Mesenchymal Stem Cell Therapy in Type 1 Diabetes Mellitus and Its Main Complications: From Experimental Findings to Clinical Practice

Type 1 diabetes mellitus (T1DM) is a complex multifactorial disorder which involves a loss of self-tolerance leading to the autoimmune destruction of pancreatic β−cells. Exogenous insulin administration cannot mimic precise pancreatic β-cell regulation of glucose homeostasis, thereby leading to severe long-term complications. Pancreas or islet transplant only provides partial exogenous insulin independence and induces several adverse effects, including increased morbidity and mortality. The scientific community and diabetic patients are thus, still waiting for an effective therapy which could preserve the remaining β-cells, replenish islet mass and protect newly-generated β-cells from autoimmune destruction. Mesenchymal stem cells (MSCs) have been envisioned as a promising tool for T1DM treatment over the past few years, since they could differentiate into glucose-responsive insulin-producing cells. Their immunomodulatory and proangiogenic roles can be used to help arrest β-cell destruction, preserve residual β-cell mass, facilitate endogenous β-cell regeneration and prevent disease recurrence, thereby making them ideal candidates for the comprehensive treatment of diabetic patients. This review focuses on recent pre-clinical data supporting MSC use in regenerating β-cell mass and also in treating several T1DM-associated complications. Clinical trial results and the ongoing obstacles which must be addressed regarding the widespread use of such therapy are also discussed.Fil: Ezquer, Marcelo. Universidad del Desarrollo. Facultad de Medicina Clínica Alemana; ChileFil: Arango Rodriguez, Martha. Universidad del Desarrollo. Facultad de Medicina Clínica Alemana; ChileFil: Giraud Billoud, Maximiliano German. Universidad del Desarrollo. Facultad de Medicina Clínica Alemana; Chile. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Ezquer, Fernando. Universidad del Desarrollo. Facultad de Medicina Clínica Alemana; Chil

Tubulointerstitial injury and proximal tubule albumin transport in early diabetic nephropathy induced by type 1 diabetes mellitus

A decrease in the tubular expression of albumin endocytic transporters megalin and cubilin has been associated with diabetic nephropathy (DN), but there are no comprehensive studies to date relating early tubulointerstitial injury and the effect of the disease on both transporters in type 1 diabetes mellitus (T1DM). We used eight-week-old male C57BL/6 mice divided into two groups; one of them received the vehicle (control group), while the other received the vehicle + 200 mg/kg streptozotocin (T1DM). Ten weeks after the injection, we evaluated plasma insulin, enzymuria, urinary vitamin D-binding protein (VDBP), tubulointerstitial fibrosis and proximal tubule histology, markers of autophagy, and megalin and cubilin levels. We found a reduction in tubular protein reabsorption (albumin and VDBP as specific substances carried by both transporters) with increased tubulointerstitial injury, development of fibrosis, thickening of tubular basement membrane, and an increase in tubular cell metalloproteases. This was associated with a decrease in the renal expression of megalin and cubilin. We also observed an increase in the amount of cellular vesicles of the phagocytic system in the tubules, which could be linked to an alteration of normal intracellular trafficking of both receptors, thus affecting the normal function of transporters in early stages of DN. In diabetic animals, the added effects of tubulointerstitial injury, the decreases in megalin and cubilin expression, and an altered intracellular trafficking of these receptors, seriously affect protein reabsorptionFil: Giraud Billoud, Maximiliano German. Universidad del Desarrollo. Facultad de Medicina Clínica Alemana; Chile. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Ezquer, Fernando. Universidad del Desarrollo. Facultad de Medicina Clínica Alemana; ChileFil: Bahamonde, Javiera. Universidad del Desarrollo. Facultad de Medicina Clínica Alemana; ChileFil: Ezquer, Marcelo. Universidad del Desarrollo. Facultad de Medicina Clínica Alemana; Chil

Diabetic nephropathy, autophagy and proximal tubule protein endocytic transport: A potentially harmful relationship

