Person: Ezquer, Marcelo
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Ezquer
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Marcelo
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Publication The Immunoregulatory and Regenerative Potential of Activated Human Stem Cell Secretome Mitigates Acute-on-Chronic Liver Failure in a Rat Mode(2024) Cuadra, Barbara; Silva, Veronica; Huang, Ya-Lin; Diaz, Yael; Rivas, Claudio; Molina, Cristobal; Simon, Valeska; Bono, Maria; Morales, Bernardo; Rosemblatt, Mario; Silva, Sebastian; Acuña, Rodrigo; Ezquer, Fernando; Ezquer, MarceloAcute-on-chronic liver failure (ACLF) is a syndrome marked by sudden liver function decline and multiorgan failure, predominantly acute kidney injury (AKY), in patients with chronic liver disease. Unregulated inflammation is a hallmark of ACLF; however, the key drivers of ACLF are not fully understood. This study explores the therapeutic properties of human mesenchymal stem cell (MSC) secretome, particularly focusing on its enhanced anti-inflammatory and pro-regenerative properties after the in vitro preconditioning of the cells. We evaluated the efficacy of the systemic administration of MSC secretome in preventing liver failure and AKI in a rat ACLF model where chronic liver disease was induced using by the administration of porcine serum, followed by D-galN/LPS administration to induce acute failure. After ACLF induction, animals were treated with saline (ACLF group) or MSC-derived secretome (ACLF-secretome group). The study revealed that MSC-secretome administration strongly reduced liver histological damage in the ACLF group, which was correlated with higher hepatocyte proliferation, increased hepatic and systemic anti-inflammatory molecule levels, and reduced neutrophil and macrophage infiltration. Additionally, renal examination revealed that MSC-secretome treatment mitigated tubular injuries, reduced apoptosis, and downregulated injury markers. These improvements were linked to increased survival rates in the ACLF-secretome group, endorsing MSC secretomes as a promising therapy for multiorgan failure in ACLF.Publication Amelioration of morphine withdrawal syndrome by systemic and intranasal administration of mesenchymal stem cell-derived secretome in preclinical models of morphine dependence(2023) Ezquer, Marcelo; Gallardo, Javiera; Quezada, Mauricio; Ponce, Carolina; Berríos, Pablo; Santapau, Daniela; De Gregorio, Cristian; Quintanilla, María; Morales, Paola; Herrera, Mario; Israel, Yedy; Andrés, Paula; Hipólito, Lucia; Ezquer, FernandoBackground: Morphine is an opiate commonly used in the treatment of moderate to severe pain. However, prolonged administration can lead to physical dependence and strong withdrawal symptoms upon cessation of morphine use. These symptoms can include anxiety, irritability, increased heart rate, and muscle cramps, which strongly promote morphine use relapse. The morphine-induced increases in neuroinflammation, brain oxidative stress, and alteration of glutamate levels in the hippocampus and nucleus accumbens have been associated with morphine dependence and a higher severity of withdrawal symptoms. Due to its rich content in potent anti-inflammatory and antioxidant factors, secretome derived from human mesenchymal stem cells (hMSCs) is proposed as a preclinical therapeutic tool for the treatment of this complex neurological condition associated with neuroinflammation and brain oxidative stress. Methods: Two animal models of morphine dependence were used to evaluate the therapeutic efficacy of hMSC-derived secretome in reducing morphine withdrawal signs. In the first model, rats were implanted subcutaneously with mini-pumps which released morphine at a concentration of 10 mg/kg/day for seven days. Three days after pump implantation, animals were treated with a simultaneous intravenous and intranasal administration of hMSC-derived secretome or vehicle, and withdrawal signs were precipitated on day seven by i.p. naloxone administration. In this model, brain alterations associated with withdrawal were also analyzed before withdrawal precipitation. In the second animal model, rats voluntarily consuming morphine for three weeks were intravenously and intranasally treated with hMSC-derived secretome or vehicle, and withdrawal signs were induced by morphine deprivation. Results: In both animal models secretome administration induced a significant reduction of withdrawal signs, as shown by a reduction in a combined withdrawal score. Secretome administration also promoted a reduction in morphine-induced neuroinflammation in the hippocampus and nucleus accumbens, while no changes were observed in extracellular glutamate levels in the nucleus accumbens. Conclusion: Data presented from two animal models of morphine dependence suggest that administration of secretome derived from hMSCs reduces the development of opioid withdrawal signs, which correlates with a reduction in neuroinflammation in the hippocampus and nucleus accumbens.Publication Therapeutic challenges in central nervous system viral infections: advancing mesenchymal stem cell-based strategies for treating neuroinflammation and promoting tissue repair(2025) Carbone, Javier; Fontecilla, Javiera; Sales, Nicolás; Chaparro, William; Molina, Alfredo; Ruete, María; González, Pablo; Machuca, Mayra; Opazo, Ma Cecilia; Ezquer, Marcelo; Duarte, LuisaAlthough significant progress has been made in medicine and antimicrobial research, viral infections continue to pose a critical global health challenge, particularly when they involve the central nervous system (CNS). Despite advances in vaccines, antiviral agents, and small molecule therapeutics, current strategies remain insufficient to address the complex consequences of many CNS infections fully. Notably, many viruses are neurotropic and can invade the CNS, triggering infectious neuroinflammation that often lead to chronic neurological disorders and lasting morbidity. Current therapeutic approaches are largely ineffective in preventing or reversing this long-term neurological damage, underscoring the urgent need for innovative prophylactic and therapeutic interventions. Mesenchymal stem cells (MSCs) have emerged as a promising strategy to counteract chronic neuroinflammation and promote tissue repair following viral CNS infections. This review provides a comprehensive overview of CNS viral infection and neuroinflammation, including epidemiology and pathophysiology, and critically examines the limitations of existing treatments, particularly their inability to mitigate persistent neurological sequelae. Furthermore, we summarize recent preclinical and clinical studies investigating the use of MSCs in the context of CNS viral infections, highlighting their immunomodulatory and neuroprotective mechanisms, and discuss the challenges and future directions for MSC-based therapies in clinical settings.