Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a group of chronic, relapsing inflammatory diseases of the gastrointestinal tract of undetermined etiology, particularly in CD, where recurrence of previously healed fistulas is common1. Current therapeutic strategies mainly focus on inflammation modulation, but prolonged immunosuppression may lead to complications such as infection and malignancy2,3. In addition, there is a lack of reliable, minimally invasive clinical biomarkers to predict disease progression or treatment response. Stem cell therapy has become a research hotspot for IBD treatment due to its multidirectional differentiation potential, immunomodulatory properties, and pro-repair ability. A recent breakthrough study published in Advanced Science by Professor Yu’s team at Zhejiang University has brought essential innovations to stem cell therapy for IBD. The study developed and evaluated a therapeutic approach using enemas containing human amniotic epithelial stem cells (hAESCs) loaded into an adhesion peptide-modified hydrogel. It accelerated the restoration of intestinal barrier function in an experimental colitis model. The study reveals for the first time that the exosomal miR-23a-TNFR1-NF-κB signaling pathway is the key mechanism of action of this treatment protocol4. However, the clinical development landscape of stem cell therapies in the overall IBD population is unclear. By systematically analyzing global clinical trial data, this paper aims to elucidate the current research status, trends, and challenges of stem cell therapy for IBD and to provide an evidence-based basis for future research directions. Based on the Trialtrove database (https://www.citeline.com/en), using keywords including (“stem cell” OR “mesenchymal stromal cell” OR “MSC” OR “amniotic epithelial stem cell”) AND (“inflammatory bowel disease” OR “IBD” OR “Crohn’s disease” OR “ulcerative colitis”) date as of May 2025, 162 clinical trials were monitored. Details of included clinical trials are provided in Supplemental Digital Content Methods, available at: https://links.lww.com/JS9/F809. This study has been reported in line with the TITAN (Transparent and Complete Reporting of Surgical Innovations, New Techniques, and Technologies) criteria5. Clinical trials of stem cell therapy for IBD started in 2004, and the number fluctuated until 2016 and peaked in 2020 (Fig. 1A), with the United States (36) and China (26) dominating the clinical trials of stem cell therapy for IBD (Fig. 1B). These trials predominantly target Crohn’s disease (CD), with many advancing to late stages (Phase III/IV). In contrast, studies involving ulcerative colitis (UC) are less frequent and confined mainly to early-phase testing (Phase I/II). While the majority of trials are “Completed,” a high proportion, particularly in the Crohn’s Disease space, have been “Terminated.” This termination rate, often attributed to recruitment difficulties, underscores the substantial practical and logistical barriers hindering the broader clinical translation of these therapies. (Fig. 1C). Figure 1.: Stem cell therapy for IBD clinical trials overview and outlook. (A) Trends in newly initiated clinical trials by year. (B) Geographic distribution of stem cell therapy for IBD clinical trials. The darker the color, the higher the number of trials conducted. (C) Distribution of trial status and trial stage of different disease types. (D) Anal fistula status and drug resistance for different IBD disease types. (E) E1. Bubble chart showing the distribution of clinical trials across phases (I–IV) for different stem cell types. E2. Bubble size represents trial count; color indicates disease type. E3. Stacked area plot demonstrating the temporal trend of trial status completion rates through development phases – heatmap visualization of trial frequency by stem cell type and disease indication. Numerical values indicate absolute counts. IBD, inflammatory bowel disease. Clinical trials of stem cell therapies in IBD are biased in favor of CD, especially in fistulizing and treatment-resistant patients, accounting for more than 70% of the trials. In contrast, UC-related trials are fewer and mostly in treatment-resistant patients, highlighting that clinical research focuses more on the refractory complications of CD (Fig. 1D). Adipose-derived MSCs (AD-MSCs) and bone marrow-derived MSCs (BM-MSCs) are the most commonly used stem cell types in