Epithelial Wound Research Articles

Interplay of geometry and mechanics in epithelial wound healing

Interplay of geometry and mechanics in epithelial wound healing

Initiation of epithelial wound closure by an active instability at the purse string.

The ability of biological systems to withstand and recover from various disruptions, such as spontaneous genetic mutations and environmental damage, largely relies on intricate feedback mechanisms. We theoretically study a mechanical response of an epithelial tissue facing damage in the form of a circular wound. Our model describes a feedback loop between the generation of active forces in the actomyosin and tissue mechanics, described by the vertex model. While the exact dynamics of wound closure may be influenced by several biophysical mechanisms that interplay in a non-trivial way, our findings suggest that the closure may initiate as an active instability, triggered by a reduced myosin-turnover rate at the wound's perimeter. We explore the interplay between myosin dynamics and the elastic properties of the tissue, elucidating their collective role in determining wound's loss of stability, leading to the initiation of the closure process.

Morphological characteristics of wound healing with aloe extract, hydrogel, and their combination: experimental research

BACKGROUND: Currently, there remains a high incidence of skin damage due to trauma, chronic diseases, burns, so it is important to study the issues of regeneration and treatment of skin wounds. AIM: To conduct a morphological analysis of wound healing using aloe extract, hydrogel, and their combination in the experiment. MATERIALS AND METHODS: The study involved 40 sexually mature guinea pigs, which were divided into a control group and 4 experimental groups (independent wound healing, application of aloe extract, hydrosorb gel, layer-by-layer application of drugs). Histological skin preparations were prepared on days 3, 7, 14, and 28 of the experiment. In each microslide, in 10 fields of view of the microscope at a magnification of ×50, morphometric parameters were measured in micrometers (µm): the thickness of the purulent-necrotic scab, inflammatory (leukocyte) infiltrate, granulation tissue, the length of the newly formed epithelium on days 3, 7, 14; the thickness of the epithelium, its length and the thickness of the connective tissue in the central part of the regenerate on the 28th day. All data were subjected to statistical processing. RESULTS: The medications led to a decrease in the inflammatory reaction, acceleration of the formation of granulation tissue, and partial wound epithelization by day 7 of the experiment; however, more pronounced signs of wound healing were observed with layer-by-layer application of aloe extract and hydrogel. By day 14, regardless of the application method, the use of medications demonstrated signs of enhanced wound healing. Thus, the length of the epithelium increased by 1.2–1.6 times, the depth of granulation tissue increased by 1.0–1.2 times compared to the control group. By the end of the experiment, all animals had complete closure of the wound with scar formation, while in the experimental groups showed signs of skin remodeling with appendages. CONCLUSION: Morphological analysis showed that aloe extract, hydrosorb gel, and their combination accelerated the wound healing processes of full-thickness skin wounds in the experiment.

An Integrated Therapeutic Nanoparticles and Quorum Quenching‐Based Microneedle Patch for Bacterial‐Infected Wound Healing

AbstractSkin injuries leading to drug‐resistant bacterial infections remain a significant challenge, posing a threat to human health. There is an urgent necessity to develop wound dressings for the treatment of such injuries. The proceeding study presents the design of a multifunctional microneedle (MNs) patch containing quorum‐quenching enzyme and manganese dioxide (MnO2) nanoparticles for treating Pseudomonas aeruginosa‐infected wounds. In co‐culture experiments with P. aeruginosa, the quorum‐quenching enzyme significantly reduced the production of virulence factors and inhibited biofilm formation. MnO2 NPs exhibited excellent scavenging ability against a wide range of free radicals when assayed in in vitro antioxidant assays. Subsequently, soluble hyaluronic acid is chosen as the substrate in order to prepare the MNs patches loaded with quorum quenching enzyme and MnO2 NPs for wound healing assessment in a P. aeruginosa‐infected mouse wound model. Evaluation of wound size and closure rate demonstrated that the patch significantly accelerated wound healing, resulting in shorter healing durations and improved wound closure. Additionally, inflammation‐related cytokine levels are reduced, indicating a lower level of inflammation. Tissue section staining shows that treatment with MNs promoted wound epithelialization, collagen deposition, and angiogenesis. The multifunctional MNs patch represents a promising treatment option for drug‐resistant bacterial infections in wound management.

