-analysis including the largest number of primary studies and participants was selected for forest plot visualization to avoid redundancy and over-representation. Forest plots summarizing efficacy and safety outcomes are shown in Figure 3A-C. According to the GRADE framework, most pooled estimates were rated as having low or very low certainty, while moderate-certainty evidence was limited and mainly confined to specific outcomes in PF and FCD. To enhance transparency, Supplementary Table 5 provides detailed effect estimates and corresponding certainty ratings for each included review.
Figure 3 Forest plots of pooled remission outcomes and pooled clinical and/or radiological healing outcomes from single-arm meta-analyses of regenerative therapies, and pooled adverse events associated with regenerative therapies.
A: Forest plots of pooled remission outcomes from single-arm meta-analyses of regenerative therapies; B: Forest plots of pooled clin/rad healing outcomes from single-arm meta-analyses of regenerative therapies; C: Forest plots of pooled adverse events associated with regenerative therapies. CI: Confidence interval; MSC: Mesenchymal stem cell; AD-MSC: Adipose-derived mesenchymal stem cell; BM-MSC: Bone marrow-derived mesenchymal stem cell; PRP: Platelet-rich plasma; CD: Crohn’s disease; HU-MSC: Human umbilical cord mesenchymal stem cell; HSC: Hematopoietic stem cell; SVF: Stromal vascular fraction; ASC: Autologous stem cell; AE: Adverse event; GRADE: Grading of Recommendations, Assessment, Development and Evaluation; W: week(s).
PF
PF, including FCD and cryptoglandular fistulas, were evaluated in 12 systematic reviews and meta-analyses, primarily assessing regenerative therapies based on MSC, PRP, and MSC-derived exosomes. Most reviews considered clinical and/or radiological healing as the primary efficacy outcome.
The findings consistently demonstrated that MSC therapies were more effective than control in achieving fistula healing. Effect sizes were generally consistent across reviews, and the certainty of evidence for MSC was mostly rated as moderate. Subgroup analyses suggested that treatment efficacy varied according to MSC type and source. Moderate-certainty evidence supported the effectiveness of adipose-derived MSC, whereas bone marrow-derived MSC did not show a statistically significant improvement compared with control, with very low-certainty evidence. Regarding cell origin, allogeneic MSC were associated with favorable healing outcomes supported by moderate-certainty evidence, while autologous MSC did not demonstrate a significant advantage over control, with low-certainty evidence. In addition, low- to moderate-certainty evidence suggested that lower or intermediate cell doses were more frequently associated with favorable healing outcomes, whereas higher doses did not confer additional benefits. Low-certainty evidence also supported the effectiveness of PRP (Figure 2).
Single-arm meta-analyses reported favorable remission and response rates. For MSC therapy, pooled effectiveness rates were 52% for combined remission, 58% for clinical and/or radiological healing, 72% for clinical remission, and 80% for clinical response. PRP and MSC-derived exosomes showed comparable effectiveness rates for combined remission (48% and 57%, respectively). Time based analyses indicated that clinical and/or radiological healing rates after MSC therapy were higher at early follow-up (71% at week 8) than the overall pooled estimate, and subsequently stabilized at 24 weeks and ≥ 48 weeks while remaining above 50%. Subgroup analyses further suggested that remission rates were broadly comparable across different MSC types and sources (Figure 3A).
FCD
Nineteen reviews focused on FCD, evaluating multiple regenerative strategies, including MSC, PRP, HSCs, Darvadstrocel, and MSC-derived exosomes. The results indicated that MSC, either alone or in combination with fibrin glue, were superior to control in terms of combined remission, clinical and/or radiological healing, and clinical response, supported by moderate-certainty evidence. Subgroup analyses showed that allogeneic MSC were associated with better fistula healing outcomes, with moderate-certainty evidence, whereas autologous MSC did not demonstrate a significant advantage overcontrol, with very low-certainty evidence. Moderate-certainty evidence also supported the effectiveness of HSCs in FCD (Figure 2).
In single-arm meta-analyses, moderate-certainty evidence showed that at 24 weeks of follow-up, MSC therapy achieved effectiveness rates of 58% for combined remission, 62% for clinical remission, and 76% for clinical response, all higher than those observed at 12 weeks or 48 weeks. Subgroup analyses suggested the pooled remission rate was 79% in studies using autologous MSC and 52% in studies using allogeneic MSC, with low certainty of evidence for both estimates. Regarding administration routes, single-arm pooled effectiveness rates were 60% for local injection and 29% for systemic administration, supported by moderate-certainty evidence. Stratification by fistula type showed effectiveness rates of 77% for PF, 76% for transsphincteric fistulas, and 27% for rectovaginal fistulas. Dose-response analyses suggested that the highest pooled effectiveness rates were observed in studies using doses of (2-4) × 107 cells. For specific MSC products, Darvadstrocel achieved combined remission rates of 61% and 70% at 24 weeks and 48 weeks, respectively. Adipose-derived MSC combined with PRP showed a pooled effectiveness rate of 86%, although the certainty of evidence was low (Figure 3A).
