Logros y conflictos en la investigación con células troncales / Achievements and struggles in stem-cell investigation research

Se relatan circunstancias, peripecias y conflictos que han rodeado a varios de los investigadores que han protagonizado el avance de los conocimientos sobre las células troncales a lo largo de cien años, desde el establecimiento del dogma de la inmortalidad celular hasta las técnicas desarrolladas para obtenerlas y utilizarlas en medicina regeneradora. En este último aspecto, se incluye un breve análisis de las perspectivas previstas para las células pluripotentes inducidas (iPS) en relación con las células troncales producidas por transferencia nuclear (NT-ESC) y la producción de embriones humanos por transferencia nuclear de células somáticas (embriones SCNT) (AU)

This report describes events, circumstances and conflicts that have surrounded to several researchers protagonists of the advances on the stem cells knowledge along a hundred of years, from the cell immortality dogma to the discovery of tecnics to produce them to be used in regenerative medicine. At this respect, a brief analysis of the expected outlook for induced human pluripotent cells (iPS) is included and compared with nuclear transfer human stem cells (NTESC) and production of human enbryos by somatic cell nuclear transfer (SCNT embryos) (AU)

MicroRNAs involved in the browning process of adipocytes

The present review focuses on the role of miRNAs in the control of white adipose tissue browning, a process which describes the recruitment of adipocytes showing features of brown adipocytes in white adipose tissue. MicroRNAs (miRNAs) are a class of short non-coding RNAs (19-22 nucleotides) involved in gene regulation. Although the main effect of miRNAs is the inhibition of the translational machinery, thereby preventing the production of the protein product, the activation of protein translation has also been described in the literature. In addition to modifying translation, miRNAs binding to its target mRNAs also trigger the recruitment and association of mRNA decay factors, leading to mRNA destabilization, degradation, and thus to the decrease in expression levels. Although a great number of miRNAs have been reported to potentially regulate genes that play important roles in the browning process, only a reduced number of studies have demonstrated experimentally an effect on this process associated to changes in miRNA expressions, so far. These studies have shown, by using either primary adipocyte cultures or experimental models of mice (KO mice, mice overexpressing a specific miRNA) that miR-196a, miR-26 and miR-30 are needed for browning process development. By contrast, miR-155, miR-133, miR-27b and miR-34 act as negative regulators of this process. Further studies are needed to fully describe the miRNA network-involved white adipose tissue browning regulation (AU)

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Erratum to: MicroRNAs involved in the browning process of adipocytes

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Las células troncales pluripotenciales en la terapia celular / Pluripotent stem cells on cell therapy

Las células con pluripotencialidad inducida (iPS) son un nuevo tipo de célula troncal derivada de células somáticas humanas, mediante reprogramación con factores de transcripción. Estas células iPS tienen características de las células troncales embrionarias, como la capacidad de convertirse en todos los tipos de células diferenciadas del organismo. A corto plazo, las células de pacientes reprogramadas están siendo útiles para crear modelos celulares de enfermedades, en las que estudiar los procesos patológicos y probar fármacos. A pesar de algunas críticas, se ha ido acumulando evidencia en los trabajos preclínicos, sobre la efectividad de la terapia celular con los clones de iPS apropiadamente seleccionados. La generación de células iPS ha propiciado el desarrollo de otras técnicas, como por ejemplo, la transdiferenciación por la que se convierte directamente in vivo fibroblastos cardiacos en miocitos. Este tipo celular pluripotencial es de un gran valor en la investigación biomedicina y abre nuevas posibilidades a la terapia celular (AU)

Induced pluripotent stem (iPS) cells are a novel stem cell population derived from human somatic cells through reprogramming using a set of transcription factors. These iPS cells were shown to share the characteristics of embryonic stem cells, including the ability to give rise to differentiated cells of every tissue type of the body. In the shorter term, iPS cells will be useful for creating patient-identical disease model cells in which the pathological process can be studied and drugs can be tested. Despite critical attitudes, accumulating preclinical evidence supports the effectiveness of iPSC based cell therapy on the selection of appropriate iPSC clones. The production of iPS cells has also spurred the development of other techniques, for example, transdifferentiation by researchers can now convert heart fibroblasts directly in vivo into myocytes by similar methods. This pluripotent cells is indeed of great value in medical research and it is opening new possibilities in cell therapy (AU)