Rac1 inhibition regenerates wounds in mouse fetuses via altered actin dynamics

Mammalian wounds leave visible scars, and there are no methods for complete regeneration. However, mouse fetuses regenerate their skin, including epidermal and dermal structures, up to embryonic day (E)13. This regeneration pattern requires the formation of actin cables in the wound margin epithelium; however, the molecular mechanisms are not fully understood. Rac1 alters actin in cells and is involved in the formation of filopodia. We investigated whether actin remodeling and skin regeneration patterns can be reproduced through the regulation of Rac1 signaling. Rac1 expression was downregulated in E13 wounds and upregulated after E15 when scars remained. NSC23766, a Rac1-specific inhibitor, altered actin dynamics at the cell margin from filopodia formation to cable formation and inhibited the migration of mouse epidermal keratinocyte, PAM212, by Rac1 signaling suppression. NSC23766 suppressed Rac1 activity and completely regenerated the fetal mouse wounds, even at E14, by changing actin dynamics. Knocked-out Rac1 transgenic mice experienced delayed epithelialization of wounds with suppressed epidermal migration in adults; however, in fetuses, complete wound regeneration via Rac1 signal suppression was observed. Therefore, Rac1 suppression in the wound epidermis can achieve regenerative wound healing in fetuses and may be a potential candidate for healing scars.

The VEGF-Mediated Cytoprotective Ability of MIF-Licensed Mesenchymal Stromal Cells in House Dust Mite-Induced Epithelial Damage.

Enhancing mesenchymal stromal cell (MSC) therapeutic efficacy through licensing with proinflammatory cytokines is now well established. We have previously shown that macrophage migration inhibitory factor (MIF)-licensed MSCs exerted significantly enhanced therapeutic efficacy in reducing inflammation in house dust mite (HDM)-driven allergic asthma. Soluble mediators released into the MSC secretome boast cytoprotective properties equal to those associated with the cell itself. In asthma, epithelial barrier damage caused by the inhalation of allergens like HDM drives goblet cell hyperplasia. Vascular endothelial growth factor (VEGF) plays a pivotal role in the repair and maintenance of airway epithelial integrity. Human bone marrow-derived MSCs expressed the MIF receptors CD74, CXCR2, and CXCR4. Endogenous MIF from high MIF expressing CATT7 bone marrow-derived macrophages increased MSC production of VEGF through the MIF CXCR4 chemokine receptor, where preincubation with CXCR4 inhibitor mitigated this effect. CATT7-MIF licensed MSC conditioned media containing increased levels of VEGF significantly enhanced bronchial epithelial wound healing via migration and proliferation in vitro. Blocking VEGFR2 or theuse of mitomycin C abrogated this effect. Furthermore, CATT7-MIF MSC CM significantly decreased goblet cell hyperplasia after the HDM challenge in vivo. This was confirmed to be VEGF-dependent, as the use of anti-human VEGF neutralising antibody abrogated this effect. Overall, this study highlights that MIF-licenced MSCs show enhanced production of VEGF, which has the capacity to repair the lung epithelium.

De-Differentiation of Corneal Epithelial Cells Into Functional Limbal Epithelial Stem Cells After the Ablation of Innate Stem Cells.

