@article {710, title = {Transcriptomic Analysis of a Diabetic Skin-Humanized Mouse Model Dissects Molecular Pathways Underlying the Delayed Wound Healing Response.}, journal = {Genes (Basel)}, volume = {12}, year = {2020}, month = {2020 12 31}, abstract = {

Defective healing leading to cutaneous ulcer formation is one of the most feared complications of diabetes due to its consequences on patients{\textquoteright} quality of life and on the healthcare system. A more in-depth analysis of the underlying molecular pathophysiology is required to develop effective healing-promoting therapies for those patients. Major architectural and functional differences with human epidermis limit extrapolation of results coming from rodents and other small mammal-healing models. Therefore, the search for reliable humanized models has become mandatory. Previously, we developed a diabetes-induced delayed humanized wound healing model that faithfully recapitulated the major histological features of such skin repair-deficient condition. Herein, we present the results of a transcriptomic and functional enrichment analysis followed by a mechanistic analysis performed in such humanized wound healing model. The deregulation of genes implicated in functions such as angiogenesis, apoptosis, and inflammatory signaling processes were evidenced, confirming published data in diabetic patients that in fact might also underlie some of the histological features previously reported in the delayed skin-humanized healing model. Altogether, these molecular findings support the utility of such preclinical model as a valuable tool to gain insight into the molecular basis of the delayed diabetic healing with potential impact in the translational medicine field.

}, keywords = {Animals, Diabetes Mellitus, Experimental, Gene Expression Profiling, Gene Expression Regulation, Gene ontology, Humans, Metabolic Networks and Pathways, Mice, Mice, Nude, Microarray Analysis, Molecular Sequence Annotation, Principal Component Analysis, Signal Transduction, Skin, Skin Transplantation, Skin Ulcer, Streptozocin, Tissue Engineering, Transcriptome, Transplantation, Heterologous, Wound Healing}, issn = {2073-4425}, doi = {10.3390/genes12010047}, author = {Le{\'o}n, Carlos and Garcia-Garcia, Francisco and Llames, Sara and Garc{\'\i}a-P{\'e}rez, Eva and Carretero, Marta and Arriba, Mar{\'\i}a Del Carmen and Dopazo, Joaquin and Del Rio, Marcela and Escamez, Maria Jos{\'e} and Mart{\'\i}nez-Santamar{\'\i}a, Luc{\'\i}a} } @article {554, title = {Fibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses.}, journal = {Br J Dermatol}, volume = {181}, year = {2019}, month = {2019 09}, pages = {512-522}, abstract = {

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer-prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders.

OBJECTIVES: To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC.

METHODS: We conducted RNA-Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies.

RESULTS: Interdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in~situ analyses validated the RNA-Seq data. In addition, enzyme-linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB.

CONCLUSIONS: Our results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury-sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS. What{\textquoteright}s already known about this topic? Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three genodermatoses with high predisposition to cancer development. Although their causal genetic mutations mainly affect epithelia, the dermal microenvironment likely contributes to the physiopathology of these disorders. What does this study add? We disclose a large overlapping transcription profile between XPC, KS and RDEB fibroblasts that points towards an activated phenotype with high matrix-synthetic capacity. This common signature seems to be independent of the primary causal deficiency, but reflects an underlying derangement of the extracellular matrix via transforming growth factor-β signalling activation and oxidative state imbalance. What is the translational message? This study broadens the current knowledge about the pathology of these diseases and highlights new targets and biomarkers for effective therapeutic intervention. It is suggested that high levels of circulating periostin could represent a potential biomarker in RDEB.

}, keywords = {Adolescent, Adult, Biopsy, Blister, Case-Control Studies, Cells, Cultured, Child, Child, Preschool, Epidermolysis Bullosa, Epidermolysis Bullosa Dystrophica, Extracellular Matrix, Extracellular Matrix Proteins, Female, Fibroblasts, Fibrosis, Gene Expression Regulation, Healthy Volunteers, Humans, Infant, Infant, Newborn, Male, Middle Aged, mutation, Periodontal Diseases, Photosensitivity Disorders, Primary Cell Culture, RNA-seq, Skin, Xeroderma Pigmentosum, Young Adult}, issn = {1365-2133}, doi = {10.1111/bjd.17698}, author = {Chac{\'o}n-Solano, E and Le{\'o}n, C and D{\'\i}az, F and Garc{\'\i}a-Garc{\'\i}a, F and Garc{\'\i}a, M and Esc{\'a}mez, M J and Guerrero-Aspizua, S and Conti, C J and Menc{\'\i}a, {\'A} and Mart{\'\i}nez-Santamar{\'\i}a, L and Llames, S and P{\'e}vida, M and Carbonell-Caballero, J and Puig-Butill{\'e}, J A and Maseda, R and Puig, S and de Lucas, R and Baselga, E and Larcher, F and Dopazo, J and Del Rio, M} } @article {501, title = {Role of CPI-17 in restoring skin homoeostasis in cutaneous field of cancerization: effects of topical application of a film-forming medical device containing photolyase and UV filters.}, journal = {Exp Dermatol}, volume = {22}, year = {2013}, month = {2013 Jul}, pages = {494-6}, abstract = {

Cutaneous field of cancerization (CFC) is caused in part by the carcinogenic effect of the cyclobutane pyrimidine dimers CPD and 6-4 photoproducts (6-4PPs). Photoreactivation is carried out by photolyases which specifically recognize and repair both photoproducts. The study evaluates the molecular effects of topical application of a film-forming medical device containing photolyase and UV filters on the precancerous field in AK from seven patients. Skin improvement after treatment was confirmed in all patients by histopathological and molecular assessment. A gene set analysis showed that skin recovery was associated with biological processes involved in tissue homoeostasis and cell maintenance. The CFC response was associated with over-expression of the CPI-17 gene, and a dependence on the initial expression level was observed (P~=~0.001). Low CPI-17 levels were directly associated with pro-inflammatory genes such as TNF (P~=~0.012) and IL-1B (P~=~0.07). Our results suggest a role for CPI-17 in restoring skin homoeostasis in CFC lesions.

}, keywords = {Administration, Topical, Adult, Aged, Aged, 80 and over, Biopsy, Deoxyribodipyrimidine Photo-Lyase, Female, Gene Expression Profiling, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Homeostasis, Humans, Inflammation, Intracellular Signaling Peptides and Proteins, Liposomes, Male, Middle Aged, Muscle Proteins, Phenotype, Phosphoprotein Phosphatases, Reactive Oxygen Species, Skin, Skin Neoplasms, Ultraviolet Rays}, issn = {1600-0625}, doi = {10.1111/exd.12177}, author = {Puig-Butille, Joan Anton and Malvehy, Josep and Potrony, Miriam and Trullas, Carles and Garcia-Garcia, Francisco and Dopazo, Joaquin and Puig, Susana} }