Cryptoglandular fistula
Six reviews evaluated cryptoglandular fistulas, focusing on MSC-based therapies and MSC-derived exosomes. Low-certainty evidence indicated that MSCs or MSC combined with fibrin glue were superior to control in achieving clinical and/or radiological healing. Single-arm meta-analyses reported effectiveness rates of 53% for MSC (moderate-certainty evidence) and 45% for MSC-derived exosomes (very low-certainty evidence).
Other fistula-related diseases
For other fistula-related conditions, including fistula after cleft palate repair, oroantral communication fistula and vesicovaginal fistula, only one systematic review was available for each condition. For fistulas after cleft palate repair, Elsamna et al[56] synthesized 5 studies involving 164 patients and evaluated the use of PRP in primary or secondary cleft palate repair. The pooled analysis showed that PRP significantly reduced the incidence of postoperative fistulas, with a pooled relative risk of 0.32 (95% confidence interval: 0.12-0.82). For oroantral communication fistula, 7 studies involving 164 patients were included[55], all of which used PRP for treatment. The overall success rate ranged from 90% to 100%. However, when the defect diameter exceeded 5 mm, platelet-derived growth factor-rich products were more suitable as adjunctive therapies. For vesicovaginal fistula, the review included two studies involving 16 patients with recurrent disease[54], all treated with transvaginal PRP injection. All patients achieved scar-free vaginal wall healing.
AEs
Fourteen systematic reviews reported safety outcomes. In patients with PF and FCD, MSC therapy did not differ significantly from control with respect to overall AE rates, with the certainty of evidence rated as moderate and low, respectively. Similarly, low-certainty evidence suggested no significant differences between MSC therapy and control regarding perianal abscesses and proctalgia. Notably, compared with control, MSC therapy was associated with a significantly lower risk of SAE, although this finding was supported only by low-certainty evidence (Figure 2). Single arm meta-analyses showed that the overall AE rates were 37% in PF and 25% in FCD, while treatment-related AEs occurred in only 1% of cases, all estimates were supported by moderate certainty evidence (Figure 3C). In patients with FCD, the incidence rates of new perianal abscesses and reoperation were 9% and 12%, respectively. Supplementary Table 6 summarizes the specific MSC-related AEs, with abscess formation and anal pain being the most commonly reported. PRP-related AEs included recurrence (18%) and fecal incontinence (27%), both supported by low-certainty evidence. For MSC-derived exosomes, the no-response rate was 18%, with very low-certainty evidence.
DISCUSSION
This umbrella review integrates evidence from 35 systematic reviews and meta-analyses and offers a broad methodological assessment of the efficacy and safety of regenerative therapies for various fistula-related diseases. The current evidence base is predominantly focused on PF and FCD, with MSC as the most extensively studied intervention, followed by PRP. Evidence for exosomes and HSC remains limited. Overall, MSC-based regenerative therapies demonstrate promising therapeutic potential in these common and refractory fistula conditions, particularly with a trend toward reduced SAE supported by low certainty evidence. However, the certainty of the overall evidence base ranges only from very low to moderate.
We constructed an evidence map stratified by disease type, follow-up duration, and regenerative modality, enabling intuitive cross-comparison of treatment strategies and patient populations while highlighting the distribution and certainty of available evidence. Compared with a recent umbrella review on stem cell therapy for fistulas[2], which did not systematically assess the quality of included reviews or construct visual evidence maps, our study provides a more comprehensive appraisal of evidence reliability.