Regeneration after tissue injury is often associated with cell fate plasticity, which restores damaged or lost cells. Here, we examined the de-differentiation of corneal epithelial cells (CECs) into functional limbal epithelial stem cells (LESCs) after the ablation of innate stem cells. The regeneration of LESCs after the ablation of innate LESCs was identified by a set of markers: ApoE+/Cx43low/CK12-. CK14-CreERT2 or Slc1a3-CreERT mice were crossed with reporter mice to trace the fate of CECs. YAP-TEAD inhibitor verteporfin (VTP) and LATS inhibitor TRULI were used to examine the role of Hippo/YAP pathway in the de-differentiation of CECs. LESCs-ablation cornea showed to be functionally normal, including the maintenance of corneal transparency, prevention of conjunctivalization, and wound healing rate equivalent to that of normal cornea. ApoE+/Cx43low/CK12- LESCs regenerated at the limbus at 6 days after the ablation of innate stem cells, and maintained for at least 6 months. Corneal epithelial lineage tracing showed that CECs migrated back to the limbus after the ablation of innate stem cells, and de-differentiated into active and quiescent LESCs (aLESCs and qLESCs), which participated in corneal epithelial homeostasis and wound healing, respectively, like their innate counterparts. However, when the limbus niche was destroyed by NaOH (1 M, 5 seconds), CECs that occupied the limbus could not de-differentiate into ApoE+/Cx43low/CK12- LESCs and cornea developed into conjunctivalization. In addition, the protein level and activity of YAP increased at the early stage (1-2 days) after the ablation of limbal epithelium, and decreased when the de-differentiation occurred. The YAP-TEAD inhibitor VTP promoted the de-differentiation, whereas LATS inhibitor TRULI inhibited the de-differentiation of CECs. However, the persistent activation of YAP prevented the de-differentiation of CECs after an additional NaOH burn to the limbal stroma, and VTP could not rescue the capacity of CECs to de-differentiate into LESCs. These results reveal the de-differentiation of CECs into functional LESCs after the ablation of innate stem cells, and suggest potential role of Hippo/YAP pathway in the de-differentiation of CECs in vivo.

Effect of TLC-NOSF Dressing on Epithelization of Diabetic Wounds: A Pilot Clinical Trial

Background: The positive effects of technology-lipid-colloid (TLC) dressings impregnated with nano-oligosaccharide factors (NOSF) have been well documented. However, there is insufficient study on the specific impact of TLC-NOSF dressings on epithelization in patients with diabetes who have partial-thickness wounds. This article presents the results of a pilot clinical trial conducted to address the aforementioned issue.Methods: Twenty patients with diabetes who underwent split-thickness skin grafting were enrolled in this study. Half of the donor site was covered with a TLC-NOSF dressing, whereas the other half was covered with a TLC dressing. The ratio of complete epithelialization within 14 days postoperatively was compared between the two groups. Furthermore, progress of epithelialization was assessed to determine whether the TLC or TLC-NOSF dressing promoted more rapid epithelialization.Results: Seventeen patients completed the study. The percentages of complete epithelialization in the TLC and TLC-NOSF dressing groups were 41% (7/17) and 53% (9/17), respectively (P = 0.49). Regarding the degree of epithelialization, the differences between the TLC-NOSF and TLC dressing were not statistically significant. The TLC-NOSF dressing was superior in nine patients, while the TLC dressing was superior in two patients. Six patients demonstrated “no significant difference” (P = 0.11).Conclusion: Based on the current results alone, it is difficult to definitively conclude that TLC-NOSF dressings are superior to TLC dressings. However, these findings suggest a potential positive effect of TLC-NOSF dressings. Further large-scale studies are required to validate these results.

Evaluation of wound healing activities of Vitex doniana (Black Plum) ethanol fruit extract

In this study, the folkloric use of Vitex doniana fruit extract for the treatment of wounds was evaluated. The mesocarps of the fresh fruits were removed, oven-dried at 40°C and pulverized. The powdered material (800 g), was exhaustively macerated in 80 % ethanol, filtered and dried in a water bath at 40°C. Phytochemical screening and acute dermal toxicity of the extract were investigated. Herbal ointments (10 and 50 %w/w) were formulated using soft paraffin base. The wound-healing effect of the extract was carried out using twenty albino rats divided into four groups (n=5). Groups I (soft paraffin) and II (10 %w/w Povidone-iodine) served as negative and positive controls, respectively. Groups III and IV were topically treated with 10 %w/w and 50 %w/w of the herbal ointment respectively. Treatments and wound grading were assessed once daily and every 4 days, respectively, as well as the timeframe for percentage wound contraction and epithelialization Both the 10 %w/w and 50 %w/w herbal ointments exhibited a concentration-related significant (P<0.05) wound contraction when compared to the control. Epithelialization period of 50 %w/w extract was less than that of the standard drug. The wound closure area of 50 %w/w extract was >positive control >10 %w/w extract > negative control. Histological study of the wounds on the 16th day indicated no sign of dermal toxicity. Some secondary metabolites such as alkaloids and tannins were present. In conclusion, the folkloric use of the fruit extract of V. doniana for the treatment of wounds may therefore be justified

