Alveolar type I cells can give rise to KRAS-induced lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and presents clinically with a high degree of biological heterogeneity and distinct clinical outcomes. The current paradigm of LUAD etiology posits alveolar epithelial type II (AT2) cells as the primary cell of origin, while the role of AT1 cells in LUAD oncogenesis remains unknown. Here, we examine oncogenic transformation in mouse Gram-domain containing 2 (Gramd2)+ AT1 cells via oncogenic KRASG12D. Activation of KRASG12D in AT1 cells induces multifocal LUAD, primarily of papillary histology. Furthermore, KRT8+ intermediate cell states were observed in both AT2- and AT1-derived LUAD, but SCGB3A2+, another intermediate cell marker, was primarily associated with AT1 cells, suggesting different mechanisms of tumor evolution. Collectively, our study reveals that Gramd2+ AT1 cells can serve as a cell of origin for LUAD and suggests that distinct subtypes of LUAD based on cell of origin be considered in the development of therapeutics.

Surgical classification for large macular hole: based on different surgical techniques results: the CLOSE study group.

BACKGROUND: The CLOSE study group proposes an updated surgical classification for large macular holes based on a systematic review of new treatments. Recently, many new techniques have been introduced to treat large full-thickness macular holes (FTMH); although the indications are not clear. An updated surgical classification is needed to help surgical decision-making. METHODS: We gathered published series by the CLOSE Study Group members and from literature search until June 2021. Techniques included: internal limiting membrane peeling (ILM peeling), ILM flaps, macular hydrodissection (macular hydro), human amniotic membrane graft (hAM), and autologous retinal transplantation (ART). Within each technique, chi-square test assessed association between the minimal linear diameter (MLD) (in µm) and closure rate; the postoperative best-corrected visual acuity (BCVA) gains were compared among groups. RESULTS: Data extraction included 31 published articles: total of 1135 eyes. Eyes were divided into the following groups: ILM peel (n: 683), ILM Flap (n: 233), macular hydrodissection (n: 64), hAM (n: 59), and ART (n: 96). The initial BCVA and size were heterogenous between the groups. ILM peel showed the best results in large FTMH ≤ 535 µm (closure rate 96.8%); adjusted mean BCVA: 0.49 (LogMAR) with a statistical difference among groups. Large FTMH between 535 and 799 µm: ILM flap technique showed better results (closure rate 99.0%); adjusted mean BCVA: 0.67(LogMAR); also with a statistical difference. For large FTMH ≥ 800 µm more invasive techniques are required. Use of hAM, macular hydrodissection and ART showed higher closure rates for this category (100%, 83.3% and 90.5% respectively), and adjusted mean BCVA varied from 0.76 to 0.89. Although there was no statistical difference between those techniques for this group due to the smaller number of cases. CONCLUSIONS: The CLOSE study group demonstrated the potential usefulness of a new surgical classification for large FTMHs and propose OCT biomarkers for use in clinical practice and future research. This new classification demonstrated that Large (400-550 µm) and X-Large (550-800 µm) holes can be treated highly successfully with ILM peel and ILM flap techniques, respectively. Further studies are necessary for the larger FTMHs (XX-Large and Giant), using the CLOSE classification, in order to determine which technique is better suited for each hole size and characteristics.

Evaluation of phakic intraocular lens power calculation using the new Linz-Homburg-Castrop formula and comparison with four conventional methods.

PURPOSE: To evaluate the accuracy of phakic intraocular lens (pIOL) power calculation in a middle European patient cohort. SETTING: EyeLaser Clinic, Linz, Austria. DESIGN: Single-center single-surgeon retrospective consecutive case series. METHODS: Patients were included after uneventful pIOL surgery implanting 91 nontoric and toric Visian implantable collamer lens model V4c. Online Calculation and Ordering System (OCOS) software, JPhakic software, Olsen-Feingold formula, Holladay formula, and Linz-Homburg-Castrop (LHC) formula were compared. When possible, lens constants were optimized for the patient cohort. Data of single eye per patient were included. Outcome measures were mean absolute prediction error, median absolute prediction error, mean prediction error with SD, and median prediction error, as well as the percentage of eyes with an absolute prediction error within limits of 0.25 diopters (D), 0.5 D, 0.75 D, and 1.0 D. RESULTS: 91 eyes of 91 patients were assessed. After application of the Cochran Q test, the Olsen-Feingold formula achieved a significantly lower percentage of eyes within an absolute prediction error of 1.0 D than all other methods. CONCLUSIONS: In the patient cohort, OCOS software, JPhakic software, and Holladay and LHC formulas showed equal results and can be cross-checked. The LHC formula was not published before. A ready-to-use Excel sheet is available as an addendum.