A key challenge in fistula management is that superficial closure does not necessarily reflect resolution of deep fistula tracts or abscess cavities. Previous studies have shown that even in patients achieving clinical healing, MRI may still detect active fistulas[58], and radiological healing typically lags behind clinical remission by approximately 12 months[59]. The outcome of combined remission, integrating both clinical and radiological assessments, partially addresses the long-standing limitation of relying solely on clinical evaluation, which may overestimate treatment efficacy. Our findings indicate that, for both PF and FCD, moderate-certainty evidence supports the superiority of MSC over control in achieving combined remission, with pooled remission rates of 52% and 56%, respectively, and more than half of patients maintaining remission at 48 weeks. Compared with existing therapies, MSC appear particularly effective when evaluated against this more stringent outcome. For example, infliximab achieves a clinical remission rate of approximately 36% at 54 weeks[60], and adalimumab achieves fistula closure rates of about 33% at 48 weeks[61], with relatively low radiological healing rates. These differences suggest that MSC may confer advantages in promoting deep tissue repair and true structural healing. Time-dependent effects were also observed. Most studies focused on short to mid-term outcomes (24-48 weeks), while long-term data beyond 48 weeks were scarce. Limited long-term evidence suggests that approximately 58% of PF patients maintain healing beyond 48 weeks after MSC therapy. However, this outcome was based on clinical and/or radiological healing rather than strict combined remission and should be interpreted cautiously. Across multiple outcomes, MSC efficacy appeared to be higher at 24 weeks than at 12 weeks or 48 weeks, suggesting a possible time-dependent attenuation of effect. Given that MSC are thought to act primarily through paracrine and immunomodulatory mechanisms rather than long-term engraftment[62], this pattern may reflect limited in vivo persistence and raises the possibility that repeat dosing could be beneficial in selected patients. The local inflammatory microenvironment may further influence the therapeutic performance of MSCs. In fistula-related diseases, persistent exposure to pro-inflammatory cytokines, bacterial contamination, hypoxia, and ongoing tissue destruction may impair cell survival, reduce persistence after injection, and limit effective tissue integration[63,64]. In Crohn’s disease in particular, disruption of the intestinal epithelial barrier and sustained transmural inflammation may perpetuate immune activation and microbial translocation, thereby creating a hostile niche for regenerative repair[65]. These biological factors may contribute to inter-study variability in treatment response and may partly influence the durability of benefit over time. However, the observed temporal patterns are derived from indirect comparisons across studies rather than longitudinal within-patient analyses and therefore should not be interpreted as definitive evidence for optimal dosing intervals or retreatment strategies.
Our review further suggests that MSC type, source, and administration strategy may influence treatment outcomes. Based on the currently available evidence, adipose-derived and allogeneic MSC were associated with more favorable outcomes compared with control, with moderate certainty. In contrast, bone marrow-derived and autologous MSC have not demonstrated clear comparative advantages, with very low and low certainty, respectively. Although single-arm meta-analyses report similar absolute healing rates across MSC types and sources, these analyses lack control groups and are susceptible to confounding by baseline disease severity. Therefore, they primarily describe efficacy ranges rather than true comparative benefits. Biologically, the shared immunomodulatory and paracrine functions of different MSC types may explain similar outcomes, while the superiority of allogeneic MSC may be due to manufacturing consistency and not necessarily to biological superiority. Regarding administration routes, moderate-certainty evidence supports local injection over systemic delivery, which is biologically plausible given the higher local cell concentration and potential synergy with surgical debridement[66]. Overall, adipose-derived, allogeneic MSC delivered locally appear to be the most evidence-supported strategy at present, while conclusions regarding bone marrow-derived and autologous MSC remain limited by low-certainty evidence.
The optimal MSC dose for fistula treatment remains undefined. Although one might intuitively assume a dose-response relationship, our umbrella review suggests that a dose of (2-4) × 107 MSC was associated with higher effectiveness than other dose ranges, albeit with very low certainty. This counterintuitive finding may reflect the confined inflammatory environment of fistulas, where excessive cell numbers could increase local pressure, exudation, or hypoxia due to cell aggregation. Several studies have adopted individualized dosing strategies based on fistula size assessed by probes and MRI[67,68], reporting favorable outcomes. However, these trials were limited by small sample sizes and short follow-up. Large, multicenter randomized controlled trials with standardized dosing protocols are needed to clarify optimal dose ranges and personalization strategies.
While MSC currently represent the most evidence-supported regenerative therapy, PRP, HSCs, and MSC-derived exosomes also show potential benefits, though the supporting evidence is largely of low or very low certainty and often derived from single reviews with limited primary studies. These interventions should therefore be regarded as promising but exploratory and are not yet suitable for routine clinical recommendation.
Cost considerations are also critical for the clinical implementation of cell-based therapies, particularly MSC. However, cost and cost-effectiveness outcomes were rarely reported in the included reviews, limiting economic evaluation. Real-world data from Sweden suggest that the average societal cost per patient with newly diagnosed anal fistula is approximately €5561, with direct medical costs accounting for 80%. Notably, approximately 36% of patients require multiple surgical procedures, with this subgroup undergoing an average of more than four surgeries. As a result, the mean total cost per patient in this group rises to €10978, which is substantially higher than that observed in patients undergoing only a single or no surgical intervention. These findings highlight disease recurrence and repeated interventions as the principal drivers of escalating costs. Against this background, decision-analytic modeling studies have estimated that, in patients with FCD, the expected total cost of a single administration of allogeneic and autologous MSC is approximately USD 13536 and USD 7536, respectively[69]. Although MSC therapy is associated with high upfront costs, its potential to reduce recurrence rates, shorten disease duration, and decrease the need for repeat surgeries, hospitalizations, and sick leave suggests that it may offer long-term economic advantages in terms of healthcare resource utilization and societal costs. Nevertheless, current evidence regarding the economic value of MSC therapy is largely derived from modeling studies, while real-world cost data and prospective cost-effectiveness analyses remain scarce. This is a major barrier to adoption. Furthermore, cost variability related to MSC source, manufacturing processes, dosing frequency, and differences across healthcare systems further complicates interpretation. Future randomized controlled trials and real-world studies should therefore systematically incorporate cost-effectiveness outcomes to more robustly define the economic value of MSC therapies.
