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

Abstract

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.

Factors Defining Human Adipose Stem/Stromal Cell Immunomodulation in Vitro

“…The impact of inflammatory diseases on the immunosuppressive properties of hASCs has been extensively investigated to include RD [ 46 , 47 , 96 , 112 , 231 , 247 – 257 ], T2D [ 67 , 109 , 156 , 258 ], sepsis [ 259 ], Crohn’s disease [ 260 – 263 ], ulcerative colitis [ 264 ], breast cancer [ 265 – 269 ], osteoporosis [ 270 ], psoriasis vulgaris [ 140 ], Parkinson's disease [ 271 ], and atherosclerosis [ 272 ]. The results are contradictory from diseased ASCs having intact immunomodulatory functions to impaired immunosuppressive effects.…”

“…With except of TNF-α , in hASCs isolated from patients with inactive disease, almost the expression levels of all those genes were comparable to the control level, indicating that immune system genes affected by methylation marks were partially restored in patients during episodes of remission [ 262 ]. Importantly, cigarette smoking favored the pro-inflammatory epigenetic changes and the blunted immunosuppressive functions of hASCs from patients with active CD [ 263 ].…”