Stem cell- and extracellular vesicle-based therapies for perianal fistulizing Crohn’s disease: An updated review

Table 1 Summary of stem cell-based therapies in perianal fistulizing Crohn’s disease[20-33]

	Stem cells/sources	Clinical/preclinical trials	Year	Duration of study	Key findings	Ref.
1	MSCs (sourced from bone marrow or adipose tissue)	Clinical trial II and III	2025	Up to 52 weeks	Complete fistula closure was observed in 71% of PFCD patients	Guillo et al[20]
2	MSC therapy	Clinical, radiological and patient-reported	2025	60 months	5 years patients experienced sustained radiological healing (16.7%)	Anand Mr et al[21]
3	Allogeneic adipose-derived MSCs	Real-world, observational cohort study	2024	14 months	61% of patients achieved and maintained clinical remission	White et al[22]
4	Allogeneic bone marrow-derived mesenchymal stromal cells	Open-label, phase I/II, single-arm study	2024	Up to 104 weeks	70% achieved fistula response (≥ 50% decrease in drainage) after 24 weeks	Swaroop et al[23]
5	Bone marrow-derived MSCs	3-phase IB/IIA randomized, placebo-controlled, single-blinded trials (perianal, rectovaginal, ileal pouch fistulas)	2024	12 months	67.7% perianal, 37.5% rectovaginal, and 46.2% peripouch fistula healing after 12 months	Lightner et al[24]
6	Allogeneic expanded adipose-derived stem cells (Cx601)	Phase III randomized, double-blind, placebo-controlled clinical trial	2018	52 weeks	56.3% combined remission and 59.2% clinical remission after 1 year	Panés et al[25]
7	Allogeneic adipose-derived stem cells (ADSCs, Cx601, Darvadstrocel, Alofisel®)	Clinical application and mechanistic review	2021	Not specified	ADSCs showed strong anti-inflammatory, immunomodulatory, anti-apoptotic, and pro-angiogenic properties, were superior to BM-MSCs in several ways, effective in refractory Crohn’s perianal fistulas, Cx601/Alofisel approved by EMA	Buscail et al[26]
8	Human amnion epithelial cells	Phase I open-label clinical trial	2023	52 weeks	Complete response in 4/10 patients, partial response in 4/10, significant improvements in fistula healing	Keung et al[27]
9	Stem cell transplantation with or without anti-TNF therapy	Retrospective clinical cohort study	2024	66 months	76.9% complete closure, anti-TNF therapy did not significantly improve closure rates	Park et al[28]
10	Allogeneic adipose-derived stem cells	Multicenter, open-label, dose-escalation pilot study	2016	8 weeks	Complete closure in 3 out of 6 patients, closure sustained up to 8 months	Park et al[29]
11	HESC-derived MSCs	Canine anal furunculosis in dogs	2016	6 months	HESC-MSCs were well-tolerated, reduced IL-2 and IL-6 levels, complete fistula healing after 3 months, partial relapse in 2 dogs after 6 months	Ferrer et al[30]
12	Adipose-derived allogeneic stem cells	Open-label clinical trial on dogs with refractory spontaneous perianal fistulas	2024	12-48 months	100% fistula closure after 1 month	Enciso et al[31]
13	Human bone marrow-derived mesenchymal stem cells	Animal study (SAMP-1/YitFc murine model of chronic small intestinal inflammation)	2024	28 days	HMSCs inhibited naive T cell proliferation via PGE2, reprogrammed macrophages to an anti-inflammatory phenotype, promoted early mucosal healing, achieved complete mucosal, histological, immunologic, and radiological healing by day 28	Dave et al[32]
14	Mesenchymal stromal cells from adipose tissue, bone marrow, or umbilical cord	Preclinical (not specified)	2014		MSC therapy (both autologous and allogeneic) is safe and potentially effective for refractory fistulizing CD, with ongoing phase III trials. MSCs show immunomodulatory effects	Liew et al[33]

MSCs: Mesenchymal stem cells; PFCD: Perianal fistulizing Crohn’s disease; ADSC: Allogeneic adipose-derived stem cell; BM-MSC: Bone marrow-derived mesenchymal stem cell; EMA: European Medicines Agency; TNF: Tumor necrosis factor; HESC: Human embryonic stem cell; IL: Interleukin; HMSC: Human bone marrow-derived mesenchymal stem cell; PGE2: Prostaglandin E2; CD: Crohn’s disease.