IBD clinical trials (over 60% of the total), mainly targeting CD (especially phase III/IV trials). In contrast, umbilical cord-derived MSCs (UC-MSCs) are more often used in early-stage studies (phase I/II) in UC (Fig. 1E1–3). According to Table 1, 25 clinical trials have reported results. Therapies using adipose- and bone marrow-derived MSCs have demonstrated specific efficacy in treating perianal fistulas in Crohn’s Disease. For instance, studies reported clinical and radiological fistula healing rates ranging from 50% to 83% at 12 months post-treatment. Regarding safety, the most commonly reported adverse events included injection site pain and abscess formation. While the overall safety profile was favorable, a risk of fistula recurrence and infection was noted in some patient cohorts. Table 1 - A summary of key studies in clinical trials of stem cell therapy for IBD: cell types, disease indications, and efficacy outcomes Protocol/trial ID Types of stem cells Trial phase Trial status Disease Outcome details TrialTroveID-577618 UC-MSCs I Completed UC Intravenous UC-MSCs were well-tolerated and induced sustained remission in 60% of patients with active UC. TrialTroveID-577591 MSCs III Completed CD This suggests that MSCs with pCD can lead to clinical radiological improvement TrialTroveID-545648 MSCs II Completed CD Safety and feasibility of hematopoietic stem cell injection in the treatment of PF in CD TrialTroveID-512 613 AD-MSCs (Cx601) IV Completed CD As a result, the success rate of CD and PF with darvadstrocel is 61%. TrialTroveID-506332 BM-MSCs I/II Completed CD The administration of allogeneic BMSCs for PF in CD demonstrates a favorable safety profile and leads to measurable improvements in both clinical and radiological outcomes. TrialTroveID-456161 MSCs IV Completed CD The short-term effect and safety of MSCs in the perianal area are also expected. TrialTroveID-430727 AD-MSCs IV Completed CD Darvadstrocel may be an effective and safe treatment for complex perianal conditions that are refractory. TrialTroveID-430576 BM-MSCs IV Completed CD The study showed that injection of locally prepared bone marrow MSCs in refractory PF in CD appears to be safe and effective. TrialTroveID-413858 MSCs I/II Completed CD The role of MSCs, combined with the proven effects of endoscopic balloon dilation, may improve outcomes in CD stenosis. NCT04791878 BM-MSCs I Completed CD Bone marrow-derived MSCs represent a promising therapeutic option for pediatric perianal fistulizing CD, demonstrating a favorable safety profile and promoting fistula healing in preliminary studies. NCT04519684 BM-MSCs I/II Completed CD Bone marrow-derived allogeneic MSCs provide a safe and effective alternative treatment for pericystic fistulas and peripouch fistulas of the CD -like pouch phenotype TrialTroveID-365779 BM-MSCs I/II Completed CD Treatment with allogeneic BMSCs for perianal fistulizing CD led to a reduction in clinical severity and promoted radiological healing, and was generally well-tolerated. ChiCTR1900026035 UC-MSCs I/II Completed UC The study showed clinical remission of refractory ulcerative colitis TrialTroveID-353113 PMSCs IV Completed CD Intrafistular administration of hPDMSCs gel matrix appears to be a safe, convenient, and effective treatment for PF in patients with CD. NCT03706456 AD-MSCs III Completed CD Combination remission was achieved at week 24 (primary endpoint) and week 52 in 59.1% and 68.2% of patients, respectively. TrialTroveID-321468 BM-MSCs II Completed Ulcerative Colitis Topical administration of allogeneic BM-MSCs appears to be safe, tolerable, and feasible for the treatment of refractory UP and shows encouraging signs of clinical efficacy. TrialTroveID-319453 MSCs IV Completed CD Our data suggest that CD34-selected aHSCT may be a highly effective treatment in refractory CD populations, but is associated with a high incidence of febrile neutropenia and infection. NCT02520843 AD-MSCs I/II Completed CD This first study evaluates the co-topical administration of ADSVF in association with fat grafting as a simple, safe, and effective surgical regenerative therapy NCT03279081 AD-MSCs (Cx601) III Completed CD The safety profile of darvadstrocel was consistent with previous studies, and no new safety signals were identified. NCT01440699 AD-MSCs (ALLO-ASCs) I/II Completed CD Allogeneic adipose-derived stem cells (ALLO-ASCs) are tolerable, safe, and have demonstrated efficacy