Trasplante celular y terapia regenerativa con células madre

Uno de los campos de la medicina que más expectativas ha levantado en los últimos años es la terapia celular con células madre. El aislamiento de células embrionarias humanas, la aparente e inesperada potencialidad de las células madre adultas y el desarrollo de la terapia génica nos llevar a imaginar un futuro esperanzador para un importante número de enfermedades actualmente incurables. A lo largo de las siguientes páginas vamos a tratar de dibujar el panorama de la investigación con células madre, describiendo los principales logros en este campo así como algunas de las preguntas pendientes de responder. A pesar de las grandes expectativas, es fundamental que mantengamos un espíritu crítico y realista a la hora de analizar los avances científicos en esta área

Stem Cells and Cardiac Disease: Where are We Going?

During the last 10 years we have witnessed the development of a new field in research termed Stem Cell Therapy. Classically, it was considered that cells had a limited division and differentiation ability; however, this dogma was challenged when new exciting results about cell multi/pluripotency were presented to the scientific community. It was found that cells from one adult tissue source were able to originate cells of a very different type. The possibility of transplanting these cells into damaged organs with the aim of substituting sick or dead tissue, triggered many studies to understand the plasticity of the stem cells and their potential in pathological situations. Nowadays, much more is understood about stem cells, although of course, many questions, especially about their mechanism of action, still need to be answered. Their benefit after transplantation has been shown experimentally and even clinically in some cases; however, the degree of stem cell contribution through their own differentiation into the transplanted tissue, has turned out to be generally low, and increasing evidence indicates that a trophic effect must play an important role in such a benefit. A better understanding of the paracrine mechanisms involved could be of great relevance in order to develop new therapies focused on stimulating endogenous cells. On the other hand, more sophisticated methods for cell transplantation combined with bio-engineering techniques have been devised in cardiac disease models. In this review we will try to provide a critical overview of the stem cell studies performed until now and to discuss some of the questions raised about the mechanisms that are involved in their putative reparative effect in cardiovascular diseases, and their origin

Future Perspectives in the Treatment of Heart Failure: From Cell Transplantation to Cardiac Regeneration

En los últimos años hemos asistido a un interés creciente por el tratamiento de la insuficiencia cardíaca mediante el trasplante de células madre. Mientras que los estudios con células madre de músculo (mioblastos) se iniciaron hace más de 10 años, la posibilidad de que las células madre de la médula ósea tengan un enorme potencial de diferenciación y proliferación ha estimulado la investigación con otros tipos de células madre. Estos estudios experimentales han demostrado, en no pocas ocasiones, resultados contradictorios, lo que ha llevado a posturas enfrentadas en cuanto a la ética de iniciar estudios clínicos. Creemos que es adecuado tratar de ofrecer una visión crítica respecto a la utilización de las células madre en la insuficiencia cardíaca. Quizá la pregunta más difícil de contestar en este momento es si la realización de ensayos clínicos está justificada o no a la luz de los conocimientos actuales, o si por el contrario debemos adquirir un conocimiento mucho más preciso de la posible eficacia de este tipo de tratamiento y de los mecanismos que justifican esta eficacia, antes de siquiera iniciar los estudios en humanos. En nuestra opinión, hay suficientes evidencias que justifican el desarrollo de ensayos clínicos a pesar de que, sin duda, existen muchos interrogantes que debemos resolver mediante estudios experimentales en animales

Utilización de células madre para la regeneración miocárdica en la insuficiencia cardíaca

La terapia celular en la reparación miocárdica se vislumbra como una de las estrategias terapéuticas con mayor futuro en el tratamiento de la insuficiencia cardíaca. Numerosos estudios in vitro recientes apoyan la potencialidad de distintos tipos de células madre de diferenciarse hacia los tejidos necesarios para regenerar el tejido miocárdico dañado, mientras que estudios en animales de experimentación sugieren que células madre de músculo (mioblastos), médula ósea (progenitores mesenquimales, endoteliales o hematopoyéticos) e incluso del propio corazón pueden contribuir in vivo a mejorar la contractilidad cardíaca. Estos trabajos han conducido a que diversos grupos hayan iniciado estudios en pacientes con infarto de miocardio. Sin embargo, la utilización de la terapia celular en ensayos clínicos no está desprovista de controversia, fundamentalmente relacionada con la necesidad de aumentar nuestro conocimiento antes de pasar a la aplicación clínica de estas estrategias terapéuticas. Aunque es fundamental aumentar significativamente el conocimiento de los procesos, no consideramos irrazonable iniciar ensayos clínicos en los que se identifiquen preguntas concretas cuya respuesta nos permita avanzar en esta dirección

