Lifelong tissue memory relies on spatially organised dedicated progenitors located distally from the injury

Abstract

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 a cell-autonomous transcriptional pre-activated state 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 organised and memory-dedicated progenitors, characterised by an epigenetic actionable cell state, that predisposes to tumour onset.

New insights into inflammatory memory of epidermal stem cells

“…These newly identified wound-distal memory cells display a cell-autonomous transcriptional pre-activated state, enhancing wound repair ability. When the damage has been resolved, and new homeostasis has been re-set, Lrig1 + SCs derived cells remain transcriptionally pre-activated ( 13 ).…”

“…Multiple studies found that repeat inflammatory stimuli can induce inflammatory memory in EpdSCs, resulting in related gene mutations and keratinocyte abnormal proliferation and differentiation ( 12 , 13 , 87 ). Chickens infected with the Rous sarcoma virus usually develop tumors along the wound site after an injury ( 88 ).…”

“…Chickens infected with the Rous sarcoma virus usually develop tumors along the wound site after an injury ( 88 ). In mice, inflammatory memory of EpdSCs after subsequent tissue damage increased the susceptibility to cancer ( 12 , 13 ). In addition, inflammatory training of tumorigenic cells can confer enhanced cancer susceptibility in human ( 89 ).…”

“…Recently, Levron et al. reported a new wound-distal memory of progenitors derived from SCs in adult mice’s hair follicle junctional zone ( 13 ).…”

“…When the skin is injured at the same site, this memory of EpdSCs can contribute to a quicker re-epithelialization process (12). Recently, Levron et al reported a new wound-distal memory of progenitors derived from SCs in adult mice's hair follicle junctional zone (13).…”