RARE DISEASE
Localized junctional epidermolysis bullosa
Localized junctional epidermolysis bullosa
Localized junctional epidermolysis bullosa
Synonyms: JEB-nH loc, Junctional epidermolysis bullosa, non-Herlitz localized type, Localized JEB
Synonyms: JEB-nH loc, Junctional epidermolysis bullosa, non-Herlitz localized type, Localized JEB
Synonyms: JEB-nH loc, Junctional epidermolysis bullosa, non-Herlitz localized type, Localized JEB
Drug discovery
0
drugs
With orphan designations
Overview
Localized junctional epidermolysis bullosa (JEB) is a rare autosomal recessive subtype characterized by neonatal-onset blistering confined primarily to hands, feet, lower legs, and face. It involves dystrophic/absent nails, enamel hypoplasia, and caries susceptibility. Skin fragility stems from mutations in genes (LAMB3, COL17A1, or others) encoding epidermal-dermal adhesion proteins. Unlike severe JEB forms, it lacks systemic complications and typically preserves lifespan [6][11].
Burden
Chronic localized wounds increase infection risk and necessitate lifelong skin monitoring [9][16]
Dental complications (enamel defects, caries) and nail loss impair quality of life [6][11]
Lower mortality than severe JEB subtypes but requires multidisciplinary care to manage psychosocial and functional impacts [4][6]
Therapies
Supportive care: Minimize trauma, meticulous wound management with non-adherent dressings, infection prophylaxis [18]
Symptomatic intervention: Dental enamel protection, podiatry for nail dystrophy, analgesics for procedural pain [6][16]
Emerging therapies: Investigational gene/cell therapies (e.g., ex vivo LAMB3 correction) show promise in clinical trials [3][13]
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare odontological diseases, rare skin diseases
Research Papers
124 drug discovery papers about Localized junctional epidermolysis bullosa, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
124 drug discovery papers about Localized junctional epidermolysis bullosa, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-11-10 | Novel eRF3a degrader enhances gentamicin-induced premature termination codon readthrough in epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) and junctional epidermolysis bullosa (JEB) are severe blistering skin disorders caused by mutations in genes encoding type VII collagen (COL7A1) and laminin 332 (LAMA3, LAMB3, or LAMC2), respectively. In RDEB, 25% of patients carry nonsense mutations that result in premature termination codons (PTCs), while in JEB, the majority of mutations in LAMB3 are nonsense mutations (80%). CC-90009, an eRF3a degrader, is effective in inducing PTC readthrough in various in vitro models of diseases caused by nonsense mutations. This study evaluated CC-90009's ability, in combination with gentamicin, to suppress PTCs and promote the expression of type VII collagen (C7) in primary RDEB keratinocytes and fibroblasts, as well as laminin 332 in primary JEB keratinocytes with nonsense mutations. While CC-90009 alone demonstrated limited efficacy, its combination with low-dose gentamicin led to a dose-dependent increase in C7 and laminin β3 production, surpassing the effects of high-dose gentamicin alone. Furthermore, CC-90009/gentamicin reversed the hypermotility and poor substratum attachment characteristic of EB cells. Finally, C7 and laminin 332 induced by CC-90009/gentamicin localized to the dermal-epidermal junction in RDEB and JEB skin equivalents. Therefore, CC-90009/gentamicin may present a novel and safe treatment option for RDEB, JEB, and other inherited skin diseases arising from nonsense mutations.
2024-10-11 | Novel readthrough agent suppresses nonsense mutations and restores functional type VII collagen and laminin 332 in epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) and junctional epidermolysis bullosa (JEB) are lethal blistering skin disorders resulting from mutations in genes coding for type VII collagen (COL7A1) and laminin 332 (LAMA3, LAMB3, or LAMC2), respectively. In RDEB, 25% of patients harbor nonsense mutations causing premature termination codons (PTCs). In JEB, a majority of mutations in LAMB3 are nonsense mutations (80%). ELX-02, an aminoglycoside analog, has demonstrated superior PTC readthrough activity and lower toxicity compared to gentamicin in various genetic disorders. This study investigated the ability of ELX-02 to suppress PTCs and promote the expression of C7 and laminin 332 in primary RDEB keratinocytes/fibroblasts and primary JEB keratinocytes harboring nonsense mutations. ELX-02 induced a dose-dependent production of C7 or laminin β3 that surpassed the results achieved with gentamicin. ELX-02 reversed RDEB and JEB cellular hypermotility and improved poor cell-substratum adhesion in JEB cells. Importantly, ELX-02-induced C7 and laminin 332 localized to the dermal-epidermal junction. This is the first study demonstrating that ELX-02 can induce PTC readthrough and restore functional C7 and laminin 332 in RDEB and JEB caused by nonsense mutations. Therefore, ELX-02 may offer a novel and safe therapy for RDEB, JEB, and other inherited skin diseases caused by nonsense mutations.
2023-08-05 | PP2A-B55alpha controls keratinocyte adhesion through dephosphorylation of the Desmoplakin C-terminus
Abstract Critical for the maintenance of epidermal integrity and function are attachments between intermediate filaments (IF) and intercellular junctions called desmosomes. The desmosomal cytoplasmic plaque protein desmoplakin (DP) is essential for anchoring IF to the junction. DP-IF interactions are regulated by a phospho-regulatory motif within the DP C-terminus controlling keratinocyte intercellular adhesion. Here we identify the protein phosphatase 2A (PP2A)-B55α holoenzyme as the major serine/threonine phosphatase regulating DP’s C-terminus and consequent intercellular adhesion. Using a combination of chemical and genetic approaches, we show that the PP2A-B55α holoenzyme interacts with DP at intercellular membranes in 2D- and 3D- epidermal models and human skin samples. Our experiments demonstrate that PP2A-B55α regulates the phosphorylation status of junctional DP and is required for maintaining strong desmosome-mediated intercellular adhesion. These data identify PP2A-B55α as part of a regulatory module capable of tuning intercellular adhesion strength and a candidate disease target in desmosome-related disorders of the skin and heart.
2023-05-29 | Trametinib-Induced Epidermal Thinning Accelerates a Mouse Model of Junctional Epidermolysis Bullosa.
Junctional epidermolysis bullosa (JEB) patients experience skin and epithelial fragility due to a pathological deficiency in genes associated with epidermal adhesion. Disease severity ranges from post-natal lethality to localized skin involvement with persistent blistering followed by granulation tissue formation and atrophic scarring. We evaluated the potential of utilizing Trametinib, an MEK inhibitor previously shown to target fibrosis, with and without the documented EB-anti-fibrotic Losartan for reducing disease severity in a mouse model of JEB; Lamc2jeb mice. We found that Trametinib treatment accelerated disease onset and decreased epidermal thickness, which was in large part ameliorated by Losartan treatment. Interestingly, a range of disease severity was observed in Trametinib-treated animals that tracked with epidermal thickness; those animals grouped with higher disease severity had thinner epidermis. To examine if the difference in severity was related to inflammation, we conducted immunohistochemistry for the immune cell markers CD3, CD4, CD8, and CD45 as well as the fibrotic marker αSMA in mouse ears. We used a positive pixel algorithm to analyze the resulting images and demonstrated that Trametinib caused a non-significant reduction in CD4 expression that inversely tracked with increased fibrotic severity. With the addition of Losartan to Trametinib, CD4 expression was similar to control. Together, these data suggest that Trametinib causes a reduction in both epidermal proliferation and immune cell infiltration/proliferation, with concurrent acceleration of skin fragility, while Losartan counteracts Trametinib's adverse effects in a mouse model of JEB.
