Metabolic coordination between skin epithelium and type 17 immunity sustains chronic skin inflammation.

Inflammatory epithelial diseases are spurred by the concomitant dysregulation of immune and epithelial cells. How these two dysregulated cellular compartments simultaneously sustain their heightened metabolic demands is unclear. Single-cell and spatial transcriptomics (ST), along with immunofluorescence, revealed that hypoxia-inducible factor 1α (HIF1α), downstream of IL-17 signaling, drove psoriatic epithelial remodeling. Blocking HIF1α in human psoriatic lesions ex vivo impaired glycolysis and phenocopied anti-IL-17 therapy. In a murine model of skin inflammation, epidermal-specific loss of HIF1α or its target gene, glucose transporter 1, ameliorated epidermal, immune, vascular, and neuronal pathology. Mechanistically, glycolysis autonomously fueled epithelial pathology and enhanced lactate production, which augmented the γδ T17 cell response. RORγt-driven genetic deletion or pharmacological inhibition of either lactate-producing enzymes or lactate transporters attenuated epithelial pathology and IL-17A expression in vivo. Our findings identify a metabolic hierarchy between epithelial and immune compartments and the consequent coordination of metabolic processes that sustain inflammatory disease.

Stem Cell Lineage Infidelity Drives Wound Repair and Cancer.

Tissue stem cells contribute to tissue regeneration and wound repair through cellular programs that can be hijacked by cancer cells. Here, we investigate such a phenomenon in skin, where during homeostasis, stem cells of the epidermis and hair follicle fuel their respective tissues. We find that breakdown of stem cell lineage confinement-granting privileges associated with both fates-is not only hallmark but also functional in cancer development. We show that lineage plasticity is critical in wound repair, where it operates transiently to redirect fates. Investigating mechanism, we discover that irrespective of cellular origin, lineage infidelity occurs in wounding when stress-responsive enhancers become activated and override homeostatic enhancers that govern lineage specificity. In cancer, stress-responsive transcription factor levels rise, causing lineage commanders to reach excess. When lineage and stress factors collaborate, they activate oncogenic enhancers that distinguish cancers from wounds.

Impaired Epidermal to Dendritic T Cell Signaling Slows Wound Repair in Aged Skin.

Aged skin heals wounds poorly, increasing susceptibility to infections. Restoring homeostasis after wounding requires the coordinated actions of epidermal and immune cells. Here we find that both intrinsic defects and communication with immune cells are impaired in aged keratinocytes, diminishing their efficiency in restoring the skin barrier after wounding. At the wound-edge, aged keratinocytes display reduced proliferation and migration. They also exhibit a dampened ability to transcriptionally activate epithelial-immune crosstalk regulators, including a failure to properly activate/maintain dendritic epithelial T cells (DETCs), which promote re-epithelialization following injury. Probing mechanism, we find that aged keratinocytes near the wound edge don't efficiently upregulate Skints or activate STAT3. Notably, when epidermal Stat3, Skints, or DETCs are silenced in young skin, re-epithelialization following wounding is perturbed. These findings underscore epithelial-immune crosstalk perturbations in general, and Skints in particular, as critical mediators in the age-related decline in wound-repair.

Identification of stem cell populations in sweat glands and ducts reveals roles in homeostasis and wound repair.

Sweat glands are abundant in the body and essential for thermoregulation. Like mammary glands, they originate from epidermal progenitors. However, they display few signs of cellular turnover, and whether they have stem cells and tissue-regenerative capacity remains largely unexplored. Using lineage tracing, we here identify in sweat ducts multipotent progenitors that transition to unipotency after developing the sweat gland. In characterizing four adult stem cell populations of glandular skin, we show that they display distinct regenerative capabilities and remain unipotent when healing epidermal, myoepithelial-specific, and lumenal-specific injuries. We devise purification schemes and isolate and transcriptionally profile progenitors. Exploiting molecular differences between sweat and mammary glands, we show that only some progenitors regain multipotency to produce de novo ductal and glandular structures, but that these can retain their identity even within certain foreign microenvironments. Our findings provide insight into glandular stem cells and a framework for the further study of sweat gland biology.

Skin stem cells orchestrate directional migration by regulating microtubule-ACF7 connections through GSK3ß.