Diferenciación neural de células del estroma de médula ósea humana en presencia de líquido cefalorraquídeo / Neural differentiation of human bone marrow stromal cells in the presence of cerebrospinal fluid

Objetivo: Analizar la influencia del LCR sobre el proceso de diferenciación neural de BMSC inducida por agentes químicos. Material y métodos: Se hizo un estudio de diferenciación química de BMSC humanas, valorando el porcentaje de ellas que expresan marcadores neurales, a diferentes tiempos tras ser expuestas in vitro a factores químicos de inducción neuronal, y se ha comparado este proceso de transdiferenciación morfológica con el obtenido tras repetir el estudio en las mismas condiciones experimentales, pero añadiendo al medio de cultivo 1 ml de LCR, con una concentración de factor neurotrófico derivado de cerebro (BDNF) de 1,5 pg/ml. Resultados: Los factores neurotróficos presentes en LCR, en las condiciones experimentales del presente estudio, no modifican el proceso de diferenciación neural de BMSC mediado in vitro por agentes químicos. Conclusiones: Este hallazgo sugiere que cuando las BMSC son administradas en el espacio subaracnoideo, los factores neurotróficos del LCR no influyen significativamente en el proceso de su diferenciación neural (AU)

Objective: To analyze the influence of cerebrospinal fluid (CSF) upon the neural differentiation of bone marrow stromal cells (BMSCs) induced by chemical agents. Material and methods: A chemical differentiation study was made of human BMSCs, assessing the percentage of the latter that express neural markers at different timepoints following in vitro exposure to chemical neural induction factors. This morphological trans-differentiation process was in turn compared with that obtained after repeating the study under the same conditions but adding 1 ml of CSF to the culture medium, with a brain derived neurotrophic factor (BDNF) concentration of 1.5 pg/ml. Results: Under the experimental conditions of this study, the neurotrophic factors present in CSF did not modify the neural differentiation process of BMSCs mediated by chemical agents in vitro. Conclusions: These findings suggest that when BMSCs are administered within the subarachnoid space, the neurotrophic factors in CSF do not significantly influence the neural differentiation of the cells (AU)

Origin of renal cell carcinomas

Cancer is a heritable disorder of somatic cells: environment and heredity are both important in the carcinogenic process. The primal force is the "two hits" of Knudson's hypothesis, which has proved true for many tumours, including renal cell carcinoma. Knudson et al. [1, 2] recognised that familial forms of cancer might hold the key to the identification of important regulatory elements known as tumour-suppressor genes. Their observations (i.e., that retinoblastoma tend to be multifocal in familial cases and unifocal in sporadic presentation) led them to propose a two-hit theory of carcinogenesis. Furthermore, Knudson postulated that patients with the familial form of the cancer would be born with one mutant allele and that all cells in that organ or tissue would be at risk, accounting for early onset and the multifocal nature of the disease. In contrast, sporadic tumours would develop only if a mutation occurred in both alleles within the same cell, and, as each event would be expected to occur with low frequency, most tumours would develop late in life and in a unifocal manner [3, 4]. The kidney is affected in a variety of inherited cancer syndromes. For most of them, both the oncogene/tumour-suppressor gene involved and the respective germline mutations have been identified. Each of the inherited syndromes predisposes to distinct types of renal carcinoma. Families with hereditary predisposition to cancer continue to provide a unique opportunity for the identification and characterisation of genes involved in carcinogenesis. A surprising number of genetic syndromes predispose to the development of renal cell carcinoma, and genes associated with five of these syndromes have been already identified: VHL, MET, FH, BHD and HRPT2. Few cancers have as many different types of genetic predisposition as renal cancer, although to date only a small proportion of renal cell cancers can be explained by genetic predisposition (AU)

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Transdiferenciación de células mesenquimales del tejido adiposo: hacia una terapia celular para enfermedades degenerativas de la retina / Transdifferentation of mesenchymal stem cells from adipose tissue: Through a cellular therapy for degenerative retinal diseases

