Person: Sierra Isturiz, Javier
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Javier
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Sierra Isturiz
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Medicina
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Item Cell therapy for spinal cord injury with olfactory ensheathing glia cells (OECs).(Glia, 2018) Gómez, Rosa M.; Sánchez, Magdy Y.; Portela Lomba, María; Ghotme, Kemel; Barreto, George E.; Sierra Isturiz, Javier; Moreno Flores, María TeresaThe prospects of achieving regeneration in the central nervous system (CNS) have changed, as most recent findings indicate that several species, including humans, can produce neurons in adulthood. Studies targeting this property may be considered as potential therapeutic strategies to respond to injury or the effects of demyelinating diseases in the CNS. While CNS trauma may interrupt the axonal tracts that connect neurons with their targets, some neurons remain alive, as seen in optic nerve and spinal cord (SC) injuries (SCIs). The devastating consequences of SCIs are due to the immediate and significant disruption of the ascending and descending spinal pathways, which result in varying degrees of motor and sensory impairment. Recent therapeutic studies for SCI have focused on cell transplantation in animal models, using cells capable of inducing axon regeneration like Schwann cells (SchCs), astrocytes, genetically modified fibroblasts and olfactory ensheathing glia cells (OECs). Nevertheless, and despite the improvements in such cell‐based therapeutic strategies, there is still little information regarding the mechanisms underlying the success of transplantation and regarding any secondary effects. Therefore, further studies are needed to clarify these issues. In this review, we highlight the properties of OECs that make them suitable to achieve neuroplasticity/neuroregeneration in SCI. OECs can interact with the glial scar, stimulate angiogenesis, axon outgrowth and remyelination, improving functional outcomes following lesion. Furthermore, we present evidence of the utility of cell therapy with OECs to treat SCI, both from animal models and clinical studies performed on SCI patients, providing promising results for future treatments.Item Human placenta-derived mesenchymal stem cells stimulate neuronal regeneration by promoting axon growth and restoring neuronal activity(Frontiers in Cell and Developmental Biology, 2023) Laorden, Elvira H. de; Simón, Diana; Milla, Santiago; Portela Lomba, María; Mellén, Marian; Sierra Isturiz, Javier; De la Villa, Pedro; Moreno Flores, María Teresa; Iglesias Badiola, MaiteIn the last decades, mesenchymal stem cells (MSCs) have become the cornerstone of cellular therapy due to their unique characteristics. Specifically human placenta-derived mesenchymal stem cells (hPMSCs) are highlighted for their unique features, including ease to isolate, non-invasive techniques for large scale cell production, significant immunomodulatory capacity, and a high ability to migrate to injuries. Researchers are exploring innovative techniques to overcome the low regenerative capacity of Central Nervous System (CNS) neurons, with one promising avenue being the development of tailored mesenchymal stem cell therapies capable of promoting neural repair and recovery. In this context, we have evaluated hPMSCs as candidates for CNS lesion regeneration using a skillful co-culture model system. Indeed, we have demonstrated the hPMSCs ability to stimulate damaged rat-retina neurons regeneration by promoting axon growth and restoring neuronal activity both under normoxia and hypoxia conditions. With our model we have obtained neuronal regeneration values of 10%–14% and axonal length per neuron rates of 19-26, μm/neuron. To assess whether the regenerative capabilities of hPMSCs are contact-dependent effects or it is mediated through paracrine mechanisms, we carried out transwell co-culture and conditioned medium experiments confirming the role of secreted factors in axonal regeneration. It was found that hPMSCs produce brain derived, neurotrophic factor (BDNF), nerve-growth factor (NGF) and Neurotrophin-3 (NT-3), involved in the process of neuronal regeneration and restoration of the physiological activity of neurons. In effect, we confirmed the success of our treatment using the patch clamp technique to study ionic currents in individual isolated living cells demonstrating that in our model the regenerated neurons are electrophysiologically active, firing action potentials. The outcomes of our neuronal regeneration studies, combined with the axon-regenerating capabilities exhibited by mesenchymal stem cells derived from the placenta, present a hopeful outlook for the potential therapeutic application of hPMSCs in the treatment of neurological disorders.Item Small molecules fail to induce direct reprogramming of adult rat olfactory ensheathing glia to mature neurons.