Homeostasis and wound healing rely on stem cells (SCs) whose activity and directed migration are often governed by Wnt signaling. In dissecting how this pathway integrates with the necessary downstream cytoskeletal dynamics, we discovered that GSK3ß, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3ß sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. Phosphorylation-refractile ACF7 rescues overall microtubule architecture, but phosphorylation-constitutive mutants do not. Neither mutant rescues polarized movement, revealing that phospho-regulation must be dynamic. This circuitry is physiologically relevant and depends upon polarized GSK3ß inhibition at the migrating front of SCs/progeny streaming from HFs during wound repair. Moreover, only ACF7 and not GSKß-refractile-ACF7 restore polarized microtubule-growth and SC-migration to ACF7 null skin. Our findings provide insights into how this conserved spectraplakin integrates signaling, cytoskeletal dynamics, and polarized locomotion of somatic SCs.

Skin keratinocyte-derived SIRT1 and BDNF modulate mechanical allodynia in mouse models of diabetic neuropathy.

Diabetic neuropathy is a debilitating disorder characterized by spontaneous and mechanical allodynia. The role of skin mechanoreceptors in the development of mechanical allodynia is unclear. We discovered that mice with diabetic neuropathy had decreased sirtuin 1 (SIRT1) deacetylase activity in foot skin, leading to reduced expression of brain-derived neurotrophic factor (BDNF) and subsequent loss of innervation in Meissner corpuscles, a mechanoreceptor expressing the BDNF receptor TrkB. When SIRT1 was depleted from skin, the mechanical allodynia worsened in diabetic neuropathy mice, likely due to retrograde degeneration of the Meissner-corpuscle innervating Aß axons and aberrant formation of Meissner corpuscles which may have increased the mechanosensitivity. The same phenomenon was also noted in skin-keratinocyte specific BDNF knockout mice. Furthermore, overexpression of SIRT1 in skin induced Meissner corpuscle reinnervation and regeneration, resulting in significant improvement of diabetic mechanical allodynia. Overall, the findings suggested that skin-derived SIRT1 and BDNF function in the same pathway in skin sensory apparatus regeneration and highlighted the potential of developing topical SIRT1-activating compounds as a novel treatment for diabetic mechanical allodynia.

Glandular stem cells in the skin during development, homeostasis, wound repair and regeneration.

Glands in the skin are essential for various physiological functions involving exocrine secretion. Like other tissues and organs, they possess the ability to repair injury and self-renew during homeostasis. Progenitor cells in glands are mostly unipotent but include some multipotent stem cells that function when extensive remodelling or regeneration is required. In this review, using two glandular models in skin, mouse sweat gland and mammary gland, we discuss lineage restriction that develops during glandular morphogenesis, as well as the mechanisms regulating cell fate and plasticity during wound repair and regeneration. Understanding the intrinsic and extrinsic factors that control the behaviours of glandular stem cell and maintain glandular functions will provide insight into future prospects for glandular regeneration.

Transgenerational inheritance of neurobehavioral and physiological deficits from developmental exposure to benzo[a]pyrene in zebrafish.

Benzo[a]pyrene (B[a]P) is a well-known genotoxic polycylic aromatic compound whose toxicity is dependent on signaling via the aryl hydrocarbon receptor (AHR). It is unclear to what extent detrimental effects of B[a]P exposures might impact future generations and whether transgenerational effects might be AHR-dependent. This study examined the effects of developmental B[a]P exposure on 3 generations of zebrafish. Zebrafish embryos were exposed from 6 to 120h post fertilization (hpf) to 5 and 10µM B[a]P and raised in chemical-free water until adulthood (F0). Two generations were raised from F0 fish to evaluate transgenerational inheritance. Morphological, physiological and neurobehavioral parameters were measured at two life stages. Juveniles of the F0 and F2 exhibited hyper locomotor activity, decreased heartbeat and mitochondrial function. B[a]P exposure during development resulted in decreased global DNA methylation levels and generally reduced expression of DNA methyltransferases in wild type zebrafish, with the latter effect largely reversed in an AHR2-null background. Adults from the F0 B[a]P exposed lineage displayed social anxiety-like behavior. Adults in the F2 transgeneration manifested gender-specific increased body mass index (BMI), increased oxygen consumption and hyper-avoidance behavior. Exposure to benzo[a]pyrene during development resulted in transgenerational inheritance of neurobehavioral and physiological deficiencies. Indirect evidence suggested the potential for an AHR2-dependent epigenetic route.

