From mesenchymal stem cells to myoblast cell sheets: A next-generation regenerative concept for fistulizing Crohn’s disease

Table 1 Summary of key clinical studies evaluating mesenchymal stem cell therapy in Crohn’s disease

Ref.	Country	n (control vs MSC)	Autologous/allogeneic	Cell type/product	Follow-up	Main outcomes
Molendijk et al[48], 2015	Netherlands	6 vs 15	Allogeneic	BM-MSC	24 weeks	Fistula healing 40% vs 0%; good safety
Panés et al[42], 2016	Europe/Israel	107 vs 105	Allogeneic	AD-MSC (Cx601, darvadstrocel)	24 weeks	Combined remission 50% vs 34%; similar safety
Panés et al[6], 2018	Europe/Israel	103 vs 102	Allogeneic	AD-MSC (Cx601)	52 weeks	Sustained remission 56% vs 36%
Zhou et al[49], 2020	China	11 vs 11	Autologous	AD-MSC	52 weeks	Healing 63.6%; CDAI & PDAI improved; safe
Garcia-Olmo et al[50], 2022	Europe/Israel	15 vs 25	Allogeneic	AD-MSC (Cx601)	104 weeks	Sustained closure approximately 65%; no long-term safety issues
Lightner et al[51], 2023	United States	2-4 vs 4-15	Allogeneic	BM-MSC/Remestemcel-L	6 weeks to 3 months	Fistula healing; CDAI & CRP improvement; acceptable safety
Lindsay et al[52], 2017	United Kingdom	9 vs 13	Autologous	HSC	48 weeks	CDAI, SES-CD, IBDQ, MARIA, PRO2 improved; reversible AEs

MSC: Mesenchymal stem cells; BM-MSC: Bone marrow-derived mesenchymal stem cells; AD-MSC: Adipose-derived mesenchymal stem cells; CDAI: Crohn’s Disease Activity Index; PDAI: Perianal Disease Activity Index; CRP: C-reactive protein; HSC: Hematopoietic stem cell; SES-CD: Simple Endoscopic Score for Crohn’s Disease; IBDQ: Inflammatory Bowel Disease Questionnaire; AEs: Adverse events.

Table 2 Comparative studies of mesenchymal stem cell sheets and cell suspensions across different disease models

Ref.	Model	MSC source	Comparison	Outcome type	Main outcome
Gao et al[62], 2022	Porcine myocardial infarction	hUC-MSC	Cell sheet vs suspension	Functional recovery	Cell sheets improved cardiac function and reduced infarct size more effectively than MSC suspension
Takemura et al[66], 2020	Rat diabetic nephropathy	AD-MSC	Cell sheet vs IV suspension	Anti-inflammatory/anti-fibrotic	Cell sheets showed greater attenuation of renal inflammation and fibrosis than suspended MSCs
Imafuku et al[65], 2019	Rat renal ischemia-reperfusion injury	BM-MSC	Cell sheet vs IV suspension	Anti-fibrotic	Cell sheets more effectively reduced renal fibrosis and preserved microvasculature than MSC suspension
Chen et al[63], 2017	Mouse skin wound/subcutaneous implantation	AD-MSC	Cell sheet vs suspension	Retention/paracrine activity	Cell sheets exhibited higher cell retention and stronger paracrine factor secretion than suspended MSCs
Long et al[64], 2014	Mouse critical-sized femoral defect	BM-MSC	Cell sheet vs suspension	Structural regeneration	Cell sheets promoted superior bone regeneration and graft integration compared with MSC suspension
Qi et al[67], 2014	Rabbit cartilage/meniscal defect	BM-MSC	Cell sheet vs suspension	Cartilage repair	Cell sheets achieved better matrix deposition and defect repair than injected MSCs

Overall, mesenchymal stem cell sheet-based delivery showed superior therapeutic efficacy compared with mesenchymal stem cell suspension, as evidenced by improved cell retention, enhanced paracrine activity, and better tissue repair. MSC: Mesenchymal stem cell; hUC-MSC: Human umbilical cord-derived mesenchymal stem cell; AD-MSC: Adipose-derived mesenchymal stem cell; BM-MSC: Bone marrow-derived mesenchymal stem cell.

Table 3 Comparison between mesenchymal stem cell therapy and myoblast cell sheet therapy

Item	MSC therapy	Myoblast cell sheet therapy
Main effect	Immunomodulation and improvement of the local inflammatory environment	Local repair with potential muscle layer reconstruction
Delivery	Usually local injection; cells may be easily lost	Transplanted as a cell sheet, with better local retention
Repair pattern	Regulatory repair	Potential structural support and repair
Evidence in CD	Supported by several clinical studies	Direct evidence remains limited
Potential role	Promotes fistula closure and inflammation control	May support tissue reconstruction in complex fistulas

MSC: Mesenchymal stem cell; CD: Crohn’s disease.