2023-05-01 | 1128 Trametinib treatment causes an increase in disease severity and reduced dermal immune cell infiltration in a mouse model of junctional epidermolysis bullosa
Junctional epidermolysis bullosa (JEB) patients experience increased skin fragility due to a pathological deficiency in genes associated with epidermal adhesion, leading to blistering, granulated tissue formation and atrophic scarring. Previous work has demonstrated the therapeutic utility of the triterpenoid RTA408 in reducing skin fragility in a LAMC2 mutated JEB mouse model (Lamc2jeb mice). We evaluated the potential of combining RTA408 with trametinib, a MEK inhibitor previously shown to target fibrosis in other mouse models, for reducing disease severity in Lamc2jeb mice. Whilst RTA408 reduced disease severity in monotherapy (P=0.015), trametinib failed to significantly alter severity trending toward an increase in severity and leading to early euthanasia in a proportion of treated animals. To examine if the difference in severity is related to immune cell infiltration, we conducted immunohistochemistry for the immune markers CD3, CD4 and CD45 in treated mouse skin. Following staining, the epidermal and dermal expression of these markers was analyzed using a positive pixel algorithm. Results revealed that while there were no changes in the epidermal expression of these markers for either RTA408 or trametinib, RTA408 did cause an increase in dermal expression of CD4 (P=0.0305) and a decrease in CD3 (P=0.0249). Conversely, trametinib treatment caused a universal reduction in CD3 (P=0.0038), CD4 (P=0.0003) and CD45 (P=0.0038) in the dermis. This broad reduction in immune markers was correlated with a significant reduction in epidermal thickness (P<0.0001) comparing treatment to control. No change in RTA408-treated mice was observed. Together this data suggest that trametinib-induced MEK inhibition causes a reduction in both epidermal proliferation and immune cell infiltration/proliferation, with concurrent acceleration of skin fragility.
gene therapies
2025-02-13 | Efficient Dual Cas9 Nickase Correction of a Prevalent Pathogenic LAMB 3 Variant for Junctional Epidermolysis Bullosa.
Gene editing facilitated by homology-directed repair represents a promising strategy for precisely correcting pathogenic variants underlying monogenic disorders, including the life-threatening skin blistering condition junctional epidermolysis bullosa (JEB). Frequent reports of unintended off-target genotoxicity associated with conventional Cas9 nuclease editing have increasingly led to the adoption of dual-Cas9 nickases (dual-Cas9n) owing to their improved safety profile. However, rates of precise repair obtained with such strategies remain low. In this study, we establish a dual-Cas9n approach targeting LAMB3, using electroporation to deliver Cas9-nickase ribonucleoproteins and modified single-stranded oligodeoxynucleotide repair templates into primary JEB keratinocytes. Targeting a hotspot pathogenic variant (c.1903C>T, p.R635∗), we report perfect correction efficiencies of up to 54% based on standard next-generation sequencing. Using a high-fidelity Cas9 nuclease, we also report perfect repair of up to 74% when using a small-molecule modulator of DNA repair. Dual-Cas9n-corrected JEB keratinocytes demonstrated restored laminin-332 expression and secretion in vitro, leading to improved cellular adhesion and accurate laminin-332 localization in engineered skin equivalents. This protocol represents a significant improvement in precision gene repair using Cas9 nickases for epidermolysis bullosa, with the potential to be applied to a large cohort of patients harboring this prevalent pathogenic variant.
2024-10-30 | The complex pathophysiology and clinical management of epidermolysis bullosa: a comprehensive review
Epidermolysis bullosa (EB) represents a group of rare, genetically heterogeneous disorders characterized by the formation of blisters and erosions of the skin and mucous membranes in response to minor mechanical trauma. EB is classified into four major types-EB simplex, junctional EB, dystrophic EB, and Kindler syndrome, each associated with mutations in specific genes that encode structural proteins essential for skin integrity. The clinical spectrum of EB ranges from mild forms, presenting with localized skin involvement, to severe variants that lead to widespread blistering, mutilating scarring, and significant morbidity. The pathophysiology of EB is complex, involving disruptions in the adhesion between the dermis and epidermis, leading to compromised structural stability of the skin. Current therapeutic strategies focus on symptom management, including wound care, infection prevention, and pain control, as no definitive cure exists. Advances in gene therapy, stem cell therapy, and protein replacement therapy hold promise for future treatment paradigms. This review aims to elucidate the molecular underpinnings, clinical manifestations, and emerging therapeutic approaches for EB, providing a comprehensive overview for clinicians and researchers engaged in the management and study of this challenging condition.
2024-07-17 | Biochemical role of FOXM1-dependent histone linker H1B in human epidermal stem cells
Abstract Epidermal stem cells orchestrate epidermal renewal and timely wound repair through a tight regulation of self-renewal, proliferation, and differentiation. In culture, human epidermal stem cells generate a clonal type referred to as holoclone, which give rise to transient amplifying progenitors (meroclone and paraclone-forming cells) eventually generating terminally differentiated cells. Leveraging single-cell transcriptomic data, we explored the FOXM1-dependent biochemical signals controlling self-renewal and differentiation in epidermal stem cells aimed at improving regenerative medicine applications. We report that the expression of H1 linker histone subtypes decrease during serial cultivation. At clonal level we observed that H1B is the most expressed isoform, particularly in epidermal stem cells, as compared to transient amplifying progenitors. Indeed, its expression decreases in primary epithelial culture where stem cells are exhausted due to FOXM1 downregulation. Conversely, H1B expression increases when the stem cells compartment is sustained by enforced FOXM1 expression, both in primary epithelial cultures derived from healthy donors and JEB patient. Moreover, we demonstrated that FOXM1 binds the promotorial region of H1B, hence regulates its expression. We also show that H1B is bound to the promotorial region of differentiation-related genes and negatively regulates their expression in epidermal stem cells. We propose a novel mechanism wherein the H1B acts downstream of FOXM1, contributing to the fine interplay between self-renewal and differentiation in human epidermal stem cells. These findings further define the networks that sustain self-renewal along the previously identified YAP-FOXM1 axis.