Objetivos: Obtención de células troncales mesenquimales de tejido adiposo para trasplante y recuperación funcional de retinas degeneradas. Material y metodología: Extracción de la grasa inguinal de ratones transgénicos para proteína verde fluorescente y aislamiento de las células troncales mesenquimales. Estas células fueron implantadas utilizando inoculaciones intravítreas y subretinianas en un modelo murino (rd10) que asemeja la retinosis pigmentaria autosomal recesiva humana. Expresión de genes involucrados en el desarrollo de la retina mediante RT-PCR. Resultados: Nuestros resultados demuestran que en ambos abordajes quirúrgicos las células trasplantadas sobreviven, migran y se integran en diferentes capas de la retina de los ratones rd10. Además hemos identificado la expresión de genes en embriones y cuerpos embrionarios (Otx2, NF200,Pax6 periferina, IRBP) que pueden ser utilizados como activadores o potenciadores de la transdiferenciación. Conclusiones: las células mesenquimales del tejido adiposo reúnen las condiciones necesarias para su potencial uso en la terapia de enfermedades degenerativas de la retina. Los cuerpos embrionarios representan un modelo útil para estudiar los mecanismos reguladores de la diferenciación de las células retinianas (AU)

Objectives: To obtain adult mesenchymal stem cells from adipose tissue to be used in cellular therapies aimed to retinal regeneration. Material and Methods: isolation of adult mesenchymal stem cells from adipose tissue of green fluorescent protein transgenic mice. Recipient mouse eyes were transplanted with these cells by using intravitreal and subretinal procedures. We have used a mice model of human autosomal recessive retinitis pigmentosa (rd10). Gene expression by means of RT-PCR of mRNA isolated from embryo eyes (E9,5 to E18,5); post-natal eyes (P1 to P10) and adults eyes .That technique was also used in mouse embryoid bodies spontaneously differentiated from embryonic stem cells ES-D3. Results: In both surgical procedures we observed survival, migration and integration of mesenchymal stem cells into several retinal layers. We have also identified the expression of some retinal genes (Otx2, NF200,Pax6, peripherin,IRBP) wich may help to drive the mesenchymal stem cells transdifferentiation. Conclusions: Mesenchimal cells are very promising to be used in degenerative retinal diseases. We emphasize the usefulness of mouse embryoid bodies as a model to study the regulatory mechanisms of retinal neurons differentiation and its potential for obtaining retinal progenitors (AU)

Capacidad regenerativa de las células de médula ósea autólogas después de un infarto agudo de miocardio / Regenerative Capability of Human Bone Marrow Cells After Myocardial Infarction

La insuficiencia cardíaca está considerada como la epidemia cardiovascular del siglo xxi. Su mortalidad y su morbilidad son muy elevadas y consumen cada vez más recursos sanitarios. Casi la mitad de los enfermos de insuficiencia cardíaca ha presentado un infarto de miocardio. El tratamiento de regeneración miocárdica con células madre ha surgido a principios de este siglo como una esperanza para el tratamiento de las enfermedades cardiovasculares. Los primeros estudios se han realizado en grupos pequeños de pacientes, pero los resultados indican cierto beneficio. El contexto del infarto agudo de miocardio es el más investigado en este campo. Para la evaluación de los resultados, la resonancia cardíaca se perfila como la herramienta más útil para el seguimiento de estos pacientes. Como toda técnica novedosa, también han surgido problemas de seguridad y, probablemente, en un futuro surgirán nuevas incógnitas, puesto que todavía hoy no conocemos el mecanismo de actuación de las células madre que trasplantamos o movilizamos hacia el corazón (AU)

Heart failure is considered the new cardiovascular epidemy of XXI century. Mortality and morbidity are very high, consuming more and more health resources. Most of these patients have suffered from a myocardial infarction. Stem cell therapy emerged at the beginning of this century as a new strategy for the treatment of cardiovascular diseases. The initial studies were done in small groups of patients showing benefits. Myocardial infarction is frequently investigated in this field. For the evaluation of these results magnetic resonance appears as a useful tool for the follow-up of these patients. As it usually happens with a new technique, safety problems have arisen and it is possible that in the near future new questions will arise as we still do not know how the progenitor cells we transplant or mobilize into the heart act (AU)