Table 2.
Summarizes the Preclinical Studies on MSCs for the Treatment of IBD Completed in Recent Years
| Author/Time References | Animal Model | SCs Sources | SCs Route | SCs Dose (Cells) | Follow-Up Period | Primary Outcomes |
|---|---|---|---|---|---|---|
| Barnhoorn (2020)145 | DSS-induced colitis | BM-MSC | IP | 2 × 106 cells | 11 days | MSCs after in vivo aggregation show a favorable RNA expression profile for the treatment of colitis. MSCs spheroids showed high expression of Ki-67 and low levels of apoptotic marker cleaved caspase-3. Locally applied MSCs and MSCs spheroids are both able to ameliorate DSS-induced colitis and show similar clinical effects. |
| Barnhoorn (2020)145 | DSS-induced colitis | BM-MSC | Endoscopic | 2 × 106 cells | 4–6 days | Endoscopic injection can be a feasible and effective novel application route for MSCs therapy in patients with luminal IBD. |
| Chao (2016)146 | TNBS-induced colitis | UCBSC | IP | 10×106 cells | 14 days | The mortality in UCBSC-treated TNBS mice was 20% (55% in colitis model). IL-20 and TGF-Beta were significantly higher in UCBSC-treated mice (p = 0.04 and 0.02 respectively). |
| Cheng (2017)147 | DSS-induced colitis | BM-MSC | IV | 5×106 cells | 8 days | IL-25-MSCs treatment significantly attenuate the colon shortening (12 ± 0.62 cm); IL-25 could enhance immunomodulatory ability of MSCs via inhibiting Th17 immune response and promoting the regulation of Tregs cells. |
| de Aguiar (2018)148 | DSS-induced colitis | ASCs | IP | 10×106 cells | 7 days | ASCs-treated mice did not present severe reduction in colon length, and presented a reduced tissue damage score index (3). Significant reduction of IFN-gamma and TNF-Alpha, and reduction of IL-6 and MCP-1 protein levels. ASCs treatment reduced DCs and macrophages presence in the colon. |
| de Aguiar (2018)148 | DSS-induced colitis | ASCs | IP | 2 × 106 cells | 7 days | ASCs ameliorated the severity of DSS-induced colitis, reducing colitis pathological score and preventing colon shortening. |
| de la Portilla (2013)149 | TNBS-induced colitis | ASCs | Local | 60×106 cells | 24 weeks | First study which shows the homing migration of ASCs to areas of experimentally-induced colitis following rectal installation. |
| de la Portilla (2018)150 | TNBS-induced colitis | ASCs | Local | 2 × 106 cells | 10 days | There were no differences in component rectal wall thicknesses with a higher Hunter score in the treated group compared with the controls. |
| Fu (2017)151 | TNBS-induced colitis | ASCs | IP | 2 × 106 cells | 6 days | Decrease the weight loss and DAI score, MPO activity. Reduced levels of ROR and IL-17A; inhibited STAT3 phosphorylation, but increased STAT5 phosphorylation. |
| González-Rey (2009)152 | DSS-induced chronic colitis | ASCs | IP | 10×106 cells | 27 days | ASCs treatment protects against DSS-induced acute colitis as well as chronic severe colitis (p 0.01 and p 0.001 respectively); reduces colonic inflammatory responses in DSS-induced chronic colitis (p 0.001). |
| Gregoire (2018)153 | Fistula Crohn’s disease | ASCs | Local | (3−30) ×106 cells | 8 weeks | 6/8 fistulas healed, 2/8 improved. |
| Heidari (2021)56 | DSS-induced colitis | ASCs | IP | 10×106 cells | 34 days | There was no significant difference in the survival rate among the study groups; however, there was a significant increase in terms of the colon length (p 0.005). In the treated mice the level of mucosal damage was significantly lower (p 0.005). |
| Heidari (2021)56 | DSS-induced colitis | ASCs | IP | 2 × 106 cells | 34 days | The regulatory effects of ASCs and their CM in inflammatory conditions because of colitis. |
| In Kap (2010)137 | DSS-induced colitis | MSCs | IV | 1 × 106 cells | 7 days | Anti-addressin Ab coating on MSCs increased cell delivery to inflamed colon and increased the efficacy of MSCs treatment of IBD. |