Deletion of the gene for adiponectin accelerates diabetic nephropathy in the Ins2 (+/C96Y) mouse.

AIMS/HYPOTHESIS: Diabetic nephropathy is one of the most common forms of chronic kidney disease. The role of adiponectin in the development of diabetic nephropathy has not been elucidated, and the aim of the present study was to investigate the hypothesis that deletion of the gene for adiponectin would accelerate diabetic nephropathy in the Akita mouse. METHODS: We followed four groups of mice from 4 weeks to 16 weeks of age (n ≥ 10 in each group): wild-type (WT) (Ins2 (+/+) Adipoq(+/+)) mice; APN(-/-) (Ins2(+/+) Adipoq(-/-)) mice; Akita (Ins2(+/C96Y) Adipoq(+/+)) mice and Akita/APN(-/-) (Ins2(+/C96Y) Adipoq(-/-)) mice. The mice were then killed and diabetic kidney injury was assessed. In vitro experiments were performed in primary mesangial cells. RESULTS: Mice from both diabetic groups exhibited increased glomerular adiponectin receptor 1 (adipoR1) expression, kidney hypertrophy, glomerular enlargement, increased albuminuria and tissue oxidative stress compared with the WT control. Deletion of the adiponectin gene had no effect on glycaemia. However, Akita/APN(-/-) mice exhibited a greater extent of renal hypertrophy. In vitro, adiponectin attenuated high-glucose-induced phosphorylation of mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase (S6K). A higher level of fibrosis was observed in the tubulointerstitial and glomerular compartments of the Akita/APN(-/-) mice and adiponectin was found to inhibit TGFß-induced Smad2 and Smad3 phosphorylation in vitro. There was an exaggerated inflammatory response in the Akita/APN(-/-) mice. Adiponectin also inhibited high-glucose-induced activation of nuclear factor κB (NFκB) in mesangial cells. CONCLUSIONS/INTERPRETATION: Our data suggest that adiponectin is an important determinant of the kidney response to high glucose in vivo and in vitro.

Autoimmune, Autoinflammatory Disease and Cutaneous Malignancy Associations with Hidradenitis Suppurativa: A Cross-Sectional Study.

BACKGROUND: Hidradenitis suppurativa (HS) is a debilitating cutaneous disease characterized by severe painful inflammatory nodules/abscesses. At present, data regarding the epidemiology and pathophysiology of this disease are limited. OBJECTIVE: To define the prevalence and comorbidity associations of HS. METHODS: This was a cross-sectional study of EPICTM Cosmos© examining over 180 million US patients. Prevalences were calculated by demographic and odds ratios (OR) and identified comorbidity correlations. RESULTS: All examined metabolism-related, psychological, and autoimmune/autoinflammatory (AI) diseases correlated with HS. The strongest associations were with pyoderma gangrenosum [OR 26.56; confidence interval (CI): 24.98-28.23], Down syndrome (OR 11.31; CI 10.93-11.70), and polycystic ovarian syndrome (OR 11.24; CI 11.09-11.38). Novel AI associations were found between HS and lupus (OR 6.60; CI 6.26-6.94) and multiple sclerosis (MS; OR 2.38; CI 2.29-2.48). Cutaneous malignancies were largely not associated in the unsegmented cohort; however, among Black patients, novel associations with melanoma (OR 2.39; CI 1.86-3.08) and basal cell carcinoma (OR 2.69; CI 2.15-3.36) were identified. LIMITATIONS: International Classification of Diseases (ICD)-based disease identification relies on coding fidelity and diagnostic accuracy. CONCLUSION: This is the first study to identify correlations between HS with melanoma and basal cell carcinoma (BCC) among Black patients as well as MS and lupus in all patients with HS.

Skin keratinocyte-derived SIRT1 and BDNF modulate mechanical allodynia in mouse models of diabetic neuropathy.

