Stem cells repurpose proliferation to contain a breach in their niche barrier

Abstract

Adult stem cells are responsible for life-long tissue maintenance. They reside in and interact with specialized tissue microenvironments (niches). Using murine hair follicle as a model, we show that when junctional perturbations in the niche disrupt barrier function, adjacent stem cells dramatically change their transcriptome independent of bacterial invasion and become capable of directly signaling to and recruiting immune cells. Additionally, these stem cells elevate cell cycle transcripts which reduce their quiescence threshold, enabling them to selectively proliferate within this microenvironment of immune distress cues. However, rather than mobilizing to fuel new tissue regeneration, these ectopically proliferative stem cells remain within their niche to contain the breach. Together, our findings expose a potential communication relay system that operates from the niche to the stem cells to the immune system and back. The repurposing of proliferation by these stem cells patch the breached barrier, stoke the immune response and restore niche integrity.

Defining Epidermal Stem Cell Fate Infidelity and Immunogenicity in Hidradenitis Suppurativa at the Single-Cell Resolution

“…It has been demonstrated in mouse models that the loss of key transcription factor Foxc1 in HF stem cells leads the inability to maintain their cells fate 34,35 , and further, the reduction of Ecadherin 35 . Moreover, in the case of complete loss of E-cad in HF stem cell niche, Cldn1 expression is down-regulated, while Ccl2 expression is upregulated, which leads to immune cell recruitment, independent of bacterial invasion 36 . These changes are consistent with the potential development of the sinus tract in HS: FOXC1 and CDH1 expression is downregulated, and CCL2 is upregulated in the HS sinus tract compared with normal infundibulum and HS infundibulum ( Figure 3E and Sup Figure 8).…”

Defining trained immunity and its role in health and disease

“…www.nature.com/nri are equipped with receptors to sense whether the epithelial barrier is breached and, in turn, actively recruit immune cells to prevent spread of bacteria and to repair the damage 7 . Although it is still unfolding, the molecular communication avenue between stem cells and immune cells appears to be bidirectional.…”

“…Stem cells do not merely take instructions but rather they also actively instruct the immune system. In the skin, for example, stem cells can sense when their niche barrier is breached and produce signals to recruit specific immune cell sentinels, even under conditions where the immune system itself has been suppressed 7 . In turn, recruited immune cells can signal to stem cells to proliferate and patch the barrier.…”

“…For a long time it was assumed that immunological memory was an exclusive hallmark of the adaptive immune response. However, a growing body of literature indicating that innate immune cells -and even tissue-resident stem cells -can show adaptive characteristics has challenged this dogma [4][5][6][7][8] . Greater protection against reinfection -a de facto immune memory function -has also been reported in plants and invertebrates [9][10][11] , which lack an adaptive immune system.…”

Choreographing Immunity in the Skin Epithelial Barrier

“…This pattern of chemokine expression is essential for recruiting LC precursors and DCs to sites of minor trauma, while keeping them away from the follicle stem cell niche, presumably to protect the stem cells from immune-mediated damage (Nagao et al, 2012). By contrast, barrier disruption caused by genetic ablation of adherens junction proteins from bulge stem cells and their suprabasal ''inner'' bulge cells uniquely induces CCL2 production by the inner bulge that results in corralling of immune cells, in particular DCs, around the bulge (Lay et al, 2018).…”