Wound Healing Activity of Hydroalcoholic Extracts of Lycopersicon Esculentum Seeds and Ficus Racemosa on Wistar Rats

In the Present study Investigation on the preliminary phytochemicals screening of ethanolic extract showed the presence of Resin, Protin, Quinones, Anthraquinon, Carbohydrates, Alkaloids, Glycoside, Steroids, and Phenols. By ethanol extract using standardized procedure and also subjected to wound healing activity exhibited significant wound healing activity with respect to control biological effects of its extracts ointment, mainly the ones related to wound process. The present data clearly showed that the extract of dried Seeds of Lycoperscon esculentum seeds and Ficus racemosa has wound healing activity the highly significant response of some extracts .The result obtained from the excision wound model, Effect of EECG on Percentage Wound Contraction and Epithelialization Period. During the course of treatment the extract was found to show its preliminary effect from day 4 up to day 16.

Alveolar Ridge Regeneration With Open Versus Closed Healing in Damaged Extraction Sockets: A Preclinical InVivo Study.

The objective of this study was to compare open versus closed healing of soft and hard tissue following alveolar ridge preservation (ARP) procedures in damaged extraction sockets. ARP was performed in five mongrel dogs using collagenated deproteinized bovine bone mineral (cDBBM) and a resorbable non-cross-linked collagen membrane (NCCM) in damaged extraction sockets, with each socket entrance left either open (open group) or closed (closed group). Clinical wound epithelization at the socket entrance and the dimensions of keratinized tissue were evaluated over time. Additionally, the augmented ridge dimensions and new bone formation were assessed radiographically and histologically at 8 weeks after surgery. The dimensions of the socket entrance gradually decreased in the open group, and wound epithelization was almost complete within 4 weeks. The mucogingival junction was maintained more apically in the open group than in the closed group (0.14 ± 0.40 mm vs. -0.86 ± 0.71 mm [mean ± SD], p < 0.05). The augmented ridge dimensions did not differ significantly between the open and closed groups (93.1% ± 5.4% vs. 88.3% ± 11.2%, p > 0.05). Histological analyses revealed no significant differences in the amount of newly formed bone. However, membrane resorption in the crestal region was more pronounced in the open group. Open and closed healing approaches for ARP in extraction sockets with damaged buccal wall resulted in similar ridge dimensions and new bone formation. However, there was less reduction of the buccal bone crest and wider keratinized tissue width after open healing.

Effect of Hyaluronic Acid Mucoadhesives on Palatal Wound Healing and Postoperative Discomfort in Free Gingival Graft Surgery: A Clinical Trial

Objectives: This study aimed to assess the effect of hyaluronic acid (HA) mucoadhesives with two different concentrations on palatal epithelial wound healing and postoperative discomfort following free gingival graft (FGG) surgery. Materials and Methods: In this triple-blind, randomized, controlled clinical trial, 39 patients undergoing FGG surgery were randomly allocated to three groups (N=13). Following palatal graft harvesting, the two experimental groups received mucoadhesives containing 0.8% and 0.2% HA, while the control group received mucoadhesives without HA. In all groups, the donor site was protected with periodontal dressing. Epithelization, color match, contour, and distortion were assessed at 3, 7, 14, 21, and 42 days, postoperatively using the Landry's healing index and modified Manchester Scar Proforma (mMSP) index. Pain level and response to thermal stimuli were evaluated after 3, 7, 14, and 21 days using a visual analog scale (VAS). Data were analyzed by the Chi-square, Kruskal-Wallis, Mann-Whitney, Friedman, and Wilcoxon signed-rank tests (alpha=0.05). Results: Significant differences were observed in the mMSP index scores among the groups at 3, 7, 14, and 42 days, favoring HA groups (P&lt;0.05). The Landry's healing index score was significantly higher in 0.8% HA group on day 21 (P=0.023), compared to the control group. No significant differences were found in pain score or thermal stimulus responses among the groups (P&gt;0.05). Conclusion: Mucoadhesives containing HA were found to enhance palatal wound healing, leading to improved outcomes in terms of epithelization, color match, contour, and distortion reduction.