Adverse Events during Vitreoretinal Surgery under Adequacy of Anesthesia Guidance-Risk Factor Analysis.

Vitreoretinal surgeries require the administration of general anesthesia (GA) in selected groups of patients. The administration of intraoperative rescue narcotic analgesia (IRNA) during GA poses the risk of postoperative nausea and vomiting (PONV). The surgical pleth index (SPI), a crucial component of the adequacy of anesthesia (AoA) guidance of GA, optimizes the intraoperative titration of IRNA. The current analysis evaluated the risk factors for the occurrence of PONV and the oculo-cardiac reflex (OCR) in patients undergoing pars plana vitrectomy (PPV) under AoA guidance. In total, 175 patients undergoing PPV were randomly allocated to receive either GA with SPI-guided IRNA administration using fentanyl alone or in addition to different preoperative analgesia techniques. Any incidence of PONV or OCR was recorded. Obesity, overweight, smoking status, motion sickness, postoperative intolerable pain perception, female gender, fluid challenge and arterial hypertension did not correlate with an increased incidence of PONV or OCR under AoA guidance. Diabetes mellitus, regardless of insulin dependence, was found to correlate with the increased incidence of PONV. The AoA regimen including SPI guidance of IRNA presumably created similar conditions for individual subjects, so no risk factors of the occurrence of PONV or OCR were found, except for diabetes mellitus. We recommend using AoA guidance for GA administration to reduce OCR and PONV rates.

360° inverted internal limiting membrane flap technique for idiopathic macular holes ≤ 250 µm, > 250 and ≤ 400 µm, and > 400 µm.

PURPOSE: To study the functional and morphological results of the inverted internal limiting membrane (ILM) flap technique for the treatment of idiopathic macular holes (MHs) sized ≤ 250 µm, > 250 and ≤ 400 µm, and > 400 µm. METHODS: Retrospective, nonrandomized interventional study of 65 eyes with primary idiopathic MHs who underwent pars plana vitrectomy (PPV) with the inverted ILM flap technique. Closure rate, best-corrected visual acuity (BCVA), and integrity of external limiting membrane (ELM) and ellipsoid zone (EZ) were analyzed by optical coherence tomography (OCT). RESULTS: Total closure rate was 96.9% with 100% in the ≤ 250 µm group, 100% in the > 250 and ≤ 400 µm group, and 91.7% in the > 400 µm group. Mean BCVA significantly improved after treatment: from 0.7 to 0.3 LogMAR in the ≤ 250 µm group (n = 15, p < 0.001), from 0.9 to 0.4 LogMAR in the > 250 and ≤ 400 µm group (n = 26, p < 0.001), and from 1.0 to 0.5 LogMAR in the > 400 µm group (n = 24, p < 0.001). A total of 16 patients had follow-up over 14 months: BCVA increased from 0.9 LogMAR preoperatively to 0.4 after 1 month (p < 0.00001) and to 0.3 LogMAR after 14 months (p = 0.03). A recovered ELM could be observed in 56.3% after 1 month and in 87.5% after 14 months. A recovered EZ could be observed in 18.8% after 1 month and in 68.8% after 14 months. CONCLUSION: The study demonstrates a high closure rate with corresponding restitution of outer retinal layers. In addition to its importance for the treatment of MHs > 400 µm, the inverted ILM flap technique also appears to be effective and safe for the treatment of MHs < 400 µm. TRIAL REGISTRATION: WHO: DRKS00021241.

[Closure of Persisting Full Thickness Macular Holes by Subretinal Fluid Application: Technical Approach and Surgical Considerations]. / Verschluss von persistierenden Makulalöchern durch subretinale Flüssigkeitsapplikation: technisches Vorgehen und chirurgische Überlegungen.