2023-10-05 | Functional analysis of Collagen 17a1: A genetic modifier of junctional epidermolysis bullosa in mice
Previous work strongly implicated Collagen 17a1 ( Col17a1 ) as a potent genetic modifier of junctional epidermolysis bullosa (JEB) caused by a hypomorphic mutation ( Lamc2 jeb ) in mice. The importance of the noncollagenous domain (NC4) of COLXVII was suggested by use of a congenic reduction approach that restricted the modifier effect to 2–3 neighboring amino acid changes in that domain. The current study utilizes TALEN and CRISPR/Cas9 induced amino acid replacements and in-frame indels nested to NC4 to further investigate the role of this and adjoining COLXVII domains both as modifiers and primary risk effectors. We confirm the importance of COLXVI AA 1275 S/G and 1277 N/S substitutions and utilize small nested indels to show that subtle changes in this microdomain attenuate JEB. We further show that large in-frame indels removing up to 1482 bp and 169 AA of NC6 through NC1 domains are surprisingly disease free on their own but can be very potent modifiers of Lamc2 jeb/jeb JEB. Together these studies exploiting gene editing to functionally dissect the Col17a1 modifier demonstrate the importance of epistatic interactions between a primary disease-causing mutation in one gene and innocuous ‘healthy’ alleles in other genes.
2023-07-12 | Seven naturally variant loci serve as genetic modifiers of Lamc2jeb induced non-Herlitz junctional Epidermolysis Bullosa in mice
Epidermolysis Bullosa (EB) is a group of rare genetic disorders that compromise the structural integrity of the skin such that blisters and subsequent erosions occur after minor trauma. While primary genetic risk of all subforms of EB adhere to Mendelian patterns of inheritance, their clinical presentations and severities can vary greatly, implying genetic modifiers. The Lamc2jeb mouse model of non-Herlitz junctional EB (JEB-nH) demonstrated that genetic modifiers can contribute substantially to the phenotypic variability of JEB and likely other forms of EB. The innocuous changes in an 'EB related gene', Col17a1, have shown it to be a dominant modifier of Lamc2jeb. This work identifies six additional Quantitative Trait Loci (QTL) that modify disease in Lamc2jeb/jeb mice. Three QTL include other known 'EB related genes', with the strongest modifier effect mapping to a region including the epidermal hemi-desmosomal structural gene dystonin (Dst-e/Bpag1-e). Three other QTL map to intervals devoid of known EB-associated genes. Of these, one contains the nuclear receptor coactivator Ppargc1a as its primary candidate and the others contain related genes Pparg and Igf1, suggesting modifier pathways. These results, demonstrating the potent disease modifying effects of normally innocuous genetic variants, greatly expand the landscape of genetic modifiers of EB and therapeutic approaches that may be applied.
proteins
2026-06-23 | FP14 Recombinant protein therapy for the treatment of junctional epidermolysis bullosa
Abstract Introduction and aims Junctional epidermolysis bullosa (JEB) is a rare genetic skin disorder leading to severe skin fragility from birth. It is caused by mutations in genes encoding the skin basement membrane proteins, Laminin 332, type XVII collagen or the basement membrane binding integrin α6β4, which anchor the epidermis to the dermis. JEB is characterized by widespread blistering of the skin and mucous membranes. The most severe form, JEB generalized severe, is caused by loss-of-function mutations in one of the chains of the trimeric protein Laminin 332. Babies diagnosed with this form of JEB generally do not survive beyond their first birthday. Patients suffer from failure to thrive, poor wound healing, anaemia, respiratory complications, and infections. The aim of this project is to explore the possibility of delivering recombinant laminin 332 (rLM332) to JEB skin to improve skin function. Methods We used a tamoxifen inducible mouse model of JEB (Lama3flox/floxK14CreERT), in which the Lama3 gene is specifically deleted in K14 expressing cells. JEB mice develop progressive blistering of skin and mucosa and exhibit reduced weight gain, mirroring the human disease. We examined the potential of rLM332 to treat JEB, exploring topical and subcutaneous injection and the impact on wound healing and disease severity biomarkers. Results We found both subcutaneous injection and topical application of rLM332 results in localization of the protein to the basement membrane. We observed improved wound healing, reduced blistering, improved basement membrane type VII collagen localization, and changes to the immune environment with rLM332 treatment. These changes persist at least 10 days following the final application. Conclusions Recombinant protein therapy presents a promising avenue for the treatment of JEB in patients, with topical application a potential noninvasive method of delivery in babies with extremely fragile skin. Murine experiments indicate durable improvements in skin health and accelerated wound healing.
2021-07-26 | Regeneration of Collagen Fibrils at the Papillary Dermis by Reconstructing Basement Membrane at the Dermal-Epidermal Junction
Abstract The epidermal basement membrane deteriorates with aging. We previously reported that basement membrane reconstruction not only serves to maintain epidermal stem/progenitor cells in the epidermis, but also increases collagen fibers in the papillary dermis. Here, we investigated the mechanism of the latter action. Collagen fibrils in the papillary dermis were increased in organotypic human skin culture treated with matrix metalloproteinase and heparinase inhibitors. The expression levels of COL5A1 and COL1A1 genes (encoding collagen type V α 1 chain and collagen type I α 1 chain, respectively) were increased in fibroblasts cultured with conditioned medium from a skin equivalent model cultured with the inhibitors and in keratinocytes cultured on laminin-511 fragment-coated plates. We then examined cytokine expression, and found that the inhibitors increased the expression of PDGF-BB (platelet-derived growth factor consisting of two B subunits) in epidermis. Expression of COL5A1 and COL1A1 genes was increased in cultured fibroblasts stimulated with PDGF-BB. Further, the bifunctional inhibitor hydroxyethyl imidazolidinone (HEI) increased skin elasticity and the thickness of the papillary dermis in the skin equivalent. Taken together, our data suggests that reconstructing the basement membrane promotes secretion of PDGF-BB by epidermal keratinocytes, leading to increased collagen expression at the papillary dermis.
2019-05-01 | Laminin 332-Dependent YAP Dysregulation Depletes Epidermal Stem Cells in Junctional Epidermolysis Bullosa
Laminin 332-deficient junctional epidermolysis bullosa (JEB) is a severe genetic skin disease. JEB is marked by epidermal stem cell depletion, the origin of which is unknown. We show that dysregulation of the YAP and TAZ pathway underpins such stem cell depletion. Laminin 332-mediated YAP activity sustains human epidermal stem cells, detected as holoclones. Ablation of YAP selectively depletes holoclones, while enforced YAP blocks conversion of stem cells into progenitors and indefinitely extends the keratinocyte lifespan. YAP is dramatically decreased in JEB keratinocytes, which contain only phosphorylated, inactive YAP. In normal keratinocytes, laminin 332 and α6β4 ablation abolish YAP activity and recapitulate the JEB phenotype. In JEB keratinocytes, laminin 332-gene therapy rescues YAP activity and epidermal stem cells in vitro and in vivo. In JEB cells, enforced YAP recapitulates laminin 332-gene therapy, thus uncoupling adhesion from proliferation in epidermal stem cells. This work has important clinical implication for ex vivo gene therapy of JEB.