Application of biomedical cell products in the treatment of congenital epidermolysis bullosa

Congenital epidermolysis bullosa is a phenotypically and genetically heterogeneous group of genodermatoses, which which is clinically manifested by the development of blisters on the skin and mucous membranes after mechanical injury. The presence of long-term erosive and ulcerative defects in patients with congenital epidermolysis bullosa reduces the quality of patients` life and also leads to malignancy of the lesions, as a result of constant stimulation of regenerative processes.Currently, there are a lot of publications describing the use of skin substitutes, three-dimensional tissue-engineered structures based on auto- and allogeneic cells that promote rapid epithelization of wounds in patients with congenital epidermolysis bullosa. The most prospective and at the same time the least studied direction of congenital epidermolysis bullosa treatment is the use of a combined skin equivalent created on the basis of keratinocytes and fibroblasts, which mixes the advantages of epidermal and dermal grafts.

Topical application of beta-blockers accelerates epithelialization to mesh skin grafted full-thickness burn in sheep

Aim : Beta-adrenergic receptor blockers are conventionally used for the treatment of hypertension, tachycardia, and glaucoma. Research has shown that beta-blockers can accelerate wound epithelialization. In this study, we tested the efficacy of the beta-blocker timolol in an ovine model of grafted full-thickness burn wound healing, which closely mimics clinical scenarios. Methods : Six full-thickness burn wounds were created on the sheep’s posterior surface. Twenty-four hours later, eschars were excised and meshed skin was grafted (Day0). The wounds in the treatment group received topical application of timolol. Blood flow was measured using a blood perfusion imager. Cardiovascular hemodynamics and blood glucose levels were recorded daily. The epithelialization rate on Day 14 was determined by planimetric assay and analyzed by paired t -test. The days that the epithelialization rate exceeded 85%, 90%, and 95% were analyzed by survival analysis. To assess the potential influence of TGFβ, epithelial-mesenchymal transition (EMT), or myofibroblast activation (MFA) on wound healing, the RNA abundance of gene products related to these pathways was measured by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). Results : The epithelialization rate on Day 14 was significantly higher in the treatment group. The days that the epithelialization rate exceeded 85%, 90%, and 95% were significantly shorter in the treatment group. There was no significant difference in wound blood flow or RNA abundance related to TGFβ, EMT, or MFA-related pathways among the groups at any time point. Conclusion : The results demonstrate that the beta-blocker timolol accelerates epithelialization of mesh skin grafted full-thickness burn wounds through a mechanism other than improving wound blood flow.

New Nanovesicles from Prickly Pear Fruit Juice: A Resource with Antioxidant, Anti-Inflammatory, and Nutrigenomic Properties.

Plant-derived nanovesicles represent a novel approach in the field of plant-derived biomaterials, offering a sustainable and biocompatible option for various biomedical applications. The unique properties of these vesicles, such as their ability to encapsulate bioactive compounds, make them suitable for therapeutic, cosmetic, and nutraceutical purposes. In this study, we have, for the first time, successfully bio-fabricated vesicles derived from Opuntia ficus-indica (FicoVes) using an efficient and cost-effective method. Characterized by a size of approximately of 114 nm and a negative zeta potential of -20.9 mV, FicoVes exhibited excellent biocompatibility and hemocompatibility, showing no reduction in the viability of human and animal cells. Our results showed that FicoVes possess significant antioxidant properties as they reduced ROS generation in TBH-stimulated cells. FicoVes displayed anti-inflammatory properties by reducing the expression of pro-inflammatory cytokines (Il 1β, TNF α) and enhancing the expression of anti-inflammatory cytokines (IL4, IL10) following an inflammatory stimulus. Furthermore, FicoVes accelerated epithelial wound closure in L929 fibroblast monolayers in a dose-dependent manner, highlighting their potential role in tissue repair. This study establishes FicoVes as a promising candidate for nutrigenomic applications, particularly in the context of inflammation-related disorders and wound healing. Further research, including in vivo studies, is essential to validate these findings and fully explore their therapeutic potential.

