Inflammatory bowel diseases (IBDs) affect millions of people worldwide and their frequencies in developed countries have increased since the twentieth century. In this context, there is an intensive search for therapies that modulate inflammation and provide tissue regeneration in IBDs. Recently, the immunomodulatory activity of adipose tissue-derived mesenchymal stromal cells (ADMSCs) has been demonstrated to play an important role on several immune cells in different conditions of inflammatory and autoimmune diseases. In this study, we explored the immunomodulatory potential of ADMSC in a classical model of DSS-induced colitis. First, we found that treatment of mice with ADMSC ameliorated the severity of DSS-induced colitis, reducing colitis pathological score and preventing colon shortening. Moreover, a prominent reduction of pro-inflammatory cytokines levels (i.e., IFN-γ, TNF-α, IL-6 and MCP-1) was observed in the colon of animals treated with ADMSC. We also observed a significant reduction in the frequencies of macrophages (F4/80+CD11b+) and dendritic cells (CD11c+CD103+) in the intestinal lamina propria of ADMSC-treated mice. Finally, we detected the up-regulation of immunoregulatory-associated molecules in intestine of mice treated with ADMSCs (i.e., elevated arginase-1 and IL-10). Thus, this present study demonstrated that ADMSC modulates the overall gut inflammation (cell activation and recruitment) in experimental colitis, providing support to the further development of new strategies in the treatment of intestinal diseases.
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We would like to thank Paulo Albe for histological assistance, Meire Hiyane and Cláudia Silva Cunha for technical support and the members of Câmara’s laboratory for their comments and suggestions. This study was supported by grants from the following funding agencies: Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP (Grant numbers: 2012/02270-2, 2012/16794-3 and 2013/25327-2), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).
All applicable national and institutional guidelines (Brazilian Federal law 6638) for the care and use of animals were followed. All procedures performed in this study involving animals were in accordance with the ethical standards of the institution and after approval by the Animal Care Committee of University of São Paulo-Register number: 122/2012.
Conflict of interest
The authors declare that they have no competing interests.
This study was supported by grants from the following funding agencies: FAPESP (Grant numbers: 2012/02270-2, 2012/16794-3 and 2013/25327-2), CAPES and CNPq.
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Supplementary Fig. 1 Analysis of TNF-α in the colon Quantification of TNFα in intestinal extract by ELISA. n = 3-6 animals/group. Representative results of two independent experiments. WT ctr = control group; WT DSS = vehicle-injected colitis group (DSS2.5% + PBS); WT DSS + ADMSC = colitis group injected with adipose tissue-derived mesenchymal stromal cells (ADMSC) on days 1 and 5. *p < 0.05 (TIFF 4816 kb)
Supplementary Fig. 2 Representative dot plots of flow cytometry analysis of colonic lamina propria leucocytes (A)(upper panel) and mesenteric lymph nodes (B)(lower panel). (TIFF 17744 kb)
Supplementary Fig. 3 (A) Representative graph of the median fluorescence intensity (MFI) of CD206 expression on lamina propria macrophages. (B) Frequency of dendritic cells expressing CD40 in the intestinal lamina propria. WT ctr = control group; WT DSS = vehicle-injected colitis group (DSS2.5% + PBS); WT DSS + ADMSC = colitis group injected with adipose tissue-derived mesenchymal stromal cells (ADMSC) on days 1 and 5. DCs = dendritic cells. a.u. = arbitrary units. *p < 0.05. (TIFF 9670 kb)
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de Aguiar, C.F., Castoldi, A., Andrade-Oliveira, V. et al. Mesenchymal stromal cells modulate gut inflammation in experimental colitis. Inflammopharmacol 26, 251–260 (2018). https://doi.org/10.1007/s10787-017-0404-6