and feasibility in the treatment of Crohn’s fistula. NCT01541579 AD-MSCs (Cx601) III Completed CD A single injection of Cx601 was statistically superior to placebo in terms of combined relief of complex PF. NCT01314079 AD-MSCs II Completed CD ASC treatment in patients with Crohn’s fistula is well tolerated, and the treatment response is good. NCT01155362 PMSCs (PDA001) II Completed CD A two-infusion regimen of PDA001 induces a clinical response in patients with moderate to severe CD. More research is needed to optimize efficacy and safety. NCT01372969 AD-MSCs (Cx601) I/II Completed CD Cx601 has a good safety profile, and the bowel is better at closing and reducing draining fistulas than after untreated treatment. NCT00294112 MSCs II Completed CD A statistically significant decrease in the CDAI score was observed. AD-MSCs, adipose-derived mesenchymal stem cells; ADSVF, adipose-derived stromal vascular fraction; ALLO-ASCs, allogeneic adipose-derived stem cells; ASC, adipose-derived stem cell; aHSCT, autologous hematopoietic stem cell transplantation; BM-MSCs, bone marrow-derived mesenchymal stem cells; BMSCs, bone marrow stem cells; CDAI, Crohn’s disease activity index; CD, Crohn’s disease; hPDMSCs, human placenta-derived mesenchymal stem cells; IBD, inflammatory bowel disease; MSCs, mesenchymal stem cells; PF, perianal fistula; PMSCs, placenta-derived mesenchymal stem cells; pCD, perianal Crohn’s disease; UC, ulcerative colitis; UC-MSCs, umbilical cord-derived mesenchymal stem cells; UP, ulcerative pouch. However, despite progress in the use of biologics (e.g., anti-TNF-α, anti-integrin agents), there is still a substantial unmet clinical need. Approximately 30%–40% of patients exhibit primary non-response to biologics, while 30% experience secondary loss of response6. Conditions such as fistulizing CD, intestinal stenosis, and other severe disease phenotypes are particularly challenging to treat. The present analysis indicates that stem cell therapies (especially MSCs) may address these refractory cases through their dual immunomodulatory and tissue-regenerative properties, which form a mechanistic basis for treating complex inflammatory and fistulizing conditions7. AD-MSCs and BM-MSCs re the most widely used in clinical trials, mainly for CD with fistula. However, currently, adipose MSCs (Alofisel®) remain the only approved stem cell therapy for CD with fistula, while other MSCs are in the trial stage. The treatment paradigm for inflammatory bowel disease (IBD) is undergoing a fundamental shift, moving from symptom control toward the goal of achieving durable mucosal healing and functional restoration. Stem cell therapy is central to this transformation, representing a novel therapeutic avenue for patients refractory to traditional biologic agents due to its dual potential for immunomodulation and tissue regeneration8.To advance this field, future research must be conducted on multiple interrelated levels. At the basic research level, this means going beyond a general understanding of immune regulation to elucidate specific therapeutic mechanisms mediated by exosomes and other factors, and developing next-generation technology platforms such as engineered CAR-MSCs or innovative biomaterial delivery systems to enhance targeting and efficacy9. At the clinical application level, demonstrating the long-term efficacy of stem cell therapy and determining the optimal treatment regimen remain key challenges facing ongoing large-scale trials. Additionally, the path from scientific innovation to patient benefit is constrained by a complex policy and regulatory environment. Guidance principles issued by regulatory agencies, such as the U.S. FDA and the European EMA, establish stringent requirements for advanced therapy medicinal products (ATMPs). These requirements, particularly concerning manufacturing process validation, product consistency, potency assays, and long-term stability, must be addressed to enable industrial-scale production and commercialization. Fulfilling the promise of stem cell therapy will require collaborative efforts among scientists, clinicians, industry, and regulatory agencies. This multi-stakeholder collaboration is critical to overcoming current bottlenecks and ultimately translating cutting-edge science into true disease-modifying therapies that provide long-lasting, treatment-free remission for patients with IBD.
Lu et al. (Wed,) studied this question.