The impact of an open-label design on human amniotic membranes vs. silver sulfadiazine dressings for second-degree burns: a randomized controlled clinical trial

BackgroundBurn wounds require optimal medical management due to associated psycho-emotional and socioeconomic impacts and severe pain. The use of synthetic and biological dressings improves healing and reduces burn wound complications. The present study aimed to compare the outcomes of using human amniotic membrane (hAM) dressings and conventional silver sulfadiazine (SSDZ) ointment dressings in the management of second-degree burn wounds.MethodsFifty patients who participated in this clinical trial were divided into two groups via simple randomization. All the enrolled patients, who had burnt in the last 24 h, had thermal damage mechanisms and were suffering from less than 20% second-degree heat-burn wounds on the skin surface. The target group (n = 25) was treated with hAM, and the control group (n = 25) was treated with SSDZ ointment. The researcher-designed checklist was used to determine the clinical performance in the follow-up assessments on days 7, 14, and 30.ResultsNo significant differences were detected in terms of sex, age, or percentage of burn wounds (p > 0.05). Wound epithelialization at days 7, 14, and 30, scar formation, wound pigmentation, pain severity, analgesia requirements, and hospital stay length (on day 30) were significantly lower in the target group (treated with hAM) than in the control group (treated with SSDZ ointment) (p < 0.05). However, treatment costs in the target group ($170) were significantly higher than those in the control group ($71) (p < 0.001).ConclusionDespite its higher cost, hAM, as a technology-based therapy dressing, demonstrates superiority over SSDZ ointment in terms of wound healing and pain management.

Calcitonin gene-related peptide promotes epithelial reparative and anti-colitic functions of IL-4 educated human macrophages.

Interleukin-4 activated human macrophages (M(IL4) promote epithelial wound healing and exert an anti-colitic effect in a murine model. Blood monocyte-derived M(IL4)s from healthy donors and individuals with Crohn's disease had increased mRNA expression of the calcitonin gene-related peptide (CGRP) receptor chain, RAMP1, raising the issue of neural modulation of the M(IL4)s reparative function. Thus, human (MIL4)s were treated with CGRP and the cells phagocytotic, epithelial wound repair and anti-colitic functions were assessed. Initial studies confirmed up-regulation of expression of the CGRP receptor, which was localized to the cell surface and was functional as determined by CGRP-evoked increases in cAMP. M(IL4,CGRP)s had increased mannose receptor (CD206) and FcgRIIa (CD32a) mRNA expression, a subtle, but significant increase in phagocytosis, and decreased chemokine production following exposure to E. coli. When delivered systemically (106 cells, ip.) to oxazolone-treated rag1-/- mice, M(IL4,CGRP) had an anti-colitic effect superior to M(IL4)s from the same blood donor. Conditioned medium (CM) from M(IL4,CGRP) had increased amounts of TGFb and increased wound-healing capacity compared to matched M(IL4)-CM in the human CaCo2 epithelial cell line in vitro wounding assay. Moreover, M(IL4,CGRP)s displayed increased cyclooxygenase (COX)-1 and prostaglandin D2, and CM from M(IL4,CGRP)s treated with indomethacin or SC-560 to inhibit COX1 activity failed to promote repair of wounded CaCo2 cell monolayers. These data confirm the human M(IL4)s' anti-colitic effect that was enhanced by CGRP, and may be partially dependent on macrophage COX1/PDG2 activity. Thus, input from neurone-derived molecules is a local modifier capable of boosting the anti-colitic effect of autologous M(IL4) transfer.

HHIP's Dynamic Role in Epithelial Wound Healing Reveals a Potential Mechanism of COPD Susceptibility.