INTRODUCTION: Firm adhesions between the retina and adjacent retinal pigment epithelium (RPE) may prevent the closure of macular holes (MH) after chromovitrectomy. Controlled application of subretinal (SR) fluid with BSS may release these adhesions leading to closure of the retracted retina in large and or refractory macular holes. METHODS: For a standardized procedure, it is recommended to exclude residues of epiretinal membranes on the retinal surface preoperatively at OCT or intraoperatively by means of vital dyes. Intraoperatively, a perfluorocarbon (PFO) bubble is placed above the MH and lowers the infusion bottle of 20 mmHg. Subsequently, SR-fluid blebs are applied in the upper, temporal and inferior quadrants with a subretinal 41-gauge cannula. After removing decalin bubble, the SR-detachment is enlarged toward the foveal center. This is essential to achieve a complete detachment of the outer macular edges from the RPE. The MH can be closed by a temporary gas endotamponade. RESULTS: With a standardized procedure, the operation can be carried out safely and with minimal effort. Additional measures, such as care for bubble-free SR-fluid sands or machine assistance, were added. In a pilot study, experienced VR surgeons performed the SR-fluid application safely and without complications. The preoperative diameter of the MH was 1150 µm (651 - 2350 µm). The secondary closure rate for our PMH was 80.9%. CONCLUSION: SR-adhesions seem to have a previously unnoticed component in persistent macular holes. An SR-fluid application can be carried out quickly, safely and with minimal material effort. The initial results show a high secondary closure rate.

Novel probabilistic model of core vitreous traction using microsurgical vitrectomy tools.

PURPOSE: Traction exerted on the vitreous base during vitrectomy poses a risk for retinal tears. We aimed to quantify core vitreous traction during vitrectomy using spring return and pneumatic cutters. METHODS: Juvenile porcine vitreous was vacuum held in a vitreous bath while traction was measured using precision force gauge during vitrectomy. The parameters included were aspiration rate, cut-rate, cutter size, and machine types. RESULTS: An empirical probabilistic model was developed. The traction was proportional to the aspiration rate but insignificantly dependent on the cut-rate. The traction probability was inversely proportional to the exponential function of the traction (p < 0.05). The traction was < 0.003 N for 99% of the time using either 23- or 25-gauge cutters. CONCLUSION: The tractions measured were considered similar to the causative forces of an iatrogenic retinal tear during a pars plana vitrectomy. The results provide a safety reference matrix of instrumental parameters during vitrectomy.

microRNA Expression Profile in the Vitreous of Proliferative Diabetic Retinopathy Patients and Differences from Patients Treated with Anti-VEGF Therapy.

Purpose: microRNAs (miRNAs) mediate the pathological mechanisms of diabetic retinopathy. In this study, we compared miRNA expression profiles in the vitreous between patients with proliferative diabetic retinopathy (PDR) and patients with a macular hole as non-diabetic controls, and between PDR patients treated with anti-vascular endothelial growth factor (VEGF) therapy and untreated PDR patients. Methods: Vitreous samples of non-diabetic and PDR patients were screened for miRNAs with quantitative polymerase chain reaction (qPCR) panels. miRNA candidates were validated in vitreous samples of a second, independent cohort. In addition, the effect of anti-VEGF therapy was investigated in the vitreous of a third study population consisting of PDR patients who had not received anti-VEGF therapy and PDR patients who had received preoperative anti-VEGF therapy. Results: During screening, seven miRNAs were found to be significantly higher in the vitreous of PDR patients, whereas two miRNAs were found to be significantly lower compared with non-diabetic controls. Validating the expression of these miRNAs in a second cohort resulted in the identification of six miRNAs that were expressed at significantly higher rates in the vitreous of PDR patients: hsa-miR-20a-5p, hsa-miR-23b-3p, hsa-miR-142-3p, hsa-miR-185-5p, hsa-miR-326, and hsa-miR-362-5p. Among these six miRNAs, hsa-miR-23b-3p levels were lower in the anti-VEGF-treated group of PDR patients compared with untreated PDR patients. Conclusions: In this study, we identified six miRNAs that are expressed more highly in PDR patients and one miRNA that is expressed at a lower levels in anti-VEGF-treated PDR patients. Translational Relevance: miRNAs identified in the vitreous of PDR patients may improve our understanding of the mechanisms leading to PDR.

