Stem cells expand potency and alter tissue fitness by accumulating diverse epigenetic memories.
Stem cells expand potency and alter tissue fitness by accumulating diverse epigenetic memories.
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DOI：
10.1126/science.abh2444
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发表时间：
2021-11-26
期刊：
影响因子：
--
通讯作者：
Fuchs E
中科院分区：
文献类型：
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作者：
Gonzales KAU;Polak L;Matos I;Tierney MT;Gola A;Wong E;Infarinato NR;Nikolova M;Luo S;Liu S;Novak JSS;Lay K;Pasolli HA;Fuchs E
组织干细胞响应并整合环境线索以决定其命运和功能。损伤诱导微环境发生根本性变化，触发干细胞经历许多精心设计的经历，包括离开其原始生态位，迁移到伤口床，克服炎症，重新生成组织，并在新的部位定居。伤口也可以诱导可塑性，动员干细胞修复相关但不同的组织。目前尚不清楚干细胞是否积累并保留了这些在损伤修复中空间和时间上定义的经历的记忆，如果是这样，这是如何发生的，后果是什么。在毛囊（HF）内，隆突干细胞（HFSC）通常只制造头发，但当伤口损伤覆盖的皮肤组织时，它们会被重新利用。使用谱系追踪，我们监测了HFSC在伤口修复和干细胞可塑性过程中的时间进展。在离开它们的小生境并再生缺失的组织后，它们可以长期留在从头表皮中，此后维持皮肤的屏障。通过探索转录组和表观基因组动力学，并询问这些移民干细胞在新生态位中的行为，我们了解到这些干细胞积累了他们过去经历的离散表观遗传记忆，每一种记忆都以不同的方式影响整体组织功能。通过剥除表皮，我们诱导下层HFSC成为上皮再生的主要反应者。这创造了一个长期的，自我更新的表皮，主要是HF衍生的。命运改变的表皮干细胞（EPDSC）在稳态功能和转录组中与天然未受伤的EPDSC没有区别。然而，使用测序（ATAC-seq）的转座酶可接近染色质的测定揭示了许多具有增加的可接近性的基因座。区分HF衍生的与天然EpdSC的开放染色质结构域以三种形式出现：（i）仅在适应新的表皮小生境（补偿性适应）期间增加可接近性的结构域，（ii）在创伤响应期间开放的结构域（创伤记忆），和（iii）在静止HFSC中已经开放的结构域（小生境起源的记忆）。每一个持久的表观遗传记忆都有其自身的后果。补偿性适应结构域使得维持皮肤屏障所必需的关键分化和免疫防御转录物能够在天然水平表达。创伤记忆域启动了参与炎症、细胞骨架重组和迁移的基因，以在继发性创伤时被强烈诱导，从而加速愈合。小生境起源域的记忆与参与HFSC命运和WNT信号传导的基因相关，赋予可塑性以在适当的环境提示下恢复到HF命运。最后，这些记忆虽然是累积的，但却是不同的、可分离的，并且依赖于过去的经历。因此，修复表皮损伤的EPDSC表现出创伤记忆，但缺乏对HF小生境起源和表皮代偿性适应的记忆。表观遗传记忆的概念最早是在炎症环境中报道的。在这里，我们发现额外的记忆被获得并保持在组织干细胞的染色质中，这表明干细胞可以存储来自它们遇到的不同经历的表观遗传记忆。通过影响干细胞对未来攻击的反应，这些记忆可以以有益或有害的方式对长期组织适应性产生影响，这取决于环境。干细胞积累了它们过去经历的表观遗传记忆。当毛囊干细胞动员起来修复受伤的皮肤表皮并作为表皮干细胞居住时，它们会暂时改变染色质状态。每一次环境接触都会留下一个离散的、持久的表观遗传记忆，使这些移民干细胞能够执行新的任务，同时也提高了未来对损伤、炎症和毛发再生的反应。免疫和组织干细胞保留了炎症的表观遗传记忆，增强了对未来遭遇的敏感性。我们研究了干细胞是否拥有和积累不同经历的记忆，以及干细胞拥有和积累不同经历的记忆的结果。监测对伤口的精心设计的反应，我们发现，随着毛囊干细胞离开它们的小生境，迁移到修复受损的表皮，并在那里长期居住，它们积累了每次经历的持久表观遗传记忆，最终在修复后的表观遗传适应中维持表皮转录程序和表面屏障。每种记忆都是不同的，可分离的，并有自己的生理影响，共同赋予这些干细胞更高的再生能力来愈合伤口，并扩大其组织再生任务相对于他们的天真的同行。
Tissue stem cells respond to and integrate environmental cues to determine their fate and function. Injury induces radical changes in the microenvironment that trigger stem cells to undergo a multitude of choreographed experiences that include departing their original niche, migrating into a wound bed, overcoming inflammation, generating tissue de novo, and taking up residence at the new site. Wounds can also induce plasticity, mobilizing stem cells to repair related but different tissues. It remains unclear whether stem cells accumulate and retain memories of these spatially and temporally defined experiences in injury repair, and if so, how this happens and what the consequences are. Within the hair follicle (HF), bulge stem cells (HFSCs) normally only make hair, but they become repurposed when a wound damages the overlying skin tissue. Using lineage tracing, we monitored HFSCs as they temporally progress through this journey of wound repair and stem cell plasticity. After leaving their niche and regenerating missing tissue, they can remain long-term in the de novo epidermis and thereafter maintain the skin’s barrier. By exploring transcriptome and epigenome dynamics and interrogating the behavior of these immigrant stem cells in their new niche, we learned that these stem cells accumulate discrete epigenetic memories of their past experiences, each of which affects overall tissue function in different ways. By denuding