Diabetic nephropathy (DN) is the most frequent cause of chronic renal failure. Until now, the pathophysiological mechanisms that determine its development and progression have not yet been elucidated. In the present study, we evaluate the role of autophagy at early stages of DN, induced in type 2 diabetes mellitus (T2DM) mouse, and its association with proximal tubule membrane endocytic receptors, megalin and cubilin. In T2DM animals we observed a tubule-interstitial injury with significantly increased levels of urinary GGT and ALP, but an absence of tubulointerstitial fibrosis. Kidney proximal tubule cells of T2DM animals showed autophagic vesicles larger than those observed in the control group, and an increase in the number of these vesicles marked with LBPA by immunofluorescence. Furthermore, a significant decrease in the ratio of LC3II/LC3I isoforms and in p62 protein expression in DN affected animals is shown. Finally, we observed a marked increase in urinary albumin and vitamin D binding-protein levels in T2DM animals as well as a significant decrease in expression of megalin in the renal cortex. These results indicate an alteration of the tubular endocytic transporters in DN, which could be related to autophagic dysfunction, which would in turn result in impaired organelle recycling, thus contributing to the progression of this disease.Fil: Giraud Billoud, Maximiliano German. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Fader Kaiser, Claudio Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Agüero, Rocio. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Ezquer, Fernando. Universidad del Desarrollo; ChileFil: Ezquer, Marcelo. Universidad del Desarrollo; Chil

Two complementary strategies to improve cell engraftment in mesenchymal stem cell-based therapy: Increasing transplanted cell resistance and increasing tissue receptivity

Over the past 2 decades, therapies based on mesenchymal stem cells (MSC) have been tested to treat several types of diseases in clinical studies, due to their potential for tissue repair and regeneration. Currently, MSC-based therapy is considered a biologically safe procedure, with the therapeutic results being very promising. However, the benefits of these therapies are not stable in the long term, and the final outcomes manifest with high inter-patient variability. The major cause of these therapeutic limitations results from the poor engraftment of the transplanted cells. Researchers have developed separate strategies to improve MSC engraftment. One strategy aims at increasing the survival of the transplanted MSCs in the recipient tissue, rendering them more resistant to the hostile microenvironment (cell-preconditioning). Another strategy aims at making the damaged tissue more receptive to the transplanted cells, favoring their interactions (tissue-preconditioning). In this review, we summarize several approaches using these strategies, providing an integral and updated view of the recent developments in MSC-based therapies. In addition, we propose that the combined use of these different conditioning strategies could accelerate the process to translate experimental evidences from pre-clinic studies to the daily clinical practice

Peak characteristics of F2 region over Tucumán: Predictions and measurements

Ionosonde measurements obtained at Tucuman are used to check the validity of the International Reference Ionosphere model to predict the maximum electron density of F2 region (NmF2) and its height (hmF2) over this station. Data corresponding to different months and solar activity conditions are considered. CCIR and URSI options are used to model calculations. The results show that, generally, the predictions of hmF2 are better than those of NmF2. Disagreements between predicted and measured NmF2 values are observed and the consequence in the vertical total electron content modeling are stressed.Fil: Ezquer, Rodolfo Gerardo. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Física. Laboratorio de Ionósfera; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mosert, Marta Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Instituto de Ciencias Astronómicas, de la Tierra y del Espacio. Universidad Nacional de San Juan. Instituto de Ciencias Astronómicas, de la Tierra y del Espacio; ArgentinaFil: Scida, Luis Alberto. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Física. Laboratorio de Ionósfera; ArgentinaFil: López, J.. Universidad Tecnológica Nacional; Argentin

