DE GREGORIO CONCHA, CRISTIAN ALEJANDRO

Preferred name
DE GREGORIO CONCHA, CRISTIAN ALEJANDRO
Main Affiliation
Email
crdegregorio@udd.cl
ORCID
0000-0002-0231-2468
Scopus Author ID
57193329776

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    Gut Microbiota‐Derived Extracellular Vesicles Influence Alcohol Intake Preferences in Rats
    (Wiley, 2025-03)
    Macarena Díaz‐Ubilla
    ;
    Aliosha I. Figueroa‐Valdés
    ;
    Hugo E. Tobar
    ;
    María Elena Quintanilla
    ;
    Eugenio Díaz
    <jats:title>ABSTRACT</jats:title><jats:p>Growing preclinical and clinical evidence suggests a link between gut microbiota dysbiosis and problematic alcohol consumption. Extracellular vesicles (EVs) are key mediators involved in bacteria‐to‐host communication. However, their potential role in mediating addictive behaviour remains unexplored. This study investigates the role of gut microbiota‐derived bacterial extracellular vesicles (bEVs) in driving high alcohol consumption. bEVs were isolated from the gut microbiota of a high alcohol‐drinking rat strain (UChB rats), either ethanol‐naïve or following chronic alcohol consumption and administered intraperitoneally or orally to alcohol‐rejecting male and female Wistar rats. Both types of UChB‐derived bEVs increased Wistar's voluntary alcohol consumption (three bottle choice test) up to 10‐fold (<jats:italic>p</jats:italic> &lt; 0.0001), indicating that bEVs are able and sufficient to transmit drinking behaviour across different rat strains. Molecular analysis revealed that bEVs administration did not induce systemic or brain inflammation in the recipient animals, suggesting that the increased alcohol intake triggered by UChB‐derived bEVs operates through an inflammation‐independent mechanism. Furthermore, we demonstrate that the vagus nerve mediates the bEV‐induced increase in alcohol consumption, as bilateral vagotomy completely abolished the high drinking behaviour induced by both intraperitoneally injected and orally administered bEVs. Thus, this study identifies bEVs as a novel mechanism underlying gut microbiota‐induced high alcohol intake in a vagus nerve‐dependent manner.</jats:p>
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    Scopus© Citations 2  3
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    Sensory neuron cultures derived from adult db/db mice as a simplified model to study type-2 diabetes-associated axonal regeneration defects
    (2021)
    DE GREGORIO CONCHA, CRISTIAN ALEJANDRO  
    ;
    EZQUER, EDUARDO FERNANDO  
    <jats:title>ABSTRACT</jats:title> <jats:p>Diabetic neuropathy (DN) is an early common complication of diabetes mellitus (DM), leading to chronic pain, sensory loss and muscle atrophy. Owing to its multifactorial etiology, neuron in vitro cultures have been proposed as simplified systems for DN studies. However, the most used models currently available do not recreate the chronic and systemic damage suffered by peripheral neurons of type-2 DM (T2DM) individuals. Here, we cultured neurons derived from dorsal root ganglia from 6-month-old diabetic db/db-mice, and evaluated their morphology by the Sholl method as an easy-to-analyze readout of neuronal function. We showed that neurons obtained from diabetic mice exhibited neuritic regeneration defects in basal culture conditions, compared to neurons from non-diabetic mice. Next, we evaluated the morphological response to common neuritogenic factors, including nerve growth factor NGF and Laminin-1 (also called Laminin-111). Neurons derived from diabetic mice exhibited reduced regenerative responses to these factors compared to neurons from non-diabetic mice. Finally, we analyzed the neuronal response to a putative DN therapy based on the secretome of mesenchymal stem cells (MSC). Neurons from diabetic mice treated with the MSC secretome displayed a significant improvement in neuritic regeneration, but still reduced when compared to neurons derived from non-diabetic mice. This in vitro model recapitulates many alterations observed in sensory neurons of T2DM individuals, suggesting the possibility of studying neuronal functions without the need of adding additional toxic factors to culture plates. This model may be useful for evaluating intrinsic neuronal responses in a cell-autonomous manner, and as a throughput screening for the pre-evaluation of new therapies for DN.</jats:p>
      2  1Scopus© Citations 6
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    Paw Skin as a Translational Model for Investigating Fibrotic and Inflammatory Wound Healing Defects in Recessive Dystrophic Epidermolysis Bullosa
    (MDPI AG, 2025-04-30)
    DE GREGORIO CONCHA, CRISTIAN ALEJANDRO  
    ;
    Giselle Ramos-Gonzalez
    ;
    Bernardo Morales-Catalán
    ;
    EZQUER, EDUARDO FERNANDO  
    ;
    EZQUER, EDUARDO MARCELO  
    Recessive dystrophic epidermolysis bullosa (RDEB) is a severe genetic disease caused by COL7A1 mutations. It leads to skin fragility, chronic inflammation, and impaired wound healing. The condition often results in fibrotic scarring, pseudosyndactyly, and cutaneous squamous cell carcinoma (SCC). However, current animal models fail to fully replicate chronic RDEB wounds. In this study, we used Collagen VII-hypomorphic mice (Col7a1flNeo/flNeo) and created full-thickness wounds on their paw skin, an area prone to fibrosis due to mechanical stress. We analyzed the healing process using histology, immunofluorescence, and electron microscopy. The RDEB mice showed delayed wound closure, increased inflammation, and poor granulation tissue formation. At 30 days post-injury, we observed persistent fibrosis, with elevated levels of Collagen I, α-SMA+ myofibroblasts, and tenascin-C. These mice also had fewer intraepidermal nerve fibers, which may help explain the neuropathic pain associated with RDEB. Our model reproduces the main features of chronic RDEB wounds. It offers a useful tool for evaluating therapies aimed at reducing inflammation, fibrosis, and tumor risk in these patients.
