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Memory beyond immunity

Memory beyond immunity
Memory beyond immunity

Stem cells remember to heal X I NG DAI T he ability of stem cells to promote healing decreases with age. But, it now emerges, their previous experience also matters. Naik and colleagues provide compelling evidence that the healing potential of skin is enhanced by previous exposure to chemical, mechanical or microbial stimuli even in the absence of key cell types of the immune system. Thus, remember-ing inflammation is not a job that is restricted to immune cells — it is also undertaken by adult stem cells for the sake of tissue fitness. The results provide a glimpse into a previously unknown aspect of stem-cell biology.Naik et al. found that many regions of chromatin in EpSCs became more open (and so more permissive to transcription of the genes packaged within them) during inflam-mation. Some of these changes persisted long after inflammation subsided. Whether persistent regions of open chromatin truly act as ‘memory carriers’ that causally confer a healing advantage remains to be proved. But in support of this idea, the researchers demonstrated that genes associated with these open chromatin domains, such as Aim2, were among the earliest to be activated in response to a subsequent injury. A fundamental issue yet to be investigated is how inflammation-induced chromatin changes are initiated and maintained at a mechanistic level.Do all inflammation-sensitized EpSCs carry the same chromatin changes? Naik et al . found that the magnitude of inflammation-induced open chromatin across EpSC populations diminished over time after the first inflam-matory event. Perhaps some EpSCs undergo differentiation to become mature skin cells, and so are no longer present in the authors’ analyses. Alternatively, this finding could indi-cate that only a subset of inflammation-experi-enced EpSCs retain regions of open chromatin.If a memory EpSC subset does exist, what mechanism enables it to selectively preserve open chromatin? Chromatin is disassembled and reassembled during DNA replication and cell division, which poses a challenge to the retention of associated landmarks 2. A low rate of cell division might therefore enable certain cells to better maintain a chromatin memory. Skin has several types of EpSC that are involved in wound repair 3 and have vari-able proliferation rates 4. The authors studied EpSCs in the epidermis and the upper portion of hair follicles; in the future, cell-lineage-trac-ing experiments could be used to examine the specific contribution of the various skin EpSC subsets to the newly formed epidermis during post-inflammation wound healing. Naik and colleagues’ work raises both basic and clinical questions. Is inflammatory memory a general feature of all adult-tissue stem cells? This is of particular interest in tis-sues such as the intestine, which, similarly to skin, acts as a gateway between the body and environment, and is therefore prone to exter-nal assaults. What are the long-term health ramifications of EpSC memory? Wound healing is a complex and highly regulated process; if memory-accelerated healing does not involve careful coordination between EpSCs and surrounding skin and immune-cell types, aberrant scarring may ensue.

Chronic inflammation is associated with an enhanced risk of cancer 5. It is possible that the lingering memory of acute inflamma-tion would lead to super-reactive EpSCs and enhanced production of inflammatory mol-

ecules called cytokines, mimicking chronic inflammation. If so, EpSC memory could be prone to becoming maladaptive, predispos-ing to skin cancer. EpSC memory might also contribute to relapses in inflammatory skin diseases such as psoriasis. Finally, preco-cious EpSC activity might eventually lead to stem-cell exhaustion and premature ageing. Investigation of these fascinating avenues of research is sure to alter our understanding of EpSC biology even further. Xing Dai is in the Department of Biological Chemistry, School of Medicine, University of California, Irvine, California 92697, USA.e-mail: xdai@https://www.sodocs.net/doc/066282966.html, Inflammatory horizons expand RU S L A N M E DZH I TOV T

wo types of immune memory are acquired when a host encounters a pathogen — life-long memory, conferred by the adaptive immune system, and the short-term memory of the innate immune system. The first involves the proliferation and differentiation of rare immune-system cells (T and B lymphocytes)specific for the pathogen, enabling a rapid protective response to subsequent encounters. The second involves temporary changes in the chromatin of immune-system cells called macrophages, altering the accessibility of their transcriptional machinery such that a particu-lar gene-expression pattern is induced following repeated pathogen stimulation during the same or subsequent infection events 6. Naik et al. add to this list EpSC memory, which, by virtue of a FORUM Inflammation Memory beyond immunity

Epithelial stem cells maintain the skin’s epidermis and promote wound healing in response to injury. Scientists from two fields discuss implications of the discovery that these stem cells harbour a memory of previous injuries, which enables skin to respond rapidly to subsequent assaults. See Article p .475

THE PAPER IN BRIEF ●Activated epithelial stem cells (EpSCs) give rise to skin-cell lineages that can replace damaged cells and heal wounds.●On page 475, Naik et al.1 report that mouse EpSCs that have been exposed to inflammation caused by damage retain a memory of the event in the form of changes to their chromatin — the material in which DNA is packaged with proteins in cells. ●Chromatin changes make key stress-response genes such as Aim2 accessible to transcription factors. This enables their rapid expression, and thus accelerated wound healing, if injury occurs again (Fig. 1). ●This is the first identification of inflammatory memory in a non-immune cell.460 | N A T U R E | V O L 550 | 26 O C T O B E R 2017

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