Lifelong tissue memory relies on spatially organized dedicated progenitors located distally from the injury [scRNAseq_gradient]

It is believed epithelial cells that have participated in a wound repair elicit a more efficient but locally  restricted response to future injuries. However here we show that the cell adaptation resulting from a localised tissue damage has a wide spatial impact at a scale not previously noticed. We demonstrate that away from injured site, after a first injury a specific epithelial stem cell population gives rise to long term wound-memory progenitors residing in their own niche of origin. Notably these progenitors have not taken part in the first wound healing but become pre-activated through priming. This adaptation differs from classical features of trained immunity previously shown to be adopted by other epithelial stem cells. Our newly identified wound-distal memory cells display an intrinsic pre-activated state, maintained at chromatin and transcriptional level, leading to an enhanced wound repair ability that can be partially recapitulated through epigenetic perturbation even in absence of an injury. Importantly, the harmful consequences of wound repair, such as exacerbated tumorigenesis, occur within these primed cells and follow their spatial distribution. Overall, we show that sub-organ scale adaptation of an injury relies on spatially organized and memory-dedicated progenitors, characterized by a chromatin actionable cell state, that establishes an epigenetic field cancerization and predisposes to tumour onset. Lrig1 GL cells were isolated from tail epidermis at 8w pw1 time point. Sca1+ cells were sorted to enrich for upper-HF cells into lysis buffer and processed for scRNA-seq, using the Smart-Seq2 protocol