2018-02-22 | Lack of K140 immunoreactivity in junctional epidermolysis bullosa skin and keratinocytes associates with misfolded laminin epidermal growth factor-like motif 2 of the β3 short arm
Recessive mutations in the LAMA3, LAMB3 and LAMC2 genes that encode laminin‐332 (LM332) (α3a, β3 and γ2 chains, respectively) cause different junctional epidermolysis bullosa (JEB) subtypes. Biallelic truncating mutations in any of these three genes usually lead to lack of protein expression resulting in the severe generalized JEB subtype, while missense or splice‐site mutations in at least one allele lead to reduced expression typical of JEB generalized intermediate (JEB‐gen intermed) or localized. Here, we molecularly characterized an adult patient with JEB showing negative skin staining for the anti‐β3 chain monoclonal antibody K140. This antibody recognizes an as yet unidentified epitope within the laminin β3 short arm. The patient harbours a homozygous splice‐site mutation resulting in highly aberrant transcripts with partial skipping of the LAMB3 exon that encodes the laminin epidermal growth factor‐like motif 2 of the β3 short arm (β3‐LE2). At the protein level, mutation consequences predict a misfolded β3‐LE2 motif and, indeed, we found that LM332 is correctly assembled but retained in the endoplasmic reticulum (ER) where it colocalizes with the lumenal ER chaperone protein BiP, leading to dramatically reduced secretion. Lack of K140 reactivity to mutant LM332 was confirmed by immunoprecipitation and Western blot analyses. Our findings not only identify the β3‐LE2 subdomain as the region recognized by K140, but also show that misfolding of LM332 structural motifs and subsequent protein retention in the ER is a common pathomechanism in JEB‐gen intermed. In addition to its usefulness in antigen mapping diagnosis of JEB subtypes, this knowledge is relevant to the design of therapeutic strategies aimed at releasing ER‐retained LM332 in JEB.
2017-07-11 | Type XVII collagen coordinates proliferation in the interfollicular epidermis
Type XVII collagen (COL17) is a transmembrane protein located at the epidermal basement membrane zone. COL17 deficiency results in premature hair aging phenotypes and in junctional epidermolysis bullosa. Here, we show that COL17 plays a central role in regulating interfollicular epidermis (IFE) proliferation. Loss of COL17 leads to transient IFE hypertrophy in neonatal mice owing to aberrant Wnt signaling. The replenishment of COL17 in the neonatal epidermis of COL17-null mice reverses the proliferative IFE phenotype and the altered Wnt signaling. Physical aging abolishes membranous COL17 in IFE basal cells because of inactive atypical protein kinase C signaling and also induces epidermal hyperproliferation. The overexpression of human COL17 in aged mouse epidermis suppresses IFE hypertrophy. These findings demonstrate that COL17 governs IFE proliferation of neonatal and aged skin in distinct ways. Our study indicates that COL17 could be an important target of anti-aging strategies in the skin.
cell therapies
2022-12-08 | Convergence of Biofabrication Technologies and Cell Therapies for Wound Healing
Cell therapy holds great promise for cutaneous wound treatment but presents practical and clinical challenges, mainly related to the lack of a supportive and inductive microenvironment for cells after transplantation. Main: This review delineates the challenges and opportunities in cell therapies for acute and chronic wounds and highlights the contribution of biofabricated matrices to skin reconstruction. The complexity of the wound healing process necessitates the development of matrices with properties comparable to the extracellular matrix in the skin for their structure and composition. Over recent years, emerging biofabrication technologies have shown a capacity for creating complex matrices. In cell therapy, multifunctional material-based matrices have benefits in enhancing cell retention and survival, reducing healing time, and preventing infection and cell transplant rejection. Additionally, they can improve the efficacy of cell therapy, owing to their potential to modulate cell behaviors and regulate spatiotemporal patterns of wound healing.The ongoing development of biofabrication technologies promises to deliver material-based matrices that are rich in supportive, phenotype patterning cell niches and are robust enough to provide physical protection for the cells during implantation.
2022-09-28 | Efficacy Of Intradermal Allogeneic Fibroblast Injections In Junctional Epidermolysis Bullosa
Objective — to assess the efficacy and safety of intradermal injections of allogeneic fibroblasts into non-healing wounds in a patient with junctional epidermolysis bullosa. Material and Methods — A 49-year-old patient with intermediate junctional epidermolysis bullosa was injected intradermally into the base of non-healing wounds with 1 mL suspension of allogeneic fibroblasts, which contained 5×106 cells/mL, 10×106 cells/mL, and 20×106 cells/mL. Immunofluorescence mapping exhibited reduced β3 chain of laminin 332 and collagen XVII expression in the basement membrane area. Paired erosions were injected with 2% albumin or saline solution. Results — At two weeks after treatment, wound areas reduced significantly, or 100% re-epithelialization occurred. Collagen XVII and β3 chain expression of laminin 332 increased at the dermal-epidermal junction. Conclusion — Our findings demonstrated that intradermal injections of allogeneic fibroblasts could be an effective therapeutic approach for treating small non-healing wounds in junctional epidermolysis bullosa.
2022-01-28 | Improving Polysaccharide-Based Chitin/Chitosan-Aerogel Materials by Learning from Genetics and Molecular Biology
Improved wound healing of burnt skin and skin lesions, as well as medical implants and replacement products, requires the support of synthetical matrices. Yet, producing synthetic biocompatible matrices that exhibit specialized flexibility, stability, and biodegradability is challenging. Synthetic chitin/chitosan matrices may provide the desired advantages for producing specialized grafts but must be modified to improve their properties. Synthetic chitin/chitosan hydrogel and aerogel techniques provide the advantages for improvement with a bioinspired view adapted from the natural molecular toolbox. To this end, animal genetics provide deep knowledge into which molecular key factors decisively influence the properties of natural chitin matrices. The genetically identified proteins and enzymes control chitin matrix assembly, architecture, and degradation. Combining synthetic chitin matrices with critical biological factors may point to the future direction with engineering materials of specific properties for biomedical applications such as burned skin or skin blistering and extensive lesions due to genetic diseases.
2022-01-24 | The application of mesenchymal stromal cells (MSCs) and their derivative exosome in skin wound healing: a comprehensive review
Recently, mesenchymal stromal cells (MSCs) and also their exosome has become a game-changing tool in the context of tissue engineering and regenerative medicine. MSCs due to their competencies to establish skin cells, such as fibroblast and keratinocyte, and also their unique attribute to suppress inflammation in wound site has attracted increasing attention among scholars. In addition, MSC's other capabilities to induce angiogenesis as a result of secretion of pro-angiogenic factors accompanied with marked anti-fibrotic activities, which mainly mediated by the releases matrix metalloproteinase (MMPs), make them a rational and effective strategy to accelerate wound healing with a small scar. Since the chief healing properties of the MSCs depend on their paracrine effects, it appears that MSCs-derived exosomes also can be an alternative option to support wound healing and skin regeneration as an innovative cell-free approach. Such exosomes convey functional cargos (e.g., growth factor, cytokine, miRNA, etc.) from MSCs to target cells, thereby affecting the recipient skin cells' biological events, such as migration, proliferation, and also secretion of ECM components (e.g., collagen). The main superiorities of exosome therapy over parental MSCs are the diminished risk of tumor formation and also lower immunogenicity. Herein, we deliver an overview of recent in vivo reports rendering the therapeutic benefits of the MSCs-based therapies to ease skin wound healing, and so improving quality of life among patients suffering from such conditions.
