Fibroblasts-microbiome crosstalk in tissue regeneration and fibrosis: unraveling novel therapeutic targets through single nucleus RNA-seq, multi-omics and spatial analysis

Upon injury or disease, most human organs yield fibrotic tissue resulting in permanent scars and the failure of tissue function, compromising the health span and lifespan of affected individuals. Organ fibrosis is influenced by a myriad of factors, including fibroblast heterogeneity, the activated signal transduction pathways and environmental cues. Fibroblasts hold a central role in fibrosis, yet a nuanced understanding of their heterogeneity driving regenerative versus fibrotic healing remains elusive. Recently, it was shown that the microbiome regulates inflammation and extracellular matrix remodeling. However, the microbiota function in tissue regeneration and fibrosis is poorly characterized. Integrating microbiome insights into anti-fibrotic approaches is an uncharted territory. REGENER-OMIX aims at investigating: 1. fibroblast heterogeneity and, specifically, the microbial components-recognizing fibroblasts, and the wound microbiome in the regenerative oral mucosa and pro-fibrotic skin; 2. the fibroblasts-microbiome crosstalk through spatial analysis; 3. the role of the microbiome in the healing outcome toward regeneration or fibrosis.To address these objectives, I will leverage advanced transgenic models, cutting-edge single nucleus RNA-seq, multi-omics and spatial biology techniques through a novel and interdisciplinary approach. The project (36 months) will unravel the interactions between fibroblasts and microbiome, and their functional role in regeneration and fibrosis. This study will offer new avenues to manipulate the healing process and antagonize fibrosis-associated pathologies.I will combine the strengths of a USA-based research group, world-leading expert in wound healing and fibrosis, with the expertise of a world-renowned Europe-based laboratory, who pioneered host-microbiome research. This sets the stage for a unique environment for my postdoctoral training, knowledge exchange and new research lines to be explored.