Diabetic neuropathy is a debilitating disorder characterized by spontaneous and mechanical pain. The role of skin mechanoreceptors in the development of mechanical pain (allodynia) is unclear. We discovered that mice with diabetic neuropathy had decreased sirtuin 1 (SIRT1) deacetylase activity in foot skin, leading to reduced expression of brain-derived neurotrophic factor (BDNF) and subsequent loss of innervation in Meissner corpuscles, a mechanoreceptor expressing the BDNF receptor TrkB. When SIRT1 was depleted from skin, the mechanical allodynia worsened in diabetic neuropathy mice, likely due to retrograde degeneration of the Meissner-corpuscle innervating Aß axons and aberrant formation of Meissner corpuscles which may have increased the mechanosensitivity. The same phenomenon was also noted in skin BDNF knockout mice. Furthermore, overexpression of SIRT1 in skin induced Meissner corpuscle reinnervation and regeneration, resulting in significant improvement of diabetic mechanical allodynia. Overall, the findings suggested that skin-derived SIRT1 and BDNF function in the same pathway in skin sensory apparatus regeneration and highlighted the potential of developing topical SIRT1-activating compounds as a novel treatment for diabetic mechanical allodynia.

Neurotransmitter signaling specifies sweat gland stem cell fate through SLN-mediated intracellular calcium regulation.

Sympathetic nerves co-develop with their target organs and release neurotransmitters to stimulate their functions after maturation. Here, we provide the molecular mechanism that during sweat gland morphogenesis, neurotransmitters released from sympathetic nerves act first to promote sweat duct elongation via norepinephrine and followed by acetylcholine to specify sweat gland stem cell fate, which matches the sequence of neurotransmitter switch. Without neuronal signals during development, the basal cells switch to exhibit suprabasal (luminal) cell features. Sarcolipin (SLN), a key regulator of sarcoendoplasmic reticulum (SR) Ca 2+ -ATPase (SERCA), expression is significantly down-regulated in the sweat gland myoepithelial cells upon denervation. Loss of SLN in sweat gland myoepithelial cells leads to decreased intracellular Ca 2+ over time in response to ACh stimulation, as well as upregulation of luminal cell features. In cell culture experiments, we showed that contrary to the paradigm that elevation of Ca 2+ promote epidermal differentiation, specification of the glandular myoepithelial (basal) cells requires high Ca 2+ while lowering Ca 2+ level promotes luminal (suprabasal) cell fate. Our work highlights that neuronal signals not only act transiently for mature sweat glands to function, but also exert long-term impact on glandular stem cell specification through regulating intracellular Ca 2+ dynamics.

Minimally and Non-invasive Approaches to Rejection Identification in Vascularized Composite Allotransplantation.

OBJECTIVE: Rejection is common and pernicious following Vascularized Composite Allotransplantation (VCA). Current monitoring and diagnostic modalities include the clinical exam which is subjective and biopsy with dermatohistopathologic Banff grading, which is subjective and invasive. We reviewed literature exploring non- and minimally invasive modalities for diagnosing and monitoring rejection (NIMMs) in VCA. METHODS: PubMed, Cochrane, and Embase databases were queried, 3125 unique articles were reviewed, yielding 26 included studies exploring 17 distinct NIMMs. Broadly, NIMMs involved Imaging, Liquid Biomarkers, Epidermal Sampling, Clinical Grading Scales, and Introduction of Additional Donor Tissue. RESULTS: Serum biomarkers including MMP3 and donor-derived microparticles rose with rejection onset. Epidermal sampling non-invasively enabled measurement of cytokine & gene expression profiles implicated in rejection. Both hold promise for monitoring. Clinical grading scales were useful diagnostically as was reflection confocal microscopy. Introducing additional donor tissue showed promise for preemptively identifying rejection but requires additional allograft tissue burden for the recipient. CONCLUSION: NIMMs have the potential to dramatically improve monitoring and diagnosis in VCA. Many modalities show promise however, additional research is needed and a multimodal algorithmic approach should be explored.

Fertility-sparing surgery for diffuse adenomyosis: a narrated, stepwise approach to the Osada procedure.

