Intestinal mesenchymal cells regulate immune responses and promote epithelial regeneration in vitro and in dextran sulfate sodium-induced experimental colitis in mice Hidalgo García, Laura Molina Tijeras, José Alberto Huertas Peña, Francisco José Ruiz Malagón, Antonio Jesús Díez Echave, Patricia Vezza, Teresa Rodríguez Sojo, María Jesús Morón Romero, María Rocío Becerra Massare, Patricia Rodríguez Nogales, Alba Gálvez Peralta, Julio Juan Rodríguez Cabezas, María Elena Anderson, Per Olof Dextran sulfate sodium colitis Immunomodulation Inflammatory bowel disease Intestinal mesenchymal cells Wound healing This work was funded by the Junta de Andalucia (CTS 164) and by the Instituto de Salud Carlos III (Spain) and Fondo Europeo de Desarrollo Regional (FEDER), from the European Union, through the research grants PI18/00826, PI0206-2016 and PI19/01058. L.H-G and A.J.R-M are predoctoral fellows funded by the Spanish Ministry of Science and Innovation ("Programa de Doctorado: Medicina Clinica y Salud Publica" B12.56.1). J.A.M-T is a predoctoral fellow from the Instituto de Salud Carlos III (FI17/00176). P.A is supported by the Consejeria de Salud, Junta de Andalucia through the contract "Nicolas Monardes" (C-0013-2018). A. R-N is a postdoctoral fellow from the Instituto de Salud Carlos III (Miguel Servet program [CP19/00191]). CIBER-EHD is funded by the Instituto de Salud Carlos III. We would like to express our gratitude to Dr E. Aksoy and Dr L. Medrano Gonzalez (William Harvey Research Institute, Queen Mary University of London, London, UK) for providing us the cell line NCM356. Additionally, we thank Juan N. Moliz, Ana Santos and Mohamed Tassi of the Centre for Scientific Instrumentation (CIC, University of Granada) for their technical guidance and assistance. Aim Disruption of the intestinal mucosal tolerance, that is, the immunological unresponsiveness to innocuous food antigens and the commensal microbiota, in the colon is associated with several chronic diseases including inflammatory bowel disease (IBD). Understanding the mechanisms responsible for intestinal mucosal tolerance has potential translational value for its therapy and management. Human intestinal mesenchymal cells (iMCs) play important roles in colonic mucosal tolerance, but further studies on their tissue regenerative and immunomodulatory capacities are necessary in order to fully understand their function in health and disease. Methods In this study, we have isolated and analysed the capacity of human iMCs to promote wound healing and modulate immune responses in vitro and in vivo, using the dextran sulfate sodium (DSS)-induced colitis model. Results Cultured iMCs were CD45(-)CD73(+)CD90(+)CD105(+) and accelerated the wound closure in a normal colon mucosa (NCM) 356 human epithelial cell wound healing assay. Furthermore, iMCs blocked the LPS-mediated induction of TNF-alpha in THP-1 macrophages and inhibited the proliferation of peripheral blood mononuclear cells, partly through the induction of indoleamine-2,3-dioxygenase. In DSS colitic mice, iMCs administration reduced the disease activity index and ameliorated intestinal tissue damage and permeability. Furthermore, iMCs reduced intestinal inflammation, evidenced by a decreased mRNA expression of pro-inflammatory cytokines, reduced IL-1 beta secretion by intestinal explants and inhibited colonic iNOS protein expression. Conclusions Our data show that human iMCs isolated from the noninflamed intestine possess tissue-regenerative and immunomodulatory capacities that could potentially be harnessed/restored in order to reduce IBD severity. 2021-07-13T09:57:54Z 2021-07-13T09:57:54Z 2021-06-05 journal article Hidalgo-Garcia, L... [et al.]. Intestinal mesenchymal cells regulate immune responses and promote epithelial regeneration in vitro and in dextran sulfate sodium-induced experimental colitis in mice. Acta Physiol. 2021; 00:e13699. [https://doi.org/10.1111/apha.13699] http://hdl.handle.net/10481/69663 10.1111/apha.13699 eng http://creativecommons.org/licenses/by-nc/3.0/es/ open access Atribución-NoComercial 3.0 España Wiley-Blackwell Publishing