J Crohns Colitis. 2020 Apr 22. pii: jjaa079. doi: 10.1093/ecco-jcc/jjaa079. [Epub ahead of print]

Cell therapy with mesenchymal stem cells induces an innate immune memory response that attenuates experimental colitis in the long-term.

Lopez-Santalla M^1,2, Hervas-Salcedo R^1,2, Fernandez-Garcia M^1,2, Bueren JA^1,2, Garin MI^1,2.

Abstract

BACKGROUND AND AIMS:

Mesenchymal stem cells (MSCs) are used, in preclinical and clinical studies, for treatment of immune-mediated disorders thanks to their immunomodulatory properties. Cell therapy with MSCs induces multiple effects in the immune system that ultimately leads to increase the number of immune cells with regulatory phenotype. In this study, we investigated whether the beneficial effects of MSC therapy are maintained in the long-term in a clinically relevant mouse model of colitis.

METHODS:

A single dose of adipose-derived MSCs (aMSCs) was infused into dextran sulfate sodium (DSS)-induced colitic mice during the induction phase of the disease. Following a latency period of twelve weeks, mice were re-challenged with a second 7-day cycle of DSS.

RESULTS:

DSS-induced colitic mice treated with aMSCs showed significant reduction in their colitic disease activity index during the second DSS challenge when compared to non-aMSC-treated DSS-induced colitic mice. Strikingly, the long-term protection induced by aMSC therapy was also observed in Rag-1-/- mice where no adaptive immune memory cell responses take place. Increased percentages of Ly6G+CD11b+ myeloid cells were observed 12 weeks after the first inflammatory challenge in the peritoneal cavity, spleen and bone marrow of DSS-induced colitic mice that were infused with aMSCs. Interestingly, upon re-challenge with DSS, these animals showed a concomitant increase in the regulatory/inflammatory macrophage ratio in the colon lamina propria.

CONCLUSIONS:

Our findings demonstrate for the first time that MSC therapy can imprint an innate immune memory-like response in mice that confers sustained protection to acute inflammation in the long-term.

© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.