A genetic variant near HHIP has been consistently identified as associated with increased risk for Chronic Obstructive Pulmonary Disease (COPD), the third leading cause of death worldwide. However HHIP's role in COPD pathogenesis remains elusive. Canonically, HHIP is a negative regulator of the hedgehog pathway and downstream GLI1 and GLI2 activation. The hedgehog pathway plays an important role in wound healing, specifically in activating transcription factors that drive the epithelial mesenchymal transition (EMT), which in its intermediate state (partial EMT) is necessary for the collective movement of cells closing the wound. Herein, we propose a mechanism to explain HHIP's role in faulty epithelial wound healing, which could contribute to the development of emphysema, a key feature of COPD. Using two different Boolean models compiled from the literature, we show dysfunctional HHIP results in a lack of negative feedback on GLI, triggering a full EMT, where cells become mesenchymal and do not properly close the wound. We validate these Boolean models with experimental evidence gathered from published scientific literature. We also experimentally test if low HHIP expression is associated with EMT at the edge of wounds by using a scratch assay in a human lung epithelial cell line. Finally, we show evidence supporting our hypothesis in bulk and single cell RNA-Seq data from different COPD cohorts. Overall, our analyses suggest that aberrant wound healing due to dysfunctional HHIP, combined with chronic epithelial damage through cigarette smoke exposure, may be a primary cause of COPD-associated emphysema.

Foxp3+ regulatory T cells reside within the corneal epithelium and co-localize with limbal stem cells

In this study we investigated the presence of resident Foxp3+ regulatory T cells (Tregs) within the cornea and assessed the role of resident Tregs in corneal epithelial wound healing. Using a mouse model, we showed that in the steady state Foxp3+Tregs are either in close proximity or co-localize with ABCG2+ limbal stem cells. We also showed that these Tregs reside within the epithelial layer and not the corneal stroma. In addition, using a mouse model of mechanical injury, we demonstrated that depletion of Tregs from the cornea prior to corneal mechanical injury, using subconjunctival injection of anti-CD25, was associated with delayed epithelial healing. These results suggest a role for cornea resident Tregs in corneal epithelial cell function and wound healing and opens doors for further exploration of the role of Tregs in limbal stem cell function and survival.

Pulmonary epithelial wound healing and the immune system. Mathematical modelling and bifurcation analysis of a bistable system

Respiratory diseases such as asthma, acute respiratory distress syndrome (ARDS), influenza or COVID-19 often directly target the epithelium. Elevated immune levels and a ‘cytokine storm’ are directly associated with defective healing dynamics of lung diseases such as COVID-19 or ARDS. The infected cells leave wounded regions in the epithelium which must be healed for the lung to return to a healthy state and carry out its main function of gas-exchange. Due to the complexity of the various interactions between cells of the lung epithelium and surrounding tissue, it is necessary to develop models that can complement experiments to fully understand the healing dynamics. In this mathematical study we model the mechanism of epithelial regeneration. We assume that healing is exclusively driven by progenitor cell proliferation, induced by a chemical activator such as epithelial growth factor (EGF) and cytokines such as interleukin-22 (IL22). Contrary to previous studies of wound healing, we consider the immune system, specifically the T effector cells TH1, TH17, TH22 and Treg to strongly contribute to the healing process, by producing IL22 or regulating the immune response. We therefore obtain a coupled system of two ordinary differential equations for the epithelial and immune cell densities and two functions for the levels of chemicals that either induce epithelial proliferation or recruit immune cells. These functions link the two cell equations. We find that to allow the epithelium to regenerate to a healthy state, the immune system must not exceed a threshold value at the onset of the healing phase. This immune threshold is supported experimentally but was not explicitly built into our equations. Our assumptions are therefore sufficient to reproduce experimental results concerning the ratio TH17/Treg cells as a threshold to predict higher mortality rates in patients. This immune threshold can be controlled by parameters of the model, specifically the base-level growth factor concentration. This conclusion is based on a mathematical bifurcation analysis and linearization of the model equations. Our results suggest treatment of severe cases of lung injury by reducing or suppressing the immune response, in an individual patient, assessed by their disease parameters such as course of lung injury and immune response levels.