Umbilical cord mesenchymal stromal cells transplantation delays the onset of hyperglycemia in the RIP-B7.1 mouse model of experimental autoimmune diabetes through multiple immunosuppressive and anti-inflammatory responses

C C Lachaud; N Cobo-Vuilleumier; E Fuente-Martin; I Diaz; E Andreu; G M Cahuana; J R Tejedo; A Hmadcha; B R Gauthier; B Soria

doi:10.3389/fcell.2023.1089817

Umbilical cord mesenchymal stromal cells transplantation delays the onset of hyperglycemia in the RIP-B7.1 mouse model of experimental autoimmune diabetes through multiple immunosuppressive and anti-inflammatory responses

Front Cell Dev Biol. 2023 Feb 15:11:1089817. doi: 10.3389/fcell.2023.1089817. eCollection 2023.

Authors

C C Lachaud¹, N Cobo-Vuilleumier¹, E Fuente-Martin¹, I Diaz¹, E Andreu^{2

3}, G M Cahuana^{4

5}, J R Tejedo^{4

5}, A Hmadcha^{5

6}, B R Gauthier^{1

4}, B Soria^{2

4

5}

Affiliations

¹ Department of Cell Therapy and Regeneration, Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain.
² Institute of Bioengineering and Health Research Institute (ISABIAL), Dr. Balmis University Hospital (HGUA), Miguel Hernández University School of Medicine, Alicante, Spain.
³ Department of Applied Physics, University Miguel Hernández, Alicante, Spain.
⁴ Biomedical Research Network on Diabetes and Related Metabolic Diseases (CIBERDEM), Institute of Health Carlos III, Madrid, Spain.
⁵ Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, Seville, Spain.
⁶ Instituto de Investigación Biosanitaria, Universidad Internacional de Valencia (VIU), Valencia, Spain.

Abstract

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder specifically targeting pancreatic islet beta cells. Despite many efforts focused on identifying new therapies able to counteract this autoimmune attack and/or stimulate beta cells regeneration, TD1M remains without effective clinical treatments providing no clear advantages over the conventional treatment with insulin. We previously postulated that both the inflammatory and immune responses and beta cell survival/regeneration must be simultaneously targeted to blunt the progression of disease. Umbilical cord-derived mesenchymal stromal cells (UC-MSC) exhibit anti-inflammatory, trophic, immunomodulatory and regenerative properties and have shown some beneficial yet controversial effects in clinical trials for T1DM. In order to clarify conflicting results, we herein dissected the cellular and molecular events derived from UC-MSC intraperitoneal administration (i.p.) in the RIP-B7.1 mouse model of experimental autoimmune diabetes. Intraperitoneal (i.p.) transplantation of heterologous mouse UC-MSC delayed the onset of diabetes in RIP-B7.1 mice. Importantly, UC-MSC i. p. transplantation led to a strong peritoneal recruitment of myeloid-derived suppressor cells (MDSC) followed by multiple T-, B- and myeloid cells immunosuppressive responses in peritoneal fluid cells, spleen, pancreatic lymph nodes and the pancreas, which displayed significantly reduced insulitis and pancreatic infiltration of T and B Cells and pro-inflammatory macrophages. Altogether, these results suggest that UC-MSC i. p. transplantation can block or delay the development of hyperglycemia through suppression of inflammation and the immune attack.

Keywords: UC-MSC; experimental autoimmune diabetes; immunomodulation; inflammation; insulitis, Type I diabetes mellitus, RIP-B7.1; intraperitoneal transplantation.

Grants and funding

This research was financed by the financial support from Institute of Health Carlos III (Co-funded by Fondos FEDER), for the projects to BS (PI14/01015 and PI-0272-2017, and Programme RETICS, call 2016 (RD16/0011/0034 discontinued in 3-5-19 by Fundación Progreso y Salud). Projects ICI21/00016 (IS Carlos III) and Agencia Valenciana de Innovacion Projects AVI-GVA COVID-19-68 and GVA-COVI19/2021/047 to BS PAIDI group CTS576, and by the European Regional Development Fund (FEDER) and the Consejería de Economía, Conocimiento, Empresas y Universidades de la Junta de Andalucía, within the framework of the operational program FEDER Andalucía 2014–2020. Specific Objective 1.2.3 “Promotion and generation of Frontier knowledge and knowledge oriented to the challenges of society, development of emerging technologies” led the reference research project (UPO-1381598) of JT.