2021-05-04 | Single-keratinocyte transcriptomic analyses identify different clonal types and proliferative potential mediated by FOXM1 in human epidermal stem cells
Abstract Autologous epidermal cultures restore a functional epidermis on burned patients. Transgenic epidermal grafts do so also in genetic skin diseases such as Junctional Epidermolysis Bullosa. Clinical success strictly requires an adequate number of epidermal stem cells, detected as holoclone-forming cells, which can be only partially distinguished from the other clonogenic keratinocytes and cannot be prospectively isolated. Here we report that single-cell transcriptome analysis of primary human epidermal cultures identifies categories of genes clearly distinguishing the different keratinocyte clonal types, which are hierarchically organized along a continuous, mainly linear trajectory showing that stem cells sequentially generate progenitors producing terminally differentiated cells. Holoclone-forming cells display stem cell hallmarks as genes regulating DNA repair, chromosome segregation, spindle organization and telomerase activity. Finally, we identify FOXM1 as a YAP-dependent key regulator of epidermal stem cells. These findings improve criteria for measuring stem cells in epidermal cultures, which is an essential feature of the graft.
small molecules
2025-11-10 | Novel eRF3a degrader enhances gentamicin-induced premature termination codon readthrough in epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) and junctional epidermolysis bullosa (JEB) are severe blistering skin disorders caused by mutations in genes encoding type VII collagen (COL7A1) and laminin 332 (LAMA3, LAMB3, or LAMC2), respectively. In RDEB, 25% of patients carry nonsense mutations that result in premature termination codons (PTCs), while in JEB, the majority of mutations in LAMB3 are nonsense mutations (80%). CC-90009, an eRF3a degrader, is effective in inducing PTC readthrough in various in vitro models of diseases caused by nonsense mutations. This study evaluated CC-90009's ability, in combination with gentamicin, to suppress PTCs and promote the expression of type VII collagen (C7) in primary RDEB keratinocytes and fibroblasts, as well as laminin 332 in primary JEB keratinocytes with nonsense mutations. While CC-90009 alone demonstrated limited efficacy, its combination with low-dose gentamicin led to a dose-dependent increase in C7 and laminin β3 production, surpassing the effects of high-dose gentamicin alone. Furthermore, CC-90009/gentamicin reversed the hypermotility and poor substratum attachment characteristic of EB cells. Finally, C7 and laminin 332 induced by CC-90009/gentamicin localized to the dermal-epidermal junction in RDEB and JEB skin equivalents. Therefore, CC-90009/gentamicin may present a novel and safe treatment option for RDEB, JEB, and other inherited skin diseases arising from nonsense mutations.
2024-10-11 | Novel readthrough agent suppresses nonsense mutations and restores functional type VII collagen and laminin 332 in epidermolysis bullosa.
Recessive dystrophic epidermolysis bullosa (RDEB) and junctional epidermolysis bullosa (JEB) are lethal blistering skin disorders resulting from mutations in genes coding for type VII collagen (COL7A1) and laminin 332 (LAMA3, LAMB3, or LAMC2), respectively. In RDEB, 25% of patients harbor nonsense mutations causing premature termination codons (PTCs). In JEB, a majority of mutations in LAMB3 are nonsense mutations (80%). ELX-02, an aminoglycoside analog, has demonstrated superior PTC readthrough activity and lower toxicity compared to gentamicin in various genetic disorders. This study investigated the ability of ELX-02 to suppress PTCs and promote the expression of C7 and laminin 332 in primary RDEB keratinocytes/fibroblasts and primary JEB keratinocytes harboring nonsense mutations. ELX-02 induced a dose-dependent production of C7 or laminin β3 that surpassed the results achieved with gentamicin. ELX-02 reversed RDEB and JEB cellular hypermotility and improved poor cell-substratum adhesion in JEB cells. Importantly, ELX-02-induced C7 and laminin 332 localized to the dermal-epidermal junction. This is the first study demonstrating that ELX-02 can induce PTC readthrough and restore functional C7 and laminin 332 in RDEB and JEB caused by nonsense mutations. Therefore, ELX-02 may offer a novel and safe therapy for RDEB, JEB, and other inherited skin diseases caused by nonsense mutations.
2023-08-05 | PP2A-B55alpha controls keratinocyte adhesion through dephosphorylation of the Desmoplakin C-terminus
Abstract Critical for the maintenance of epidermal integrity and function are attachments between intermediate filaments (IF) and intercellular junctions called desmosomes. The desmosomal cytoplasmic plaque protein desmoplakin (DP) is essential for anchoring IF to the junction. DP-IF interactions are regulated by a phospho-regulatory motif within the DP C-terminus controlling keratinocyte intercellular adhesion. Here we identify the protein phosphatase 2A (PP2A)-B55α holoenzyme as the major serine/threonine phosphatase regulating DP’s C-terminus and consequent intercellular adhesion. Using a combination of chemical and genetic approaches, we show that the PP2A-B55α holoenzyme interacts with DP at intercellular membranes in 2D- and 3D- epidermal models and human skin samples. Our experiments demonstrate that PP2A-B55α regulates the phosphorylation status of junctional DP and is required for maintaining strong desmosome-mediated intercellular adhesion. These data identify PP2A-B55α as part of a regulatory module capable of tuning intercellular adhesion strength and a candidate disease target in desmosome-related disorders of the skin and heart.
2023-05-29 | Trametinib-Induced Epidermal Thinning Accelerates a Mouse Model of Junctional Epidermolysis Bullosa.
Junctional epidermolysis bullosa (JEB) patients experience skin and epithelial fragility due to a pathological deficiency in genes associated with epidermal adhesion. Disease severity ranges from post-natal lethality to localized skin involvement with persistent blistering followed by granulation tissue formation and atrophic scarring. We evaluated the potential of utilizing Trametinib, an MEK inhibitor previously shown to target fibrosis, with and without the documented EB-anti-fibrotic Losartan for reducing disease severity in a mouse model of JEB; Lamc2jeb mice. We found that Trametinib treatment accelerated disease onset and decreased epidermal thickness, which was in large part ameliorated by Losartan treatment. Interestingly, a range of disease severity was observed in Trametinib-treated animals that tracked with epidermal thickness; those animals grouped with higher disease severity had thinner epidermis. To examine if the difference in severity was related to inflammation, we conducted immunohistochemistry for the immune cell markers CD3, CD4, CD8, and CD45 as well as the fibrotic marker αSMA in mouse ears. We used a positive pixel algorithm to analyze the resulting images and demonstrated that Trametinib caused a non-significant reduction in CD4 expression that inversely tracked with increased fibrotic severity. With the addition of Losartan to Trametinib, CD4 expression was similar to control. Together, these data suggest that Trametinib causes a reduction in both epidermal proliferation and immune cell infiltration/proliferation, with concurrent acceleration of skin fragility, while Losartan counteracts Trametinib's adverse effects in a mouse model of JEB.