(Frontiers in Molecular Neuroscience, 2023) Portela Lomba, María; Simón, Diana; Fernández de Sevilla, David; Moreno Flores, María Teresa; Sierra Isturiz, JavierAn approach to generate new neurons after central nervous system injury or disease is direct reprogramming of the individual's own somatic cells into differentiated neurons. This can be achieved either by transduction of viral vectors that express neurogenic transcription factors and/or through induction with small molecules, avoiding introducing foreign genetic material in target cells. In this work, we propose olfactory ensheathing glia (OEG) as a candidate for direct reprogramming to neurons with small molecules due to its well-characterized neuro-regenerative capacity. After screening different combinations of small molecules in different culture conditions, only partial reprogramming was achieved: induced cells expressed neuronal markers but lacked the ability of firing action potentials. Our work demonstrates that direct conversion of adult olfactory ensheathing glia to mature, functional neurons cannot be induced only with pharmacological tools.Item Transcriptional analysis of the dachsous gene uncovers novel isoforms expressed during development in Drosophila.(FEBS Letters, 2015) Revilla Yates, Eva; Varas, Laura; Sierra Isturiz, Javier; Rodríguez, IsabelThe Drosophila cadherin-related protein Dachsous (Ds) plays a prominent role in planar cell polarity (PCP) and growth. The regulation of these two processes is based on the interaction between Ds and Fat proteins, generating an intracellular response required for tissue polarization and modulation of Hippo pathway activity. Here we have performed a comprehensive molecular study of the ds gene during larval development that has shown an unexpected complexity in its transcriptional regulation and revealed the expression of hitherto unsuspected transcripts. Also, knockdown of several isoforms provides new evidence on the importance of the cytoplasmic domain in the mechanism of action of Ds during development.Item Opiniones de profesores y alumnos sobre un programa integral online en medicina durante el confinamiento por COVID-19.(Educación médica, 2021) Ruiz Moral, Roger; Sierra Isturiz, Javier; Garcia Miguel Piedras, María José; Cerro, Álvaro; García de Leonardo Mena, Cristina; Turpín Sevilla, María del Carmen; Monge Martín, Diana; Caballero Martínez, FernandoIntroducción La crisis por COVID-19 supuso en marzo del 2020 el cierre de las universidades del país, con interrupción total de actividad presencial. Para afrontar el último cuatrimestre 2019/20 en confinamiento, nuestra Facultad de Medicina elaboró y aplicó un programa docente íntegramente online con un enfoque «autorregulativo» (enfocado en el aprendizaje autónomo del alumno). Este estudio presenta las opiniones de profesores y alumnos. Métodos Las características educativas del Programa online ante COVID-19 (POLAC), para primero y segundo cursos, estructuración, organización de la intervención y resultados académicos, han sido descritos en otro trabajo. Este estudio mediante encuestas online, explora opiniones de profesores y alumnos tras su desarrollo. Dos investigadores codificaron temática e independientemente las respuestas abiertas obtenidas, clasificándolas en categorías. Resultados Respondieron los ocho profesores implicados y un número variable por asignatura de alumnos, recibiéndose 234 cuestionarios (17%). Los alumnos destacan de positivo la optimización de recursos docentes utilizados, la utilidad de las herramientas online, especialmente autoevaluaciones y sistema de gestión de dudas. El desarrollo de las prácticas y aspectos propios de la presencialidad se destacaron como negativos. La dedicación de los profesores recibió comentarios, tanto positivos como negativos. Los profesores resaltaron la potenciación de la autonomía del alumno, la utilidad de las herramientas online y la necesidad adicional de presencialidad. Conclusión Globalmente, los comentarios positivos y negativos están en línea con las fortalezas y debilidades tanto de la enseñanza online como de enfoques docentes «autorregulativos». Se precisan estudios de diseños más robustos para comprobar el alcance real de estos resultados.Item Análisis comparativo de la región citoplasmática de las caderinas de polaridad planar celular Daschous de Drosophila y Dachsous1, Dachsous2 y CDH23 murinas(2011-09-05) Sierra Isturiz, Javier; Revilla, Eva; Rodríguez, Isabel; Varas, LauraCurso (2010/2011)Item Olfactory ensheathing cell-conditioned medium reverts 3 Ab25–35-induced oxidative damage in SH-SY5Y cells 4 by modulating the mitochondria-mediated apoptotic pathway.