Application of subretinal fluid to close refractory full thickness macular holes: treatment strategies and primary outcome: APOSTEL study.

INTRODUCTION: Persisting macular holes (PMH) after surgical release of any epiretinal traction of the vitreous and adjacent membrane may rely on secondary firm adhesions between the retracted retina and adjacent retinal pigment epithelium. Secondary application of subretinal (SR)-fluid may release these adhesions followed by an anatomical closure. METHODS: Twelve surgeons applied in a consecutive case series SR-fluid in 41 eyes with PMH and reported retrospectively their initial surgical, anatomical and functional experience with this approach. RESULTS: The mean duration of the MH prior to SR-fluid application was 17 months (6-96 months). The mean age of the patients at the time of surgery was 72 years (54-88). The mean preoperative aperture diameter of the opening was 1212 µm (239-4344 µm), base diameter 649 µm (SD 320 µm). The mean preoperative BCVA prior to surgery was 0.1 (0.01-0.3). All patients (41/41) complained about reduced BCVA and a significant central scotoma (negative scotoma) in their central field of vision. The secondary closure rate for our PMH was 85.36% (35 out of 41 eyes) at 6 weeks after surgery. The postoperative BCVA improved to 0.22 (0.02-0.5). The application of SR-fluid was not associated with major intraoperative adverse effects. CONCLUSION: Remaining SR-adhesions may inhibit PMH closure. Their release by application of SR-fluid will lead to a fast and immediate anatomical closure in many cases without serious adverse events.

Subretinal Implantation of a Human Embryonic Stem Cell-Derived Retinal Pigment Epithelium Monolayer in a Porcine Model.

The goal of this study was to quantitatively assess retinal thickness using spectral domain optical coherence tomography (SD-OCT) after subretinal implantation of human embryonic stem cell-derived retinal pigment epithelium in a porcine model. The implant is called CPCB-RPE1 for the California Project to Cure Blindness-Retinal Pigment Epithelium 1. Data were derived from previous experiments on 14 minipigs that received either subretinal implantation of CPCB-RPE1 (n = 11) or subretinal bleb formation alone (sham; n = 3) using previously described methods and procedures (Brant Fernandes et al. Ophthalmic Surg Lasers Imaging Retina 47:342-51, 2016; Martynova et al. (2016) Koss et al. Graefes Arch Clin Exp Ophthalmol 254:1553-65, 2016; Hu et al. Ophthalmic Res 48:186-91, 2016; Martynova et al. ARVO Abstract 2016. SD-OCT retinal thickness (RT) and sublayer thickness over the implant were compared with topographically similar preimplantation regions as described previously Martynova et al. ARVO Abstract 2016. Imaging results were compared to postmortem histology using hematoxylin-eosin staining. RT overlying the CPCB-RPE1 postimplantation was not significantly different from preimplantation (308 ± 72 µm vs 292 ± 41 µm; p = 0.44). RT was not significantly different before and after implantation in any retinal sublayer at 1 month. Histology demonstrated grossly normal retinal anatomy as well as photoreceptor interdigitation with RPE.

Author Correction: A population of luminous accreting black holes with hidden mergers.

In this Letter, the spelling of author Benny Trakhtenbrot was corrected; the affiliation for author Sylvain Veilleux was amended; and a new ref. 9 was added to the Abstract with subsequent references renumbered; these errors have been corrected online.

Evaluation of Cyclin D1 as a Discriminatory Immunohistochemical Biomarker for Idiopathic Pulmonary Fibrosis.