2023-05-01 | 1128 Trametinib treatment causes an increase in disease severity and reduced dermal immune cell infiltration in a mouse model of junctional epidermolysis bullosa
Junctional epidermolysis bullosa (JEB) patients experience increased skin fragility due to a pathological deficiency in genes associated with epidermal adhesion, leading to blistering, granulated tissue formation and atrophic scarring. Previous work has demonstrated the therapeutic utility of the triterpenoid RTA408 in reducing skin fragility in a LAMC2 mutated JEB mouse model (Lamc2jeb mice). We evaluated the potential of combining RTA408 with trametinib, a MEK inhibitor previously shown to target fibrosis in other mouse models, for reducing disease severity in Lamc2jeb mice. Whilst RTA408 reduced disease severity in monotherapy (P=0.015), trametinib failed to significantly alter severity trending toward an increase in severity and leading to early euthanasia in a proportion of treated animals. To examine if the difference in severity is related to immune cell infiltration, we conducted immunohistochemistry for the immune markers CD3, CD4 and CD45 in treated mouse skin. Following staining, the epidermal and dermal expression of these markers was analyzed using a positive pixel algorithm. Results revealed that while there were no changes in the epidermal expression of these markers for either RTA408 or trametinib, RTA408 did cause an increase in dermal expression of CD4 (P=0.0305) and a decrease in CD3 (P=0.0249). Conversely, trametinib treatment caused a universal reduction in CD3 (P=0.0038), CD4 (P=0.0003) and CD45 (P=0.0038) in the dermis. This broad reduction in immune markers was correlated with a significant reduction in epidermal thickness (P<0.0001) comparing treatment to control. No change in RTA408-treated mice was observed. Together this data suggest that trametinib-induced MEK inhibition causes a reduction in both epidermal proliferation and immune cell infiltration/proliferation, with concurrent acceleration of skin fragility.
gene therapies
2025-02-13 | Efficient Dual Cas9 Nickase Correction of a Prevalent Pathogenic LAMB 3 Variant for Junctional Epidermolysis Bullosa.
Gene editing facilitated by homology-directed repair represents a promising strategy for precisely correcting pathogenic variants underlying monogenic disorders, including the life-threatening skin blistering condition junctional epidermolysis bullosa (JEB). Frequent reports of unintended off-target genotoxicity associated with conventional Cas9 nuclease editing have increasingly led to the adoption of dual-Cas9 nickases (dual-Cas9n) owing to their improved safety profile. However, rates of precise repair obtained with such strategies remain low. In this study, we establish a dual-Cas9n approach targeting LAMB3, using electroporation to deliver Cas9-nickase ribonucleoproteins and modified single-stranded oligodeoxynucleotide repair templates into primary JEB keratinocytes. Targeting a hotspot pathogenic variant (c.1903C>T, p.R635∗), we report perfect correction efficiencies of up to 54% based on standard next-generation sequencing. Using a high-fidelity Cas9 nuclease, we also report perfect repair of up to 74% when using a small-molecule modulator of DNA repair. Dual-Cas9n-corrected JEB keratinocytes demonstrated restored laminin-332 expression and secretion in vitro, leading to improved cellular adhesion and accurate laminin-332 localization in engineered skin equivalents. This protocol represents a significant improvement in precision gene repair using Cas9 nickases for epidermolysis bullosa, with the potential to be applied to a large cohort of patients harboring this prevalent pathogenic variant.
2024-10-30 | The complex pathophysiology and clinical management of epidermolysis bullosa: a comprehensive review
Epidermolysis bullosa (EB) represents a group of rare, genetically heterogeneous disorders characterized by the formation of blisters and erosions of the skin and mucous membranes in response to minor mechanical trauma. EB is classified into four major types-EB simplex, junctional EB, dystrophic EB, and Kindler syndrome, each associated with mutations in specific genes that encode structural proteins essential for skin integrity. The clinical spectrum of EB ranges from mild forms, presenting with localized skin involvement, to severe variants that lead to widespread blistering, mutilating scarring, and significant morbidity. The pathophysiology of EB is complex, involving disruptions in the adhesion between the dermis and epidermis, leading to compromised structural stability of the skin. Current therapeutic strategies focus on symptom management, including wound care, infection prevention, and pain control, as no definitive cure exists. Advances in gene therapy, stem cell therapy, and protein replacement therapy hold promise for future treatment paradigms. This review aims to elucidate the molecular underpinnings, clinical manifestations, and emerging therapeutic approaches for EB, providing a comprehensive overview for clinicians and researchers engaged in the management and study of this challenging condition.
2024-07-17 | Biochemical role of FOXM1-dependent histone linker H1B in human epidermal stem cells
Abstract Epidermal stem cells orchestrate epidermal renewal and timely wound repair through a tight regulation of self-renewal, proliferation, and differentiation. In culture, human epidermal stem cells generate a clonal type referred to as holoclone, which give rise to transient amplifying progenitors (meroclone and paraclone-forming cells) eventually generating terminally differentiated cells. Leveraging single-cell transcriptomic data, we explored the FOXM1-dependent biochemical signals controlling self-renewal and differentiation in epidermal stem cells aimed at improving regenerative medicine applications. We report that the expression of H1 linker histone subtypes decrease during serial cultivation. At clonal level we observed that H1B is the most expressed isoform, particularly in epidermal stem cells, as compared to transient amplifying progenitors. Indeed, its expression decreases in primary epithelial culture where stem cells are exhausted due to FOXM1 downregulation. Conversely, H1B expression increases when the stem cells compartment is sustained by enforced FOXM1 expression, both in primary epithelial cultures derived from healthy donors and JEB patient. Moreover, we demonstrated that FOXM1 binds the promotorial region of H1B, hence regulates its expression. We also show that H1B is bound to the promotorial region of differentiation-related genes and negatively regulates their expression in epidermal stem cells. We propose a novel mechanism wherein the H1B acts downstream of FOXM1, contributing to the fine interplay between self-renewal and differentiation in human epidermal stem cells. These findings further define the networks that sustain self-renewal along the previously identified YAP-FOXM1 axis.
2023-10-05 | Functional analysis of Collagen 17a1: A genetic modifier of junctional epidermolysis bullosa in mice
Previous work strongly implicated Collagen 17a1 ( Col17a1 ) as a potent genetic modifier of junctional epidermolysis bullosa (JEB) caused by a hypomorphic mutation ( Lamc2 jeb ) in mice. The importance of the noncollagenous domain (NC4) of COLXVII was suggested by use of a congenic reduction approach that restricted the modifier effect to 2–3 neighboring amino acid changes in that domain. The current study utilizes TALEN and CRISPR/Cas9 induced amino acid replacements and in-frame indels nested to NC4 to further investigate the role of this and adjoining COLXVII domains both as modifiers and primary risk effectors. We confirm the importance of COLXVI AA 1275 S/G and 1277 N/S substitutions and utilize small nested indels to show that subtle changes in this microdomain attenuate JEB. We further show that large in-frame indels removing up to 1482 bp and 169 AA of NC6 through NC1 domains are surprisingly disease free on their own but can be very potent modifiers of Lamc2 jeb/jeb JEB. Together these studies exploiting gene editing to functionally dissect the Col17a1 modifier demonstrate the importance of epistatic interactions between a primary disease-causing mutation in one gene and innocuous ‘healthy’ alleles in other genes.