      4Scopus© Citations 3
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    A Novel Morphine Drinking Model of Opioid Dependence in Rats
    (2022)
    BERRIOS CARCAMO, PABLO ANDRES  
    ;
    Mauricio Quezada
    ;
    Daniela Santapau
    ;
    Paola Morales
    ;
    OLIVARES, MARIA BELEN  
    <jats:p>An animal model of voluntary oral morphine consumption would allow for a pre-clinical evaluation of new treatments aimed at reducing opioid intake in humans. However, the main limitation of oral morphine consumption in rodents is its bitter taste, which is strongly aversive. Taste aversion is often overcome by the use of adulterants, such as sweeteners, to conceal morphine taste or bitterants in the alternative bottle to equalize aversion. However, the adulterants’ presence is the cause for consumption choice and, upon removal, the preference for morphine is not preserved. Thus, current animal models are not suitable to study treatments aimed at reducing consumption elicited by morphine itself. Since taste preference is a learned behavior, just-weaned rats were trained to accept a bitter taste, adding the bitterant quinine to their drinking water for one week. The latter was followed by allowing the choice of quinine or morphine (0.15 mg/mL) solutions for two weeks. Then, quinine was removed, and the preference for morphine against water was evaluated. Using this paradigm, we show that rats highly preferred the consumption of morphine over water, reaching a voluntary morphine intake of 15 mg/kg/day. Morphine consumption led to significant analgesia and hyperlocomotion, and to a marked deprivation syndrome following the administration of the opioid antagonist naloxone. Voluntary morphine consumption was also shown to generate brain oxidative stress and neuroinflammation, signs associated with opioid dependence development. We present a robust two-bottle choice animal model of oral morphine self-administration for the evaluation of therapeutic interventions for the treatment of morphine dependence.</jats:p>
      1Scopus© Citations 18
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    Human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic BKS db/db mice
    (2020)
    DE GREGORIO CONCHA, CRISTIAN ALEJANDRO  
    ;
    CONTADOR MARTINEZ, DAVID ERNESTO  
    ;
    Cristian Acosta
    ;
    Diego Díaz
    ;
    Constanza Cárcamo
    <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Diabetic polyneuropathy (DPN) is the most common and early developing complication of diabetes mellitus, and the key contributor for foot ulcers development, with no specific therapies available.</jats:p> <jats:p>Different studies have shown that mesenchymal stem cell (MSC) administration is able to ameliorate DPN; however, limited cell survival and safety reasons hinder its transfer from bench to bedside. MSCs secrete a broad range of antioxidant, neuroprotective, angiogenic, and immunomodulatory factors (known as conditioned medium), which are all decreased in the peripheral nerves of diabetic patients. Furthermore, the abundance of these factors can be boosted in vitro by incubating MSCs with a preconditioning stimulus, enhancing their therapeutic efficacy. We hypothesize that systemic administration of conditioned medium derived from preconditioned MSCs could reverse DPN and prevent foot ulcer formation in a mouse model of type II diabetes mellitus.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>Diabetic BKS <jats:italic>db/db</jats:italic> mice were treated with systemic administration of conditioned medium derived from preconditioned human MSCs; conditioned medium derived from non-preconditioned MSCs or vehicle after behavioral signs of DPN was already present. Conditioned medium or vehicle administration was repeated every 2 weeks for a total of four administrations, and several functional and structural parameters characteristic of DPN were evaluated. Finally, a wound was made in the dorsal surface of both feet, and the kinetics of wound closure, re-epithelialization, angiogenesis, and cell proliferation were evaluated.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>Our molecular, electrophysiological, and histological analysis demonstrated that the administration of conditioned medium derived from non-preconditioned MSCs or from preconditioned MSCs to diabetic BKS <jats:italic>db/db</jats:italic> mice strongly reverts the established DPN, improving thermal and mechanical sensitivity, restoring intraepidermal nerve fiber density, reducing neuron and Schwann cell apoptosis, improving angiogenesis, and reducing chronic inflammation of peripheral nerves. Furthermore, DPN reversion induced by conditioned medium administration enhances the wound healing process by accelerating wound closure, improving the re-epithelialization of the injured skin and increasing blood vessels in the wound bed in a skin injury model that mimics a foot ulcer.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Studies conducted indicate that MSC-conditioned medium administration could be a novel cell-free therapeutic approach to reverse the initial stages of DPN, avoiding the risk of lower limb amputation triggered by foot ulcer formation and accelerating the wound healing process in case it occurs.</jats:p> </jats:sec>
      1  4Scopus© Citations 97