Time variation of total electron content over Tucumán

Este trabajo presenta un análisis de la variabilidad del contenido electrónico total, TEC, sobre Tucumán (26.9S; 294.6E; Dip: -21.1) usando mediciones obtenidas por medio de la técnica Faraday durante el período de alta actividad solar comprendido entre abril de 1982 (R12=114) y marzo de 1983 (R12= 75). Los parámetros de variabilidad seleccionados para el estudio han sido la desviación standard del valor promedio s y el índice de variabilidad v = (desviación estándar / promedio) x 100. Las variaciones diurnas y estacionales de ambos parámetros de variabilidad han sido analizadas. Un estudio comparativo con la variabilidad día a día de la frecuencia crítica de la región F2, foF2, ha sido también llevado a cabo. Una tabla de valores de la variabilidad relativa v es presentada. Estudios adicionales se recomiendan con el objeto de extender este tipo de análisis a datos de TEC obtenidos en distintas condiciones geográficas y geofísicas.12=114) y marzo de 1983 (R12= 75). Los parámetros de variabilidad seleccionados para el estudio han sido la desviación standard del valor promedio s y el índice de variabilidad v = (desviación estándar / promedio) x 100. Las variaciones diurnas y estacionales de ambos parámetros de variabilidad han sido analizadas. Un estudio comparativo con la variabilidad día a día de la frecuencia crítica de la región F2, foF2, ha sido también llevado a cabo. Una tabla de valores de la variabilidad relativa v es presentada. Estudios adicionales se recomiendan con el objeto de extender este tipo de análisis a datos de TEC obtenidos en distintas condiciones geográficas y geofísicas.The day-to-day variability of total electron content, TEC, at Tucumán (26.9S; 294.6E; Dip: -21.1) has been studied. The database includes TEC measurements by Faraday rotation during the high solar activity period from April 1982 (R12= 114) to March 1983 (R12= 75). Two variability parameters have been used in the analysis: the standard deviation from the mean values s and the variability index v = (standard deviation/mean value) x100. The diurnal and seasonal variations of both variability parameters have been analyzed. A comparative analysis with the day-to-day variability of critical frequency in the F2 region, foF2, is presented. A table of values of the relative variability v is presented in terms of seasons and typical hours. Additional studies are suggested in order to extend the results to other geographical and geophysical conditions.Fil: Mosert, Marta Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Complejo Astronómico "El Leoncito". Universidad Nacional de Córdoba. Complejo Astronómico "El Leoncito". Universidad Nacional de la Plata. Complejo Astronómico "El Leoncito". Universidad Nacional de San Juan. Complejo Astronómico "El Leoncito"; ArgentinaFil: Ezquer, Rodolfo Gerardo. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Física. Laboratorio de Ionósfera; Argentina. Universidad Tecnológica Nacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán; ArgentinaFil: Jadur, Camilo Alberto. Universidad Nacional de Salta. Facultad de Ciencias Exactas. Departamento de Matemáticas; ArgentinaFil: Oviedo, Rosario del Valle. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Física. Laboratorio de Ionósfera; Argentin

Comparing TOPEX TEC measurements with IRI predictions

TEC values obtained from TOPEX satellite were compared with the International Reference Ionosphere (IRI) 2001 model estimates. The present work also shows results of the IRI model with the option of a new topside electron density distribution (NeQuick model). TOPEX TEC measurements, which include years of high and middle to low solar activity (2000 and 2004), were analyzed by binning the region covered by the satellite (±66°) every five degrees of modip. In general, there is good agreement between IRI predictions and Topex measurements. Cases with large disagreements are observed at low and high latitudes during high solar activity. Comparing the model predictions using the default IRI2001 model and the NeQuick topside option show that the default IRI 2001 version represents the observed data in a more realistic way, but appears to be less reliable at high and low latitudes in some cases.Fil: Migoya Orue, Yenca Olivia. Universidad Tecnológica Nacional; ArgentinaFil: S.M. Radicella. Aeronomy and Radiopropagation Laboratory; ItaliaFil: P. Coïsson. Aeronomy and Radiopropagation Laboratory; ItaliaFil: Ezquer, Rodolfo Gerardo. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Física. Laboratorio de Ionósfera; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán; ArgentinaFil: Nava, B.. Aeronomy and Radiopropagation Laboratory; Itali

F2 region maximum electron density height predictions for South American latitudes

Values of the F2 region maximum electron density height (hmF2) calculated using ground ionosonde data at South American latitudes are used to check the validity of the International Reference Ionosphere (IRI) to predict this variable. With this in mind we compare hmF2 predictions given by the model when measurements of critical frequency of F2 region and propagation parameter M(3000)F2 were used as input parameter in IRI (hmF2IRI-Exp), against those obtained using the standard International Radio Consultative Committee (CCIR) option (hmF2IRI-CCIR)- In this paper we used hmF2 IRI-Exp values because hmF2 measurements were not available for the considered cases. Moreover, a comparison of the measured M(3000)F2 values with the CCIR predictions have been done. The results show that, in general, the standard predictions follow the diurnal tendency observed in the hmF2 IRI-Exp values. At low latitudes the hmF2IRI-Exp values show oscillations not reproduced by the standard option. Cases with disagreements for 24 hours have been observed at high latitudes. Other cases with good agreement have been also obtained. The results suggest that, in general, the standard option of the model gives good hmF2 predictions at South American latitudes. Few cases showed deviation between 15 and 25%. As we expected, the obtained results suggest that the deviation between predicted and measured M(3000)F2 values is the main contribution for the deviation between hmF2IRI-CCIR and hmF2IRI-Exp. The comparison with the results obtained in previous work shows that the IRI performance in predicting M(3000)F2 and hmF2 is better than in predicting foF2.Fil: Ezquer, Rodolfo Gerardo. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Física. Laboratorio de Ionósfera; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán; ArgentinaFil: Scidá, Luis. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Física. Laboratorio de Ionósfera; ArgentinaFil: Mansilla, Gustavo Adolfo. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Física. Laboratorio de Ionósfera; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán; ArgentinaFil: Mosert, Marta Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Instituto de Ciencias Astronómicas, de la Tierra y del Espacio. Universidad Nacional de San Juan. Instituto de Ciencias Astronómicas, de la Tierra y del Espacio; ArgentinaFil: Herrera, Marcelo F.. Universidad Nacional de Tucumán. Facultad de Ciencias Exactas y Tecnología. Departamento de Física. Laboratorio de Ionósfera; Argentin

