Smoking Suppresses the Therapeutic Potential of Adipose Stem Cells in Crohn’s Disease Patients through Epigenetic Changes

Abstract

Cell therapy; Chronic inflammatory disease; Cigarette

Terapia celular; Enfermedad inflamatoria crónica; Cigarrillo

Teràpia cel·lular; Malaltia inflamatòria crònica; Cigarret

Patients with Crohn’s disease (CD) who smoke are known to have a worse prognosis than never-smokers and a higher risk for post-surgical recurrence, whereas patients who quit smoking after surgery have significantly lower post-operative recurrence. The hypothesis was that smoking induces epigenetic changes that impair the capacity of adipose stem cells (ASCs) to suppress the immune system. It was also questioned whether this impairment remains in ex-smokers with CD. ASCs were isolated from non-smokers, smokers and ex-smokers with CD and their interactions with immune cells were studied. The ASCs from both smokers and ex-smokers promoted macrophage polarization to an M1 pro-inflammatory phenotype, were not able to inhibit T- and B-cell proliferation in vitro and enhanced the gene and protein expression of inflammatory markers including interleukin-1b. Genome-wide epigenetic analysis using two different bioinformatic approaches revealed significant changes in the methylation patterns of genes that are critical for wound healing, immune and metabolic response and p53-mediated DNA damage response in ASCs from smokers and ex-smokers with CD. In conclusion, cigarette smoking induces a pro-inflammatory epigenetic signature in ASCs that likely compromises their therapeutic potential.

This study was supported by a grant from the Spanish Ministry of Economy and Competitiveness (PI18/00037 to CS), co-financed by the European Regional Development Fund (ERDF). C.S. acknowledges support from “Ramón y Cajal’ program from the Ministerio de Educación y Ciencia (RYC2013-13186), co-financed by the ERDF. A.B.-T. acknowledge support from PI-AGAUR 2022-B00577. I.V. acknowledges support from INVESTIGO-AGAUR (100036TC2). D.M.-F. acknowledges support from PERIS-PFI-Salut SLT01720000021.