In terms of safety, our synthesis indicates that MSC therapy does not significantly increase overall AE rates compared with control. Treatment-related AEs, which were predominantly mild and procedure-related (e.g., local injection-site reactions), occurred in approximately 1% of cases and were supported by moderate-certainty evidence. Importantly, low-certainty evidence suggests a reduced risk of sAEs in patients with FCD. Given the frequent history of immunosuppressive therapy and repeated surgeries in this population, this finding is clinically meaningful. However, interpretation should remain cautious, as commonly reported AEs such as abscess formation and anal pain may reflect disease progression or procedural complications rather than direct treatment effects, and AE reporting and attribution varied substantially across studies. Moreover, safety reporting across the included reviews and primary studies was inconsistent, and long-term follow-up was often insufficient to assess recurrence or delayed adverse outcomes. Future studies would benefit from a core outcome set incorporating standardized safety endpoints, recurrence measures, and prespecified assessment time points. Where feasible, safety analyses should distinguish short-term and long-term findings and prioritize follow-up of at least 12 months. Standardized reporting metrics, such as events per patient-year, and linkage with registry or real-world data sources may further strengthen long-term safety assessment.
From a clinical perspective, non-cellular sphincter-preserving approaches such as anal fistula plugs and fibrin glue have reported healing rates ranging from approximately 30% to 60% in previous studies[70,71], with considerable variability across patient populations and fistula complexity. While direct comparisons cannot be made due to differences in study design and eligibility criteria, the pooled remission rates observed for MSC therapies appear to fall within or above this reported range. These observations provide contextual insight but should not be interpreted as evidence of comparative superiority.
Several limitations should be considered. This review focused exclusively on cell-based regenerative therapies to evaluate active cellular mechanisms, which limited comparisons with other non-cellular biologic approaches such as anal fistula plugs and fibrin glue. As a result, the findings should be interpreted within the context of regenerative cellular strategies rather than the full spectrum of sphincter-preserving treatments for anal fistula. We restricted inclusion to English-language publications, which may have introduced language bias, although the majority of high-quality systematic reviews in this field are published in English. The definitions of control intervention measures vary across various systematic reviews, and some reports are insufficient. This study has been reported faithfully as per the original text and has been summarized in the Supplementary material. However, this may still affect the interpretation of the results. According to the AMSTAR 2 criteria, most included systematic reviews were rated as having low or critically low confidence. Methodological shortcomings directly compromise the reliability of the evidence; reviews with critically low confidence may overestimate or underestimate treatment effects, thereby affecting the robustness of the pooled conclusions and their clinical applicability. Another key limitation was poor characterization of concomitant therapies and other major confounders. In clinical practice, MSC therapy is often combined with biologics, immunomodulators, antibiotics, or surgical drainage, but these co-interventions were inadequately reported in most included reviews. As an umbrella review, we could not extract trial-level co-intervention data or conduct adjusted analyses. Future de novo reviews should systematically collect data on co-interventions, disease severity, and prior treatment history, and assess their impact through stratified, adjusted, or ideally individual patient data meta-analyses. Future studies should also report resource use and economic outcomes, such as hospitalization, reoperation, and direct costs.
Looking forward, advances in artificial intelligence may further refine imaging-based assessment of perianal disease. For example, recent deep learning-based MRI analyses have demonstrated high diagnostic accuracy for fistula identification and classification[72], suggesting a potential role for more objective and reproducible imaging endpoints in future regenerative therapy trials. Additionally, future systematic reviews and meta-analyses should prioritize methodological rigor and transparent reporting.
CONCLUSION
This umbrella review provides an integrated synthesis of the currently available evidence on cell-based regenerative therapies for fistula-related diseases. Among these approaches, MSC-based therapy appears the most promising for PF and FCD, with possible benefits in combined remission and healing outcomes and no clear increase in overall AEs. Nevertheless, the overall certainty of the evidence is limited by methodological weaknesses of the included reviews, heterogeneity across studies, and inadequate adjustment for concomitant treatments. These findings should therefore be interpreted with caution, and more rigorous studies are required before firm clinical recommendations can be made.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge the support and contributions of all individuals and groups who played a pivotal role in the development and completion of this manuscript.
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P-Reviewer: Jeong KY, Assistant Professor, PhD, South Korea; Zhang W, PhD, Post Doctoral Researcher, China S-Editor: Wang JJ L-Editor: A P-Editor: Zhao YQ