| Jianxia Hu (2016)154 | Luminal Crohn’s disease | UCBSC | IV | 0.5×106 cells | 3 months | 30/36 patients showed good response and diffuse and deep ulcer formation and severe inflammatory mucosa were improved markedly. |
| Lee (2016)155 | DSS-induced colitis | BM-MSC | IV | 10×106 cells | 33 days | IL-10 production was upregulated by about 10-fold in BM-MSC-treated mice and showed a preventive effect on weight loss. |
| Lee (2016)155 | DSS-induced colitis | BM-MSC | IV | 30×106 cells | 33 days | Infusion of BM-MSC at the onset of disease exerted preventive and rapid recovery effects. |
| Lee (2018)156 | DSS-induced colitis | UCBSC | IP | 2×106 cells | 12 days | The survival rate was further increased by co-treatment compared to UCBSC or MIS416 single treatments; colon lengths were significantly increased in cotreatment; colonic inflammation was more effectively resolved by co-treatment with MIS416 and UCBSC, and only co-treatment markedly decreased fibrosis and enhanced tissue regeneration. |
| Legaki (2016)147 | DSS-induced colitis | ASCs | IP | 1.5×106 cells 200 µL /dose |
7 days | CM treatment significantly decreased the extension and severity of the inflammation in comparison to the DSS-treated mice; the relative expression levels of IL-10 mRNA were significantly increased, and TGFb1 was significantly higher (p 0.0001). |
| Mao (2017)157 | DSS-induced colitis | UCBSC | IV | 1.3×106 cells | 11 days | Exosomes from MSC have profound effects on alleviating DSS-induced IBD and may exert their impact through the modulation of IL-7 expression in macrophages. |
| Martín (2018)103 | TNBS-induced colitis | ASCs | Local | 10×106 cells | 11 days | Submucosal injection of human ASCs ameliorates the course of TNBS colitis in immunocompetent rats. |
| Martin Arranz (2018)158 | TNBS-induced colitis | ASCs | Endoscopic | 10× 06 cells | 11 days | The endoscopic score improved in the ASCs group by 47.1% ± 5.3% vs 21.8% ± 6.6% in the vehicle group. |
| Miyamoto (2017)159 | TNBS-induced colitis | ASCs | IV and Local | 1×106 cells IV and 400 µL Local |
7 days | ASCs transplantation significantly decreased the number of neutrophils, attenuated acute inflammation. In the TNBS-CM gel group ulcers were shallow and bleeding was not detected, therefore improved endoscopic score. In the gel group mRNA expression levels of TNF-Alpha, CXCL1, CCL2 and IL-6 were increased. |
| Molendijk (2015)160 | Fistula Crohn’s disease | BM-MSC | Local | 10,30, 90×106 cells | 6, 12, 24 weeks | At week twelve, 3 of 9 individual fistulas had healed in group 1 (33.3%), 6 of 7 had healed in group 2 (85.7%), 2 of 7 had healed in group 3 (28.6%), and 3 of 9 had healed in the placebo group (33.3%). |
| Pak (2018)161 | DSS-induced colitis | BM-MSC ASCs |
Endoscopic | 8×105, 1.1×106 cells | 1–3 days | The success rate was 37.60% for ASCs group and 35.20% for BM-MSC group. |
| Panés (2016)109 | Fistula Crohn’s disease | ASCs | Local | 120×106 cells | 24 weeks | Remission in the ITT (53 of 107 [50%] vs 36 of 105 [34%]; difference 15.2%, 97.5% CI 0.2–30.3; p = 0.024) C × 601 vs placebo. |
| Panés (2018)157 | Fistula Crohn’s disease | ASCs | Local | 120×106 cells | 52 weeks | C × 601 achieved combined remission (56.3%) vs controls (38.6%). |
| Park (2018)109 | DSS-induced colitis | ASCs | IP | 10×106 cells | 20 days | The results suggest that PGE2, produced by co-culture of ASCs and THP-1, reduces M1 population, decreased the frequency of macrophage transition. |
| Park (2018)162 | DSS-induced colitis | ASCs | IP | 2 × 106 cells | 20 days | ASCs can suppress the inflammatory response by controlling the macrophage population, and ASCs may be therapeutically useful for the treatment of IBD. |
| Pouya (2018)163 | DSS-induced colitis | MSCs | IP | 500 µL, ×3 | 10 days | After infusion, colon inflammation was reduced and histopathological analysis showed a decrease in mucosal degeneration. |
| Song (2017)164 | DSS-induced colitis | MSC-Exo UCBSC |
IP | 150µg 10×106 cells; |