BACKGROUND: Distinction of idiopathic pulmonary fibrosis (IPF) from other chronic fibrosing interstitial pneumonitides, such as hypersensitivity pneumonitis (HP) and connective tissue diseases, is critical due to varied biological and clinical outcomes. However, their histologic overlaps often pose diagnostic challenges. A recent study suggested an association of herpesvirus saimiri infection with IPF. Productive viral infection is associated with coexpression of pirated mammalian protein cyclin D1, shown to be overexpressed by immunohistochemistry (IHC) in the regenerating alveolar epithelium in IPF but not in normal lungs. We evaluated the diagnostic utility of cyclin D1 to discriminate between IPF and other fibrosing interstitial lung diseases. MATERIALS AND METHODS: A retrospective study of cyclin D1 IHC expression in 27 consecutive cases of chronic fibrosing interstitial lung diseases from 2011 to 2017: 12 usual interstitial pneumonia (UIP) pattern; 5 nonspecific interstitial pneumonia pattern; 3 HP pattern; 7 unclassifiable was performed. Five cases of normal lung obtained from lobectomy specimen for malignancy are included as control. Immunoreactivity was graded semiquantitatively on a scale of 0 to 3. RESULTS: Cyclin D1 staining was uniformly strongly positive in all cases evaluated in the study, particularly in proliferating type II pneumocytes in the region of fibrosing areas. There was no statistical difference in the extent of cyclin D1 expression between UIP and non-UIP groups (2.7 vs. 2.5) and IPF versus non-IPF groups (2.7 vs. 2.4). Cyclin D1 expression is lower in control group compared with UIP groups (1.2 vs. 2.7). CONCLUSIONS: Cyclin D1 is not a specific marker of UIP pattern/IPF. The high expression of cyclin D1 in lung tissue of fibrosing interstitial pneumonitides regardless of etiology most likely correlates with proliferation in type II pneumocytes.

Suppression of Murine Lupus by CD4+ and CD8+ Treg Cells Induced by T Cell-Targeted Nanoparticles Loaded With Interleukin-2 and Transforming Growth Factor ß.

OBJECTIVE: To develop a nanoparticle (NP) platform that can expand both CD4+ and CD8+ Treg cells in vivo for the suppression of autoimmune responses in systemic lupus erythematosus (SLE). METHODS: Poly(lactic-co-glycolic acid) (PLGA) NPs encapsulating interleukin-2 (IL-2) and transforming growth factor ß (TGFß) were coated with anti-CD2/CD4 antibodies and administered to mice with lupus-like disease induced by the transfer of DBA/2 T cells into (C57BL/6 × DBA/2)F1 (BDF1) mice. The peripheral frequency of Treg cells was monitored ex vivo by flow cytometry. Disease progression was assessed by measuring serum anti-double-stranded DNA antibody levels by enzyme-linked immunosorbent assay. Kidney disease was defined as the presence of proteinuria or renal histopathologic features. RESULTS: Anti-CD2/CD4 antibody-coated, but not noncoated, NPs encapsulating IL-2 and TGFß induced CD4+ and CD8+ FoxP3+ Treg cells in vitro. The optimal dosing regimen of NPs for expansion of CD4+ and CD8+ Treg cells was determined in in vivo studies in mice without lupus and then tested in BDF1 mice with lupus. The administration of anti-CD2/CD4 antibody-coated NPs encapsulating IL-2 and TGFß resulted in the expansion of CD4+ and CD8+ Treg cells, a marked suppression of anti-DNA antibody production, and reduced renal disease. CONCLUSION: This study shows for the first time that T cell-targeted PLGA NPs encapsulating IL-2 and TGFß can expand both CD4+ and CD8+ Treg cells in vivo and suppress murine lupus. This approach, which enables the expansion of Treg cells in vivo and inhibits pathogenic immune responses in SLE, could represent a potential new therapeutic modality in autoimmune conditions characterized by impaired Treg cell function associated with IL-2 deficiency.

A population of luminous accreting black holes with hidden mergers.