OBJECTIVE: To equip reproductive surgeons with an approach to the Osada procedure and critical prophylactic hemostatic measures that optimize perioperative outcomes. DESIGN: Stepwise demonstration of the Osada procedure with narrated video footage. SETTING: Definitive management of symptomatic adenomyosis requires hysterectomy. However, adenomyomectomy can improve symptoms and restore anatomy while maintaining fertility potential. Limited but comparable perioperative outcomes exist for minimally invasive methods of adenomyomectomy, and most involve resection of focal, not diffuse, adenomyosis. Among the literature involving resection of diffuse adenomyosis using minimally invasive methods, relatively small volumes of resected tissue are reported and none include obstetric outcomes. Most published reports for excision of diffuse adenomyosis involve laparotomic resection, likely because of specific intraoperative challenges curtailed by this approach. In response, a laparoscopic-assisted laparotomic approach was developed in 2011 by Dr. Hisao Osada, a reproductive surgeon in Japan. This procedure involves aggressive excision of adenomyotic tissue with prophylactic hemostatic techniques and subsequent uterine wall reconstruction using a triple-flap method. Compared with other excisional methods for diffuse adenomyomectomy, the Osada procedure has the best reported obstetric outcomes. PATIENT(S): A 37-year-old nulliparous female presented with pelvic pain, bulk symptoms, abnormal uterine bleeding, and infertility. Physical examination demonstrated a 20-week, bulky uterus with limited bimanual mobility. Her endometrial cavity was inaccessible because of marked anatomic distortion. Magnetic resonance imaging revealed marked abnormality of her endometrial contour because of a 15 cm adenomyoma with diffuse adenomyomatous tissue in the posterior uterine compartment. Prior interventions included a trial of combined hormonal contraceptive, leuprolide acetate, and tranexamic acid. She was interested in fertility-sparing adenomyomectomy to address symptoms and fertility potential and chose to proceed with the Osada procedure. She was optimized medically with oral and parenteral iron therapy to bring her hemoglobin from 55-111 g/L preoperatively. Institutional review board approval and informed consent from the patient were obtained. INTERVENTION(S): The Osada procedure was performed using the following 8 surgical steps: Systemic administration of tranexamic acid was also administered intraoperatively. MAIN OUTCOME MEASURE(S): Perioperative blood loss, anatomic normalization, symptom remediation, and maintenance of fertility potential. RESULTS: Perioperative blood loss was minimal, 469 g of adenomyotic tissue was extracted, and discharge was on postoperative day 2 without any complications. Three months later, cyclic pain and bleeding had improved markedly, ultrasound confirmed Doppler flow throughout the uterus, hysterosalpingogram demonstrated a nonobliterated endometrial cavity and tubal patency, and magnetic resonance imaging confirmed normalized uterine dimensions measuring 11 × 7 cm from 19 × 10 cm. Most literature supports waiting at least 6-12 months and until demonstration of normalized uterine blood flow in the operated area before attempting conception. CONCLUSION: Fertility-sparing excision of diffuse adenomyosis can be achieved safely using the Osada procedure, following the 8 discrete steps demonstrated in this video. Reproductive surgeons can reference this video to teach and maintain this important procedure.

Safer outcomes for placenta accreta spectrum disorders: A decade of quality improvement.

OBJECTIVE: To describe the evolution and evaluation of protocol-based multidisciplinary quality improvement (QI) in women undergoing cesarean hysterectomy for radiologically suspected and pathologically confirmed placenta accreta spectrum (PAS) disorders. METHODS: A single-center, retrospective cohort study was conducted of all patients undergoing cesarean hysterectomy for PAS disorders between March 2009 and June 2018. Two distinct periods were defined to compare outcomes: 2009-2011 (initial period) and 2017-2018 (current period). Primary outcomes included blood loss and administration of blood products. Secondary outcomes included perioperative levels of hemoglobin, adverse events and complications, time to mobilization, and length of hospitalization. RESULTS: Among the 105 consecutive patients identified, there were 26 in the initial period and 32 in the current period. With the implementation of all QI care bundles, median estimated surgical blood loss halved from 2000 ml in the initial period to 1000 ml in the current period, and fewer patients required allogenic blood transfusion (61.5% vs 25%). Patients in the current period demonstrated improved postoperative levels of hemoglobin compared to those in the initial period (101 g/L vs 89 g/L) and had a shorter median postoperative hospital stay (3 days vs 5 days). CONCLUSION: These results support the implementation of a multifaceted QI and patient care initiative for women with PAS disorders.

Amino acid residues in Rag1 crucial for DNA hairpin formation.

