Improved efficacy of mesenchymal stromal cells stably expressing CXCR4 and IL-10 in a xenogeneic graft versus host disease mouse model

• Published in: Frontiers in immunology Vol. 14; p. 1062086
• Main Authors: Hervás-Salcedo, Rosario, Fernández-García, María, Hernando-Rodríguez, Miriam, Suárez-Cabrera, Cristian, Bueren, Juan A, Yáñez, Rosa M
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 01.02.2023
• Subjects: Animals; CXCR4; Cytokines - metabolism; graft vs host disease; Graft vs Host Disease - metabolism; Humans; IL10; Immunology; immunomodulation; Interleukin-10 - metabolism; Mesenchymal Stem Cells - metabolism; mesenchymal stromal cells; Mice; Receptors, CXCR4 - metabolism; stem cell therapy; Transplantation, Homologous; IL10; immunomodulation; graft vs host disease; stem cell therapy; mesenchymal stromal cells; CXCR4; lentiviral vector
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2023.1062086

Previous clinical trials have shown that mesenchymal stromal cells (MSCs) can modulate graft versus host disease (GvHD) after allogeneic hematopoietic transplantation, although with variable efficacy. To improve the anti-GvHD effect of these cells, adipose tissue derived-human MSCs (Ad-MSCs) were transduced with a lentiviral vector conferring stable expression of CXCR4, a molecule involved in cell migration to inflamed sites, and IL-10, a cytokine with potent anti-inflammatory properties. experiments showed that the expression of these molecules in Ad-MSCs (named CXCR4-IL10-MSCs) efficiently enhanced their migration towards SDF-1α and also improved their immunomodulatory properties compared to unmodified Ad-MSCs (WT-MSCs). Moreover, using a humanized GvHD mouse model, CXCR4-IL10-MSCs showed improved therapeutic effects, which were confirmed by histopathologic analysis in the target organs. Additionally, compared to WT-MSCs, CXCR4-IL10-MSCs induced a more marked reduction in the number of pro-inflammatory Th1 and Th17 cells, a higher polarization towards an anti-inflammatory T cell profile (CD3 -IL10 cells), and increased the number of regulatory T and B cells. Our and studies strongly suggest that CXCR4-IL10-MSCs should constitute an important new generation of MSCs for the treatment of GvHD in patients transplanted with allogeneic hematopoietic grafts.