2023-07-12 | Seven naturally variant loci serve as genetic modifiers of Lamc2jeb induced non-Herlitz junctional Epidermolysis Bullosa in mice
Epidermolysis Bullosa (EB) is a group of rare genetic disorders that compromise the structural integrity of the skin such that blisters and subsequent erosions occur after minor trauma. While primary genetic risk of all subforms of EB adhere to Mendelian patterns of inheritance, their clinical presentations and severities can vary greatly, implying genetic modifiers. The Lamc2jeb mouse model of non-Herlitz junctional EB (JEB-nH) demonstrated that genetic modifiers can contribute substantially to the phenotypic variability of JEB and likely other forms of EB. The innocuous changes in an 'EB related gene', Col17a1, have shown it to be a dominant modifier of Lamc2jeb. This work identifies six additional Quantitative Trait Loci (QTL) that modify disease in Lamc2jeb/jeb mice. Three QTL include other known 'EB related genes', with the strongest modifier effect mapping to a region including the epidermal hemi-desmosomal structural gene dystonin (Dst-e/Bpag1-e). Three other QTL map to intervals devoid of known EB-associated genes. Of these, one contains the nuclear receptor coactivator Ppargc1a as its primary candidate and the others contain related genes Pparg and Igf1, suggesting modifier pathways. These results, demonstrating the potent disease modifying effects of normally innocuous genetic variants, greatly expand the landscape of genetic modifiers of EB and therapeutic approaches that may be applied.
proteins
2026-06-23 | FP14 Recombinant protein therapy for the treatment of junctional epidermolysis bullosa
Abstract Introduction and aims Junctional epidermolysis bullosa (JEB) is a rare genetic skin disorder leading to severe skin fragility from birth. It is caused by mutations in genes encoding the skin basement membrane proteins, Laminin 332, type XVII collagen or the basement membrane binding integrin α6β4, which anchor the epidermis to the dermis. JEB is characterized by widespread blistering of the skin and mucous membranes. The most severe form, JEB generalized severe, is caused by loss-of-function mutations in one of the chains of the trimeric protein Laminin 332. Babies diagnosed with this form of JEB generally do not survive beyond their first birthday. Patients suffer from failure to thrive, poor wound healing, anaemia, respiratory complications, and infections. The aim of this project is to explore the possibility of delivering recombinant laminin 332 (rLM332) to JEB skin to improve skin function. Methods We used a tamoxifen inducible mouse model of JEB (Lama3flox/floxK14CreERT), in which the Lama3 gene is specifically deleted in K14 expressing cells. JEB mice develop progressive blistering of skin and mucosa and exhibit reduced weight gain, mirroring the human disease. We examined the potential of rLM332 to treat JEB, exploring topical and subcutaneous injection and the impact on wound healing and disease severity biomarkers. Results We found both subcutaneous injection and topical application of rLM332 results in localization of the protein to the basement membrane. We observed improved wound healing, reduced blistering, improved basement membrane type VII collagen localization, and changes to the immune environment with rLM332 treatment. These changes persist at least 10 days following the final application. Conclusions Recombinant protein therapy presents a promising avenue for the treatment of JEB in patients, with topical application a potential noninvasive method of delivery in babies with extremely fragile skin. Murine experiments indicate durable improvements in skin health and accelerated wound healing.
2021-07-26 | Regeneration of Collagen Fibrils at the Papillary Dermis by Reconstructing Basement Membrane at the Dermal-Epidermal Junction
Abstract The epidermal basement membrane deteriorates with aging. We previously reported that basement membrane reconstruction not only serves to maintain epidermal stem/progenitor cells in the epidermis, but also increases collagen fibers in the papillary dermis. Here, we investigated the mechanism of the latter action. Collagen fibrils in the papillary dermis were increased in organotypic human skin culture treated with matrix metalloproteinase and heparinase inhibitors. The expression levels of COL5A1 and COL1A1 genes (encoding collagen type V α 1 chain and collagen type I α 1 chain, respectively) were increased in fibroblasts cultured with conditioned medium from a skin equivalent model cultured with the inhibitors and in keratinocytes cultured on laminin-511 fragment-coated plates. We then examined cytokine expression, and found that the inhibitors increased the expression of PDGF-BB (platelet-derived growth factor consisting of two B subunits) in epidermis. Expression of COL5A1 and COL1A1 genes was increased in cultured fibroblasts stimulated with PDGF-BB. Further, the bifunctional inhibitor hydroxyethyl imidazolidinone (HEI) increased skin elasticity and the thickness of the papillary dermis in the skin equivalent. Taken together, our data suggests that reconstructing the basement membrane promotes secretion of PDGF-BB by epidermal keratinocytes, leading to increased collagen expression at the papillary dermis.
2019-05-01 | Laminin 332-Dependent YAP Dysregulation Depletes Epidermal Stem Cells in Junctional Epidermolysis Bullosa
Laminin 332-deficient junctional epidermolysis bullosa (JEB) is a severe genetic skin disease. JEB is marked by epidermal stem cell depletion, the origin of which is unknown. We show that dysregulation of the YAP and TAZ pathway underpins such stem cell depletion. Laminin 332-mediated YAP activity sustains human epidermal stem cells, detected as holoclones. Ablation of YAP selectively depletes holoclones, while enforced YAP blocks conversion of stem cells into progenitors and indefinitely extends the keratinocyte lifespan. YAP is dramatically decreased in JEB keratinocytes, which contain only phosphorylated, inactive YAP. In normal keratinocytes, laminin 332 and α6β4 ablation abolish YAP activity and recapitulate the JEB phenotype. In JEB keratinocytes, laminin 332-gene therapy rescues YAP activity and epidermal stem cells in vitro and in vivo. In JEB cells, enforced YAP recapitulates laminin 332-gene therapy, thus uncoupling adhesion from proliferation in epidermal stem cells. This work has important clinical implication for ex vivo gene therapy of JEB.
2018-02-22 | Lack of K140 immunoreactivity in junctional epidermolysis bullosa skin and keratinocytes associates with misfolded laminin epidermal growth factor-like motif 2 of the β3 short arm
Recessive mutations in the LAMA3, LAMB3 and LAMC2 genes that encode laminin‐332 (LM332) (α3a, β3 and γ2 chains, respectively) cause different junctional epidermolysis bullosa (JEB) subtypes. Biallelic truncating mutations in any of these three genes usually lead to lack of protein expression resulting in the severe generalized JEB subtype, while missense or splice‐site mutations in at least one allele lead to reduced expression typical of JEB generalized intermediate (JEB‐gen intermed) or localized. Here, we molecularly characterized an adult patient with JEB showing negative skin staining for the anti‐β3 chain monoclonal antibody K140. This antibody recognizes an as yet unidentified epitope within the laminin β3 short arm. The patient harbours a homozygous splice‐site mutation resulting in highly aberrant transcripts with partial skipping of the LAMB3 exon that encodes the laminin epidermal growth factor‐like motif 2 of the β3 short arm (β3‐LE2). At the protein level, mutation consequences predict a misfolded β3‐LE2 motif and, indeed, we found that LM332 is correctly assembled but retained in the endoplasmic reticulum (ER) where it colocalizes with the lumenal ER chaperone protein BiP, leading to dramatically reduced secretion. Lack of K140 reactivity to mutant LM332 was confirmed by immunoprecipitation and Western blot analyses. Our findings not only identify the β3‐LE2 subdomain as the region recognized by K140, but also show that misfolding of LM332 structural motifs and subsequent protein retention in the ER is a common pathomechanism in JEB‐gen intermed. In addition to its usefulness in antigen mapping diagnosis of JEB subtypes, this knowledge is relevant to the design of therapeutic strategies aimed at releasing ER‐retained LM332 in JEB.