Major galaxy mergers are thought to play an important part in fuelling the growth of supermassive black holes1. However, observational support for this hypothesis is mixed, with some studies showing a correlation between merging galaxies and luminous quasars2,3 and others showing no such association4,5. Recent observations have shown that a black hole is likely to become heavily obscured behind merger-driven gas and dust, even in the early stages of the merger, when the galaxies are well separated6-8 (5 to 40 kiloparsecs). Merger simulations further suggest that such obscuration and black-hole accretion peaks in the final merger stage, when the two galactic nuclei are closely separated9 (less than 3 kiloparsecs). Resolving this final stage requires a combination of high-spatial-resolution infrared imaging and high-sensitivity hard-X-ray observations to detect highly obscured sources. However, large numbers of obscured luminous accreting supermassive black holes have been recently detected nearby (distances below 250 megaparsecs) in X-ray observations10. Here we report high-resolution infrared observations of hard-X-ray-selected black holes and the discovery of obscured nuclear mergers, the parent populations of supermassive-black-hole mergers. We find that obscured luminous black holes (bolometric luminosity higher than 2 × 1044 ergs per second) show a significant (P < 0.001) excess of late-stage nuclear mergers (17.6 per cent) compared to a sample of inactive galaxies with matching stellar masses and star formation rates (1.1 per cent), in agreement with theoretical predictions. Using hydrodynamic simulations, we confirm that the excess of nuclear mergers is indeed strongest for gas-rich major-merger hosts of obscured luminous black holes in this final stage.

Reprint of: The pathology of pulmonary sarcoidosis: update.

Sarcoidosis is a multi-system disease of unknown etiology, usually affecting the respiratory tract and other organs, and is characterized by the formation of nonnecrotizing epithelioid granulomas. The diagnosis depends on a combination of a typical clinicoradiological presentation, the finding of nonnecrotizing epithelioid granulomas in a tissue biopsy, and exclusion of other possible diseases, especially those of infectious etiology. The granulomas contain epithelioid cells, giant cells, CD4+ T cells in their center, and CD8+ T lymphocytes and B lymphocytes at their periphery. The granulomas are present in a lymphatic pattern around bronchovascular structures and, because of this, may show angioinvasion. The bronchial involvement produces a high diagnostic yield for transbronchial and endobronchial biopsies in this disease. Finally, small amounts of fibrinoid necrosis may occur within granulomas of sarcoidosis and do not exclude the diagnosis. Larger amounts suggest either infection or the rare disease necrotizing sarcoid granulomatosis (NSG). A number of cytoplasmic structures/inclusions can be identified within the granulomas of sarcoidosis, including asteroid bodies, Schaumann's bodies, calcium oxalate crystals, and Hamazaki-Wesenberg bodies; the last two of these can cause difficulties in differential diagnosis. Extra-pulmonary sarcoid can be an important factor in prognosis. Involved sites include (in decreasing frequency): skin, endocrine organs, extra-thoracic lymph nodes, neurologic sites, eyes, liver, spleen, bone marrow, cardiac, ear/nose/throat, parotid/salivary, muscles, bones/joint, and kidney. NSG is a controversial variant of sarcoidosis consisting of granulomatous pneumonitis with sarcoid-like granulomas, variable amounts of necrosis, and granulomatous vasculitis. The lesions are most often confined to lung, and they usually appear as multiple nodules or nodular infiltrates, but occasionally as solitary or unilateral nodules ranging up to 5 cm in diameter. Nodular sarcoidosis is rare, varying from 1.6% to 4% of patients with sarcoidosis, and, as the name suggests, it shows radiographic nodules measuring 1 to 5 cm in diameter that typically consist of coalescent granulomas. Lung transplantation can be used in selected patients with fibrotic late-stage sarcoidosis. There is a high reported frequency of recurrence of disease in the pulmonary allograft, ranging from 47% to 67%, but recurrence is usually not clinically significant. Studies of the pathogenesis of sarcoidosis suggest that it is a chronic immunological response produced by a genetic susceptibility and exposure to specific environmental factors.

Claudin-18-mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis.

Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice. Inhibition of YAP decreased proliferation and colony-forming efficiency (CFE) of Cldn18-/- AT2 cells and prevented increased lung size, while CLDN18 overexpression decreased YAP nuclear localization, cell proliferation, CFE, and YAP transcriptional activity. CLDN18 and YAP interacted and colocalized at cell-cell contacts, while loss of CLDN18 decreased YAP interaction with Hippo kinases p-LATS1/2. Additionally, Cldn18-/- mice had increased propensity to develop lung adenocarcinomas (LuAd) with age, and human LuAd showed stage-dependent reduction of CLDN18.1. These results establish CLDN18 as a regulator of YAP activity that serves to restrict organ size, progenitor cell proliferation, and tumorigenesis, and suggest a mechanism whereby TJ disruption may promote progenitor proliferation to enhance repair following injury.