Browsing by Author "Palisson, Francis"

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    Antiviral drugs prolong survival in murine recessive dystrophic epidermolysis bullosa
    (2024) Tartaglia, Grace; Fuentes, Ignacia; Patel, Neil; Varughese, Abigail; Israel, Lauren E.; Park, Pyung Hun; Alexander, Michael H.; Poojan, Shiv; Cao, Qingqing; Solomon, Brenda; Padron, Zachary M.; Dyer, Jonathan A.; Mellerio, Jemima E.; McGrath, John A.; Palisson, Francis; Salas-Alanis, Julio; Han, Lin; South, Andrew P.
    Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin disease characterized by defects in type VII collagen leading to a range of fibrotic pathologies resulting from skin fragility, aberrant wound healing, and altered dermal fibroblast physiology. Using a novel in vitro model of fibrosis based on endogenously produced extracellular matrix, we screened an FDA-approved compound library and identified antivirals as a class of drug not previously associated with anti-fibrotic action. Preclinical validation of our lead hit, daclatasvir, in a mouse model of RDEB demonstrated significant improvement in fibrosis as well as overall quality of life with increased survival, weight gain and activity, and a decrease in pruritus-induced hair loss. Immunohistochemical assessment of daclatasvir-treated RDEB mouse skin showed a reduction in fibrotic markers, which was supported by in vitro data demonstrating TGF beta pathway targeting and a reduction of total collagen retained in the extracellular matrix. Our data support the clinical development of antivirals for the treatment of patients with RDEB and potentially other fibrotic diseases.
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    Epidemiology of epidermolysis bullosa in Chile
    (2024) Palisson, Francis; Yubero, Maria Joao; Lecaros, Cristobal; Kramer, Susanne; Fuentes, Constanza; Morande, Pilar; Noya, Belkis; Cofre, Glenda; Castillo, Jimena; Acevedo, Francisco; Burattini, Natalia; Munoz, Antonella; Klausseger, Alfred; Fuentes, Ignacia
    In this manuscript we are presenting the first National Epidermolysis Bullosa Epidemiology study done in South America. Our manuscript describes not only population-level estimates, such as incidence, prevalence and mortality of EB, but also genetic data that are unique to this underrepresented population. We report new data about this rare disease showing comparable life expectancy to wealthier nations, demonstrating the value of specialized EB care centres.
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    Epithelial HMGB1 Delays Skin Wound Healing and Drives Tumor Initiation by Priming Neutrophils for NET Formation
    (2019) Hoste, Esther; Maueroder, Christian; van Hove, Lisette; Catrysse, Leen; Vikkula, Hanna-Kaisa; Sze, Mozes; Maes, Bastiaan; Karjosukarso, Dyah; Martens, Liesbet; Goncalves, Amanda; Parthoens, Eef; Roelandt, Ria; Declercq, Wim; Fuentes, Ignacia; Palisson, Francis; Gonzalez, Sergio; Salas-Alanis, Julio C.; Boon, Louis; Huebener, Peter; Mulder, Klaas Willem; Ravichandran, Kodi; Saeys, Yvan; Schwabe, Robert Felix; van Loo, Geert
    Regenerative responses predispose tissues to tumor formation by largely unknown mechanisms. High-mobility group box 1 (HMGB1) is a danger-associated molecular pattern contributing to inflammatory pathologies. We show that HMGB1 derived from keratinocytes, but not myeloid cells, delays cutaneous wound healing and drives tumor formation. In wounds of mice lacking HMGB1 selectively in keratinocytes, a marked reduction in neutrophil extracellular trap (NET) formation is observed. Pharmacological targeting of HMGB1 or NETs prevents skin tumorigenesis and accelerates wound regeneration. HMGB1-dependent NET formation and skin tumorigenesis is orchestrated by tumor necrosis factor (TNF) and requires RIPK1 kinase activity. NETs are present in the microenvironment of keratinocyte-derived tumors in mice and lesional and tumor skin of patients suffering from recessive dystrophic epidermolysis bullosa, a disease in which skin blistering predisposes to tumorigenesis. We conclude that tumorigenicity of the wound microenvironment depends on epithelial-derived HMGB1 regulating NET formation, thereby establishing a mechanism linking reparative inflammation to tumor initiation.