the epidermis, we coaxed underlying HFSCs to be the primary responders to re-epithelialization. This creates a long-term, self-renewing epidermis that is largely HF-derived. The fate-changed epidermal stem cells (EpdSCs) were indistinguishable from native unwounded EpdSCs in homeostatic function and transcriptome. However, assay for transposase-accessible chromatin using sequencing (ATAC-seq) revealed many loci with increased accessibility. Open chromatin domains distinguishing HF-derived from native EpdSCs came in three forms: (i) domains that increased accessibility only during adaptation to the new epidermal niche (compensatory adaptation), (ii) domains that opened during the wound response (memory of wound), and (iii) domains that were already open in quiescent HFSCs (memory of niche origin). Each enduring epigenetic memory had its own consequence. Compensatory adaptation domains enabled key differentiation and immune defense transcripts necessary for maintaining the skin’s barrier to be expressed at native levels. Wound memory domains primed genes involved in inflammation, cytoskeletal reorganization, and migration to be robustly induced upon secondary wounds, thus accelerating healing. Memory of niche origin domains were associated with genes involved in HFSC fate and WNT signaling, imparting plasticity to revert to the HF fate given the right environmental cues. Finally, these memories, although cumulative, were distinct, separable, and dependent on past experiences. Thus, EpdSCs that repaired epidermal injuries exhibited a wound memory but lacked memories of HF niche origin and epidermal compensatory adaptation. The concept of epigenetic memory was first reported in inflammatory contexts. Here, we found that additional memories are acquired and maintained in the chromatin of tissue stem cells, which suggests that stem cells can store epigenetic memories from different experiences they encounter. By influencing a stem cell’s responses to future assaults, such memories can have an impact on long-term tissue fitness in either beneficial or detrimental ways, depending on context. Stem cells accumulate epigenetic memories of their past experiences. As hair follicle stem cells mobilize to repair wounded skin epidermis and take up residence as epidermal stem cells, they temporally change chromatin states. Each environmental encounter leaves a discrete long-lasting epigenetic memory, enabling these immigrant stem cells to perform their new tasks while also heightening future responses to injury, inflammation, and hair regeneration. Immune and tissue stem cells retain an epigenetic memory of inflammation that intensifies sensitivity to future encounters. We investigated whether and to what consequence stem cells possess and accumulate memories of diverse experiences. Monitoring a choreographed response to wounds, we found that as hair follicle stem cells leave their niche, migrate to repair damaged epidermis, and take up long-term foreign residence there, they accumulate long-lasting epigenetic memories of each experience, culminating in post-repair epigenetic adaptations that sustain the epidermal transcriptional program and surface barrier. Each memory is distinct, separable, and has its own physiological impact, collectively endowing these stem cells with heightened regenerative ability to heal wounds and broadening their tissue-regenerating tasks relative to their naïve counterparts.