2017-07-11 | Type XVII collagen coordinates proliferation in the interfollicular epidermis
Type XVII collagen (COL17) is a transmembrane protein located at the epidermal basement membrane zone. COL17 deficiency results in premature hair aging phenotypes and in junctional epidermolysis bullosa. Here, we show that COL17 plays a central role in regulating interfollicular epidermis (IFE) proliferation. Loss of COL17 leads to transient IFE hypertrophy in neonatal mice owing to aberrant Wnt signaling. The replenishment of COL17 in the neonatal epidermis of COL17-null mice reverses the proliferative IFE phenotype and the altered Wnt signaling. Physical aging abolishes membranous COL17 in IFE basal cells because of inactive atypical protein kinase C signaling and also induces epidermal hyperproliferation. The overexpression of human COL17 in aged mouse epidermis suppresses IFE hypertrophy. These findings demonstrate that COL17 governs IFE proliferation of neonatal and aged skin in distinct ways. Our study indicates that COL17 could be an important target of anti-aging strategies in the skin.
cell therapies
2022-12-08 | Convergence of Biofabrication Technologies and Cell Therapies for Wound Healing
Cell therapy holds great promise for cutaneous wound treatment but presents practical and clinical challenges, mainly related to the lack of a supportive and inductive microenvironment for cells after transplantation. Main: This review delineates the challenges and opportunities in cell therapies for acute and chronic wounds and highlights the contribution of biofabricated matrices to skin reconstruction. The complexity of the wound healing process necessitates the development of matrices with properties comparable to the extracellular matrix in the skin for their structure and composition. Over recent years, emerging biofabrication technologies have shown a capacity for creating complex matrices. In cell therapy, multifunctional material-based matrices have benefits in enhancing cell retention and survival, reducing healing time, and preventing infection and cell transplant rejection. Additionally, they can improve the efficacy of cell therapy, owing to their potential to modulate cell behaviors and regulate spatiotemporal patterns of wound healing.The ongoing development of biofabrication technologies promises to deliver material-based matrices that are rich in supportive, phenotype patterning cell niches and are robust enough to provide physical protection for the cells during implantation.
2022-09-28 | Efficacy Of Intradermal Allogeneic Fibroblast Injections In Junctional Epidermolysis Bullosa
Objective — to assess the efficacy and safety of intradermal injections of allogeneic fibroblasts into non-healing wounds in a patient with junctional epidermolysis bullosa. Material and Methods — A 49-year-old patient with intermediate junctional epidermolysis bullosa was injected intradermally into the base of non-healing wounds with 1 mL suspension of allogeneic fibroblasts, which contained 5×106 cells/mL, 10×106 cells/mL, and 20×106 cells/mL. Immunofluorescence mapping exhibited reduced β3 chain of laminin 332 and collagen XVII expression in the basement membrane area. Paired erosions were injected with 2% albumin or saline solution. Results — At two weeks after treatment, wound areas reduced significantly, or 100% re-epithelialization occurred. Collagen XVII and β3 chain expression of laminin 332 increased at the dermal-epidermal junction. Conclusion — Our findings demonstrated that intradermal injections of allogeneic fibroblasts could be an effective therapeutic approach for treating small non-healing wounds in junctional epidermolysis bullosa.
2022-01-28 | Improving Polysaccharide-Based Chitin/Chitosan-Aerogel Materials by Learning from Genetics and Molecular Biology
Improved wound healing of burnt skin and skin lesions, as well as medical implants and replacement products, requires the support of synthetical matrices. Yet, producing synthetic biocompatible matrices that exhibit specialized flexibility, stability, and biodegradability is challenging. Synthetic chitin/chitosan matrices may provide the desired advantages for producing specialized grafts but must be modified to improve their properties. Synthetic chitin/chitosan hydrogel and aerogel techniques provide the advantages for improvement with a bioinspired view adapted from the natural molecular toolbox. To this end, animal genetics provide deep knowledge into which molecular key factors decisively influence the properties of natural chitin matrices. The genetically identified proteins and enzymes control chitin matrix assembly, architecture, and degradation. Combining synthetic chitin matrices with critical biological factors may point to the future direction with engineering materials of specific properties for biomedical applications such as burned skin or skin blistering and extensive lesions due to genetic diseases.
2022-01-24 | The application of mesenchymal stromal cells (MSCs) and their derivative exosome in skin wound healing: a comprehensive review
Recently, mesenchymal stromal cells (MSCs) and also their exosome has become a game-changing tool in the context of tissue engineering and regenerative medicine. MSCs due to their competencies to establish skin cells, such as fibroblast and keratinocyte, and also their unique attribute to suppress inflammation in wound site has attracted increasing attention among scholars. In addition, MSC's other capabilities to induce angiogenesis as a result of secretion of pro-angiogenic factors accompanied with marked anti-fibrotic activities, which mainly mediated by the releases matrix metalloproteinase (MMPs), make them a rational and effective strategy to accelerate wound healing with a small scar. Since the chief healing properties of the MSCs depend on their paracrine effects, it appears that MSCs-derived exosomes also can be an alternative option to support wound healing and skin regeneration as an innovative cell-free approach. Such exosomes convey functional cargos (e.g., growth factor, cytokine, miRNA, etc.) from MSCs to target cells, thereby affecting the recipient skin cells' biological events, such as migration, proliferation, and also secretion of ECM components (e.g., collagen). The main superiorities of exosome therapy over parental MSCs are the diminished risk of tumor formation and also lower immunogenicity. Herein, we deliver an overview of recent in vivo reports rendering the therapeutic benefits of the MSCs-based therapies to ease skin wound healing, and so improving quality of life among patients suffering from such conditions.
2021-05-04 | Single-keratinocyte transcriptomic analyses identify different clonal types and proliferative potential mediated by FOXM1 in human epidermal stem cells
Abstract Autologous epidermal cultures restore a functional epidermis on burned patients. Transgenic epidermal grafts do so also in genetic skin diseases such as Junctional Epidermolysis Bullosa. Clinical success strictly requires an adequate number of epidermal stem cells, detected as holoclone-forming cells, which can be only partially distinguished from the other clonogenic keratinocytes and cannot be prospectively isolated. Here we report that single-cell transcriptome analysis of primary human epidermal cultures identifies categories of genes clearly distinguishing the different keratinocyte clonal types, which are hierarchically organized along a continuous, mainly linear trajectory showing that stem cells sequentially generate progenitors producing terminally differentiated cells. Holoclone-forming cells display stem cell hallmarks as genes regulating DNA repair, chromosome segregation, spindle organization and telomerase activity. Finally, we identify FOXM1 as a YAP-dependent key regulator of epidermal stem cells. These findings improve criteria for measuring stem cells in epidermal cultures, which is an essential feature of the graft.
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