(Cellular and Molecular Neurobiology, 2016) Fu, Qing-Qing; Sierra Isturiz, Javier; Cheng, Jian-Zhang; Moreno Flores, María Teresa; You, Hua; Hua-Rong, YuOlfactory ensheathing cells (OECs) are a type of 10 glia from the mammalian olfactory system, with neuro- 11 protective and regenerative properties. b-Amyloid peptides 12 are a major component of the senile plaques characteristic 13 of the Alzheimer brain. The amyloid beta (Ab) precursor 14 protein is cleaved to amyloid peptides, and Ab25–35 is 15 regarded to be the functional domain of Ab, responsible for 16 its neurotoxic properties. It has been reported that Ab25–35 17 triggers reactive oxygen species (ROS)-mediated oxidative 18 damage, altering the structure and function of mitochon- 19 dria, leading to the activation of the mitochondrial intrinsic 20 apoptotic pathway. Our goal is to investigate the effects of 21 OECs on the toxicity of aggregated Ab25–35, in human 22 neuroblastoma SH-SY5Y cells. For such purpose, SH- 23 SY5Y cells were incubated with Ab25–35 and OEC-conditioned medium (OECCM). OECCM promoted the 24 cell viability and reduced the apoptosis, and decreased the 25 intracellular ROS and the lipid peroxidation. In the pres- 26 ence of OECCM, mRNA and protein levels of antioxidant 27 enzymes (SOD1 and SOD2) were upregulated. Concomi- 28 tantly, OECCM decreased mRNA and the protein expres- 29 sion levels of cytochrome c, caspase-9, caspase-3, and Bax 30 in SH-SY5Y cells, and increased mRNA and the protein 31 expression level of Bcl-2. However, OECCM did not alter 32 intracellular Ca 33 2? concentration in SH-SY5Y cells. Taken together, our data suggest that OECCM ameliorates 34 Ab25–35-induced oxidative damage in neuroblastoma SH- 35 SY5Y cells by inhibiting the mitochondrial intrinsic path- 36 way. These data provide new insights into the functional 37 actions of OECCM on oxidative stress-induced cell 38 damage.Item Dichotomous colorectal cancer behaviour.(Critical Reviews in Oncology/Hematology, 2023) Aljama, Sara; Pérez Lago, Estela; Zafra Amorós, Olga; Sierra Isturiz, Javier; Simón, Diana; Santos Tejedor, Cruz; Rodriguez Pascual, Jesus; García Romero, NoemíColorectal cancer (CRC) is the third most common malignant tumor and one of the deadliest cancers. At molecular level, CRC is a heterogeneous disease that could be divided in four Consensus Molecular Subtypes. Given the differences in the disease due to its anatomical location (proximal and distal colon), another classification should be considered. Here, we review the current knowledge on CRC dichotomic´s behaviour based on two different entities; right and left-sided tumors, their impact on clinical trial data, microbiota spatial composition and the interaction with the nervous system. We discuss recent advances in understanding how the spatial tumor heterogeneity influences the tumor growth, progression, and responses to current therapiesItem Transduction of an immortalized olfactory ensheathing glia cell line with the green fluorescent protein (GFP) gene: Evaluation of its neuroregenerative capacity as a proof of concept.(Neuroscience Letters, 2016) Plaza, N.; Simón, D.; Sierra Isturiz, Javier; Moreno Flores, María TeresaOlfactory ensheathing glia (OEG) cells are known to foster axonal regeneration of central nervous system (CNS) neurons. Several lines of reversibly immortalized human OEG (ihOEG) have been previously established that enabled to develop models for their validation in vitro and in vivo. In this work, a constitutively GFP-expressing ihOEG cell line was obtained, and named Ts14-GFP. Ts14-GFP neuroregenerative ability was similar to that found for the parental line Ts14 and it can be assayed using in vivo transplantation experimental paradigms, after spinal cord or optic nerve damage. Additionally, we have engineered a low-regenerative ihOEG line, hTL2, using lentiviral transduction of the large T antigen from SV40 virus, denominated from now on Ts12. Ts12 can be used as a low regeneration control in these experiments.Item Coculture of Axotomized Rat Retinal Ganglion Neurons with Olfactory Ensheathing Glia, as an In Vitro Model of Adult Axonal Regeneration.(Journal of Visualized Experiments, 2020) Portela Lomba, María; Simón, Diana; Russo, Cristina; Sierra Isturiz, Javier; Moreno Flores, María Teresa