The Rag proteins carry out V(D)J recombination through a process mechanistically similar to cut-and-paste transposition. Specifically, Rag complexes form DNA hairpins through direct transesterification, using a catalytic Asp-Asp-Glu (DDE) triad in Rag1. How is sufficient DNA distortion introduced to allow hairpin formation? We hypothesized that, like certain transposases, the Rag proteins might use aromatic amino acid residues to stabilize a flipped-out base. Through in vivo and in vitro experiments and structural predictions, we identified residues in Rag1 crucial for hairpin formation. One of these, a conserved tryptophan (Trp893), probably participates in base-stacking interactions near the cleavage site, as do Trp298, Trp265 and Trp319 in the Tn5, Tn10 and Hermes transposases, respectively. Other residues surrounding the catalytic glutamate (YKEFRK) may share functional similarities with the YREK motif in IS4 family transposases.

A RAG1 mutation found in Omenn syndrome causes coding flank hypersensitivity: a novel mechanism for antigen receptor repertoire restriction.

Hypomorphic RAG mutants with severely reduced V(D)J recombination activity cause Omenn Syndrome (OS), an immunodeficiency with features of immune dysregulation and a restricted TCR repertoire. Precisely how RAG mutants produce autoimmune and allergic symptoms has been unclear. Current models posit that the severe recombination defect restricts the number of lymphocyte clones, a few of which are selected upon Ag exposure. We show that murine RAG1 R972Q, corresponding to an OS mutation, renders the recombinase hypersensitive to selected coding sequences at the hairpin formation step. Other RAG1 OS mutants tested do not manifest this sequence sensitivity. These new data support a novel mechanism for OS: by selectively impairing recombination at certain coding flanks, a RAG mutant can cause primary repertoire restriction, as opposed to a more random, limited repertoire that develops secondary to severely diminished recombination activity.

Understanding how the V(D)J recombinase catalyzes transesterification: distinctions between DNA cleavage and transposition.

The Rag1 and Rag2 proteins initiate V(D)J recombination by introducing site-specific DNA double-strand breaks. Cleavage occurs by nicking one DNA strand, followed by a one-step transesterification reaction that forms a DNA hairpin structure. A similar reaction allows Rag transposition, in which the 3'-OH groups produced by Rag cleavage are joined to target DNA. The Rag1 active site DDE triad clearly plays a catalytic role in both cleavage and transposition, but no other residues in Rag1 responsible for transesterification have been identified. Furthermore, although Rag2 is essential for both cleavage and transposition, the nature of its involvement is unknown. Here, we identify basic amino acids in the catalytic core of Rag1 specifically important for transesterification. We also show that some Rag1 mutants with severe defects in hairpin formation nonetheless catalyze substantial levels of transposition. Lastly, we show that a catalytically defective Rag2 mutant is impaired in target capture and displays a novel form of coding flank sensitivity. These findings provide the first identification of components of Rag1 that are specifically required for transesterification and suggest an unexpected role for Rag2 in DNA cleavage and transposition.

NFI transcription factors provide chromatin access to maintain stem cell identity while preventing unintended lineage fate choices.

Tissue homeostasis and regeneration rely on resident stem cells (SCs), whose behaviour is regulated through niche-dependent crosstalk. The mechanisms underlying SC identity are still unfolding. Here, using spatiotemporal gene ablation in murine hair follicles, we uncover a critical role for the transcription factors (TFs) nuclear factor IB (NFIB) and IX (NFIX) in maintaining SC identity. Without NFI TFs, SCs lose their hair-regenerating capability, and produce skin bearing striking resemblance to irreversible human alopecia, which also displays reduced NFIs. Through single-cell transcriptomics, ATAC-Seq and ChIP-Seq profiling, we expose a key role for NFIB and NFIX in governing super-enhancer maintenance of the key hair follicle SC-specific TF genes. When NFIB and NFIX are genetically removed, the stemness epigenetic landscape is lost. Super-enhancers driving SC identity are decommissioned, while unwanted lineages are de-repressed ectopically. Together, our findings expose NFIB and NFIX as crucial rheostats of tissue homeostasis, functioning to safeguard the SC epigenome from a breach in lineage confinement that otherwise triggers irreversible tissue degeneration.