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    Longitudinal study of wound healing status and bacterial colonisation of Staphylococcus aureus and Corynebacterium diphtheriae in epidermolysis bullosa patients
    (2022) Fuentes, Ignacia; Yubero, María Joao; Morandé, Pilar; Varela, Carmen; Oróstica, Karen; Acevedo, Francisco; Rebolledo‐Jaramillo, Boris; Arancibia, Esteban; Porte, Lorena; Palisson, Francis
    Epidermolysis bullosa (EB) is an inherited disorder characterised by skin fragility and the appearance of blisters and wounds. Patient wounds are often colonised or infected with bacteria, leading to impaired healing, pain and high risk of death by sepsis. Little is known about the impact of bacterial composition and susceptibility in wound resolution, and there is a need for longitudinal studies to understand healing outcomes with different types of bacterial colonisation. A prospective longitudinal study of 70 wounds from 15 severe EB patients (Junctional and Recessive Dystrophic EB) from Chile. Wounds were selected independently of their infected status. Wound cultures, including bacterial species identification, composition and Staphylococcus aureus (SA) antibiotic susceptibility were registered. Wounds were separated into categories according to their healing capacity, recognising chronic, and healing wounds. Hundred-one of the 102 wound cultures were positive for bacterial growth. From these, 100 were SA-positive; 31 were resistant to Ciprofloxacin (31%) and only seven were methicillin-resistant SA (7%). Ciprofloxacin-resistant SA was found significantly predominant in chronic wounds (**P < .01). Interestingly, atoxigenic Corynebacterium diphtheriae (CD) was identified and found to be the second most abundant recovered bacteria (31/101), present almost always in combination with SA (30/31). CD was only found in Recessive Dystrophic EB patients and not related to wound chronicity. Other less frequent bacterial species found included Pseudomonas aeruginosa, Streptococus spp. and Proteus spp. Infection was negatively associated with the healing status of wounds.
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    Maintenance of chronicity signatures in fibroblasts isolated from recessive dystrophic epidermolysis bullosa chronic wound dressings under culture conditions
    (2023) De Gregorio, Cristian; Catalán, Evelyng; Garrido, Gabriel; Morandé, Pilar; Bennett, Jimena C.; Muñoz, Catalina; Cofré, Glenda; Huang, Ya-Lin; Cuadra, Bárbara; Murgas, Paola; Calvo Bascuñan, Margarita; Altermatt Couratier, Fernando René; Yubero, María J.; Palisson, Francis; South, Andrew P.; Ezquer, Marcelo; Fuentes, Ignacia
    Background Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a rare inherited skin disease caused by variants in the COL7A1 gene, coding for type VII collagen (C7), an important component of anchoring fibrils in the basement membrane of the epidermis. RDEB patients suffer from skin fragility starting with blister formation and evolving into chronic wounds, inflammation and skin fibrosis, with a high risk of developing aggressive skin carcinomas. Restricted therapeutic options are limited by the lack of in vitro models of defective wound healing in RDEB patients. Results In order to explore a more efficient, non-invasive in vitro model for RDEB studies, we obtained patient fibroblasts derived from discarded dressings) and examined their phenotypic features compared with fibroblasts derived from non-injured skin of RDEB and healthy-donor skin biopsies. Our results demonstrate that fibroblasts derived from RDEB chronic wounds (RDEB-CW) displayed characteristics of senescent cells, increased myofibroblast differentiation, and augmented levels of TGF-β1 signaling components compared to fibroblasts derived from RDEB acute wounds and unaffected RDEB skin as well as skin from healthy-donors. Furthermore, RDEB-CW fibroblasts exhibited an increased pattern of inflammatory cytokine secretion (IL-1β and IL-6) when compared with RDEB and control fibroblasts. Interestingly, these aberrant patterns were found specifically in RDEB-CW fibroblasts independent of the culturing method, since fibroblasts obtained from dressing of acute wounds displayed a phenotype more similar to fibroblasts obtained from RDEB normal skin biopsies. Conclusions Our results show that in vitro cultured RDEB-CW fibroblasts maintain distinctive cellular and molecular characteristics resembling the inflammatory and fibrotic microenvironment observed in RDEB patients’ chronic wounds. This work describes a novel, non-invasive and painless strategy to obtain human fibroblasts chronically subjected to an inflammatory and fibrotic environment, supporting their use as an accessible model for in vitro studies of RDEB wound healing pathogenesis. As such, this approach is well suited to testing new therapeutic strategies under controlled laboratory conditions.
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    Recessive dystrophic epidermolysis bullosa results in painful small fibre neuropathy
    (2017) Von Bischhoffshausen, Sofia; Ivulic, Dinka; Alvarez, Paola; Schuffeneger, Victor C.; Idiaquez, Juan; Fuentes, Constanza; Morandé, Pilar; Fuentes, Ignacia; Palisson, Francis; Calvo Bascuñan, Margarita; Bennet, David L. H.
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    Replenishment of type VII collagen and re-epithelialization of chronically ulcerated skin after intradermal administration of allogeneic mesenchymal stromal cells in two patients with recessive dystrophic epidermolysis bullosa
    (INFORMA HEALTHCARE, 2010) Conget, Paulette; Rodriguez, Fernando; Kramer, Susanne; Allers, Carolina; Simon, Valeska; Palisson, Francis; Gonzalez, Sergio; Yubero, Maria J.
    In animal models it has been shown that mesenchymal stromal cells (MSC) contribute to skin regeneration and accelerate wound healing. We evaluated whether allogeneic MSC administration resulted in an improvement in the skin of two patients with recessive dystrophic epidermolysis bullosa (RDEB; OMIM 226600). Patients had absent type VII collagen immunohistofluorescence and since birth had suffered severe blistering and wounds that heal with scarring. Vehicle or 0.5x10