Spatial maps and oscillations in the healthy hippocampus of Octodon degus, a natural model of sporadic Alzheimer’s disease

The Octodon degus is a South American rodent that is receiving increased attention as a potential model of aging and sporadic late-onset Alzheimer’s disease (AD). Impairments in spatial memory tasks in Octodon degus have been reported in relation to either advanced AD-like disease or hippocampal lesion, opening the way to investigate how the function of hippocampal networks affects behavior across AD stages. However, no characterization of hippocampal electrophysiology exists in this species. Here we describe in young, healthy specimens the activity of neurons and local field potential rhythms during spatial navigation tasks with and without objects. Our findings show similarities between the Octodon degus and laboratory rodents. First, place cells with characteristics similar to those found in rats and mice exist in the CA1 subfield of the Octodon degus. Second, the introduction of objects elicits novelty-related exploration and an increase in activity of CA1 cells, with location specific and unspecific components. Third, oscillations of the local field potential are organized according to their spectral content into bands similar to those found in laboratory rodents. These results suggest a common framework of underlying mechanisms, opening the way to future studies of hippocampal dysfunction in this species associated to aging and disease.Fil: Mugnaini, Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Polania, Diana. Universidad de Chile; ChileFil: Díaz, Yannina Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Ezquer, Marcelo. Universidad del Desarrollo; ChileFil: Ezquer, Fernando. Universidad del Desarrollo; ChileFil: Deacon, Robert M. J.. Universidad de Chile; ChileFil: Cogram, Patricia. Universidad de Chile; Chile. University of California at Irvine; Estados UnidosFil: Kropff, Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin

Plant cell walls tackling climate change : insights into plant cell wall remodeling, its regulation, and biotechnological strategies to improve crop adaptations and photosynthesis in response to global warming

Plant cell wall (CW) is a complex and intricate structure that performs several functions throughout the plant life cycle. The CW of plants is critical to the maintenance of cells\u2019 structural integrity by resisting internal hydrostatic pressures, providing flexibility to support cell division and expansion during tissue differentiation, and acting as an environmental barrier that protects the cells in response to abiotic stress. Plant CW, comprised primarily of polysaccharides, represents the largest sink for photosynthetically fixed carbon, both in plants and in the biosphere. The CW structure is highly varied, not only between plant species but also among different organs, tissues, and cell types in the same organism. During the developmental processes, the main CW components, i.e., cellulose, pectins, hemicelluloses, and different types of CW-glycoproteins, interact constantly with each other and with the environment to maintain cell homeostasis. Differentiation processes are altered by positional effect and are also tightly linked to environmental changes, affecting CW both at the molecular and biochemical levels. The negative effect of climate change on the environment is multifaceted, from high temperatures, altered concentrations of greenhouse gases such as increasing CO2 in the atmosphere, soil salinity, and drought, to increasing frequency of extreme weather events taking place concomitantly, therefore, climate change affects crop productivity in multiple ways. Rising CO2 concentration in the atmosphere is expected to increase photosynthetic rates, especially at high temperatures and under water-limited conditions. This review aims to synthesize current knowledge regarding the effects of climate change on CW biogenesis and modification. We discuss specific cases in crops of interest carrying cell wall modifications that enhance tolerance to climate change-related stresses; from cereals such as rice, wheat, barley, or maize to dicots of interest such as brassica oilseed, cotton, soybean, tomato, or potato. This information could be used for the rational design of genetic engineering traits that aim to increase the stress tolerance in key crops. Future growing conditions expose plants to variable and extreme climate change factors, which negatively impact global agriculture, and therefore further research in this area is critical