Enhanced anti-inflammatory effects of mesenchymal stromal cells mediated by the transient ectopic expression of CXCR4 and IL10

Stem Cell Research & Therapy

Pablo Minguez¹  Carmen Ayuso¹  Rosa María Yañez²  Jose-Carlos Segovia²  María Luisa Lamana²  Miriam Hernando-Rodríguez²  Rosario Hervás-Salcedo²  María Fernández-García²  Oscar Quintana-Bustamante²  Juan A. Bueren²  Marta Rodríguez de Alba³  Mariano García-Arranz³  Damián García-Olmo³  Victoria del Pozo⁴  Marcio Alvarez-Silva⁵ 

[1] Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain;Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain;Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Av. Complutense 40, 28040, Madrid, Spain;Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain;Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain;Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain;Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain;Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain;Stem Cell and Bioengineering Laboratory, Universidade Federal de Santa Catarina, Florianópolis, Brazil;

关键词: Mesenchymal stromal cells;    CXCR4;    IL10;    mRNA-modified MSCs;    Inflammation;    MSC homing;   

DOI  :  10.1186/s13287-021-02193-0

来源: Springer

【 摘 要 】

BackgroundMesenchymal stromal cells (MSCs) constitute one of the cell types most frequently used in cell therapy. Although several studies have shown the efficacy of these cells to modulate inflammation in different animal models, the results obtained in human clinical trials have been more modest. Here, we aimed at improving the therapeutic properties of MSCs by inducing a transient expression of two molecules that could enhance two different properties of these cells. With the purpose of improving MSC migration towards inflamed sites, we induced a transient expression of the C-X-C chemokine receptor type 4 (CXCR4). Additionally, to augment the anti-inflammatory properties of MSCs, a transient expression of the anti-inflammatory cytokine, interleukin 10 (IL10), was also induced.MethodsHuman adipose tissue-derived MSCs were transfected with messenger RNAs carrying the codon-optimized versions of CXCR4 and/or IL10. mRNA-transfected MSCs were then studied, first to evaluate whether the characteristic phenotype of MSCs was modified. Additionally, in vitro and also in vivo studies in an LPS-induced inflamed pad model were conducted to evaluate the impact associated to the transient expression of CXCR4 and/or IL10 in MSCs.ResultsTransfection of MSCs with CXCR4 and/or IL10 mRNAs induced a transient expression of these molecules without modifying the characteristic phenotype of MSCs. In vitro studies then revealed that the ectopic expression of CXCR4 significantly enhanced the migration of MSCs towards SDF-1, while an increased immunosuppression was associated with the ectopic expression of IL10. Finally, in vivo experiments showed that the co-expression of CXCR4 and IL10 increased the homing of MSCs into inflamed pads and induced an enhanced anti-inflammatory effect, compared to wild-type MSCs.ConclusionsOur results demonstrate that the transient co-expression of CXCR4 and IL10 enhances the therapeutic potential of MSCs in a local inflammation mouse model, suggesting that these mRNA-modified cells may constitute a new step in the development of more efficient cell therapies for the treatment of inflammatory diseases.

【 授权许可】

CC BY