Background and Aims: Adipose -derived mesenchymal Stromal Cells (ASCs) have emerged since a decade as a promising therapeutic tool due to their ability to migrate to injured tissues, modulate immune responses, and promote tissue repair. However, the biological functions and therapeutic efficacy of ASCs are dependent on their tissue of origin and can be further enhanced through pharmaceutical or cytokine-based pre-activation. As we were looking for the most effective ASCs to treat skin lesions, we studied the biological function of ASCs isolated from an atypical adipose tissue, the buccal fat pad (BFP), which is located in the facial area and is a rich source of ASCs. The BFP is commonly used in maxillofacial surgery but the therapeutic properties of the BFP-ASCs remain poorly characterized.

Methodology : To do so, we analyzed transcriptomic, phenotypic and functional analysis of human BFP-ASCs that we compare to subcutaneous adipose tissue-derived ASCs (SC-ASCs) obtained from the same patient during organ removal. Transcriptomic results lead to the comparison of migration capacity, using Incucyte cell migration assay, and immunosuppressive functions using flow cytometry and ELISA.

Results: Transcriptomic analysis confirms that BFP-ASCs have a distinct embryological origin compared to SC-ASCs and shows that BFP-ASCs exhibit lower expression of genes associated with cell migration. Our migration assays demonstrated that BFP-ASCs display less migration ability than SC-ASCs, and this is associated with a weak FAK-RhoA signaling activation and fewer stress fibers. Moreover, BFP-ASCs are more immunosuppressive against T lymphocytes and induce macrophages with a more pro-resolutive phenotype than SC-ASCs. In parallel, to potentiate their therapeutic capacity, several molecules have been tested to enhance migration and immunomodulation capacity of SC- and BFP-ASCs. We identified molecule T as a potent enhancer of BFP-ASCs migration. Interestingly, molecule T also boosts the immunosuppressive capacity of BFP-ASCs by upregulating gene expression of key immunomodulatory molecules such as IDO and COX2. Similar results were obtained with SC-ASCs pre-treated with molecule T.

Conclusion: In conclusion, BFP-ASCs represent a promising therapeutic cell source and molecule T offers a novel strategy to generate "super-migratory" and "super-immunosuppressive" ASCs, providing innovative tools to control inflammation, to stimulate tissue repair and treat inflammatory diseases.