36 days | MSC-Exo ameliorates the clinical parameters in DSS-induced colitis; the treated group showed significantly less MPO activity. The level of IL-17 was significantly decreased, whereas those of IL-10 and TGF-Beta1 were increased. |
| Song (2018)165 | DSS-induced colitis | Canine ASCs | IP | 2×106 + TSG-6 siRNA | 10 days | ASCs-secreted TSG-6 reduced inflammatory response and apoptosis in the colon; intraperitoneally infused ASCs did not migrate to the inflamed colon; increased M2 macrophages in the inflamed colon. |
| Soontararak (2018)48 | DSS-induced colitis | iMSCs ASCs |
IV | 3 × 106 cells | 19 days | Colonic tissues from mice treated with either iMSCs or ASCs exhibited an overall reduction in transmural inflammation, with significantly less infiltration of inflammatory. Cells in the lamina propria, diminished mucosal ulceration and decreased mucosal collapse and granulation tissue formation. |
| Tanaka (2008)166 | DSS-induced colitis | BM-MSC | IV | 5 × 106 cells | 7 days | In the rectum of treated rats the mRNA expression of TNF-alpha and IL-1Beta was markedly decreased to (43.7 ± 25.5% p 0.05 and 14.5 ± 12% p 0.01 respectively), as well as COX-2 16.5 ± 15.2% (p 0.01). |
| Tanaka (2008)166 | DSS-induced colitis | MSCs | IV | 5 × 106 cells | 7 days | Exogenous MSCs accumulated in inflamed tissues and ameliorated DSS-induced colitis via a local anti-inflammatory action. |
| Wang (2016)130 | DSS-induced colitis | BM-MSC | IP | 0.5×106 cells | 10 days | Intraperitoneal injection is the best delivery way for MSCs: showed better mucosa recovery and higher cell engraftment at inflamed colon. |
| Wu (2018)167 | DSS-induced colitis | UCBSC | IV | 400µg UC-MSC | 11 days | Exosomes from UCBSCs have profound effects on alleviating DSS-induced IBD and may exert their function by regulating the ubiquitin modification level. |
| Xu (2018)168 | DSS-induced colitis | ERC | IV | 3 × 106 cells | 10 days | ERC treatment significantly reduced the levels of TNF-Alpha, IL-1Beta and IL-6; ERC downregulated the expanded Th1 and Th17 cells in colitis, and elevated the proportion of Tregs in lymphocytes; ERC inhibited B-cell activation, differentiation and IgG production in colitis. |
| Yu (2017)169 | DSS-induced colitis | T-MSCs | IP | 20,40, × 106 cells | 30 days | Co-culture with T-MSCs clearly inhibited the PMA-stimulated proliferation of splenocytes by 60%; T-MSCs [×4] treated mice’s survival rate was improved to that of the normal. T-MSCs [×2] injection also significantly improved the survival rate to 89% of the control. T-MSCs [×4] treatment inhibits DSS-induced colon shortening. |
Abbreviations: AF-MSC, Amniotic fluid Mesenchymal stem cell; ASCs, adipose mesenchymal stem cells; BM-MSCs, Bone marrow mesenchymal stem cells; CCL2, Chemokine Ligand 2; CD, Crohn’s disease; CXCL1, Chemokine Ligand 1; DAI, Disease activity index; DCs, Dendritic cells; DSS, Dextran Sulfate Sodium Salt; ERC, Endometrial regenerative cells; IBD, Inflammatory bowel disease; IFN-γ, interferon-γ; IL-10, interleukin-10; IL-17A, interleukin-17A; IL-1β, interleukin-1β; IL-20, interleukin-20; IL-25, interleukin-25; IL-6, interleukin-6; IL-7, interleukin-7; iMSCs, mesenchymal stem cells derived from induced pluripotent stem cells; IP, intraperitoneal injection; iPSCs, induced pluripotent stem cells; IV, intravenous injection; MCP-1, Monocyte Chemotactic Protein-1; MPO, myeloperoxidase; MSC-Exo, Mesenchymal stem cell exosomes; MSCs, mesenchymal stem cells; MSCT, mesenchymal stem cells transplantation; PFCD, perianal fistula Crohn’s disease; PGE2, prostaglandin E2; PMA, THP-1 nuclear extract lysate; ROR, Retinoic acid related orphan receptor; SCs, stem cells; STAT3, signal transducer and activator of translation-3; TGF-β, transforming growth factor-β; THP-1, Tohoku Hospital Pediatrics-1; T-MSCs, Tonsil MSCs; TNBS, 2,4,6-trinitro-Benzenesulfonic acid; TNF-alpha, tumor necrosis factor alpha; TSG-6, tumor necrosis factor α stimulated gene-6; UCBSCs, Umbilical Cord Blood stem cells.