Somatic stem cells and the origin of cancer

Most human cancers derive from a single cell targeted by genetic and epigenetic alterations that initiate malignant transformation. Progressively, these early cancer cells give rise to different generations of daughter cells that accumulate additional mutations, acting in concert to drive the full neoplastic phenotype1,2. As we have currently deciphered many of the gene pathways disrupted in cancer, our knowledge about the nature of the normal cells susceptible to transformation upon mutation has remained more elusive. Adult stem cells are those that show long-term replicative potential, together with the capacities of self-renewal and multi-lineage differentiation. These stem cell properties are tightly regulated in normal development, yet their alteration may be a critical issue for tumorigenesis. This concept has arisen from the striking degree of similarity noted between somatic stem cells and cancer cells, including the fundamental abilities to self-renew and differentiate. Given these shared attributes, it has been proposed that cancers are caused by transforming mutations occurring in tissue-specific stem cells3-9. This hypothesis has been functionally supported by the observation that among all cancer cells within a particular tumor, only a minute cell fraction has the exclusive potential to regenerate the entire tumor cell population3,10-13; these cells with stem-like properties have been termed cancer stem cells. Cancer stem cells can originate from mutation in normal somatic stem cells that deregulate their physiological programs. Alternatively, mutations may target more committed progenitor cells or even mature cells, which become reprogrammed to acquire stem-like functions14,15 In any case, mutated genes should promote expansion of stem/progenitor cells, thus increasing their predisposition to cancer development by expanding self-renewal and pluripotency over their normal tendency towards relative quiescency and proper differentiation

Stem Cells to Regenerate Cardiac Tissue in Heart Failure

Myocardial regeneration is one of the most promising therapeutic strategies for heart failure patients. Many experimental studies have demonstrated that different types of stem cell can differentiate into myocardial cells and tissues necessary for regeneration of the damaged myocardium, while studies in experimental animals suggest that muscle (myoblast), bone marrow (mesenchymal, endothelial or hematopoietic progenitors) and even heart cells can help to improve heart contractility in vivo. These findings have led several groups to undertake studies in patients with myocardial infarction. However, the use of cellular therapy in clinical trials is not without controversy, mainly related with the need for better knowledge before these therapeutic strategies are used in clinical practice. Although significant enhancement of our knowledge of the processes involved is fundamental, we do not consider it unreasonable to initiate clinical trials in which specific questions are posed, whose answers will allow us to make further progress

Nuevas estrategias terapéuticas en diabetes mellitus tipo 1

El principal determinante del riesgo de complicaciones derivadas de la diabetes mellitus tipo 1 se debe a los altos niveles de glucosa en sangre mantenidos durante largo tiempo. Para conseguir un beneficio terapéutico en pacientes con diabetes mellitus es necesario desarrollar tratamientos que permitan de manera segura, efectiva y estable mantener la normoglucemia. Lamentablemente, el tratamiento de la diabetes mellitus tipo 1 mediante el aporte exógeno de insulina no es capaz de conseguir niveles estables de glucosa en sangre, de manera que con frecuencia se producen casos de severa hipoglucemia o hiperglucemia. Hasta la fecha la única solución para reestablecer de manera permanente la normoglucemia se consigue mediante el trasplante de páncreas o de islotes pancreáticos. Sin embargo, a medida que se incrementa el número de centros especializados en el trasplante de islotes, mayor es la necesidad de islotes para su trasplante. Así pues, el estudio de nuevas fuentes de células productoras de insulina así como de nuevos tratamientos que permitan preservar o incluso aumentar la masa de células beta en los pacientes con diabetes mellitus representa un objetivo de primera necesidad en este campo. En este sentido, en la última década ha habido un avance significativo en el campo de la biología de las células madre. Sin embargo, la identificación de células apropiadas para la generación de nuevas células beta, además del desarrollo de técnicas para la caracterización de estas células, así como de ensayos y modelos animales apropiados para probar su capacidad de diferenciación tanto in vitro como in vivo son de vital importancia para la puesta en marcha de nuevas estrategias terapéuticas basadas en la aplicación de las células madre para el tratamiento de la diabetes mellitus tipo 1

NALP1 is a transcriptional target for cAMP-response-element-binding protein (CREB) in myeloid leukaemia cells

NALP1 (also called DEFCAP, NAC, CARD7) has been shown to play a central role in the activation of inflammatory caspases and processing of pro-IL1β (pro-interleukin-1β). Previous studies showed that NALP1 is highly expressed in peripheral blood mononuclear cells. In the present study, we report that expression of NALP1 is absent from CD34+ haematopoietic blast cells, and its levels are upregulated upon differentiation of CD34+ cells into granulocytes and to a lesser extent into monocytes. In peripheral blood cells, the highest levels of NALP1 were observed in CD3+ (T-lymphocytes), CD15+ (granulocytes) and CD14+ (monocytes) cell populations. Notably, the expression of NALP1 was significantly increased in the bone marrow blast cell population of some patients with acute leukaemia, but not among tissue samples from thyroid and renal cancer. A search for consensus sites within the NALP1 promoter revealed a sequence for CREB (cAMP-response-element-binding protein) that was required for transcriptional activity. Moreover, treatment of TF1 myeloid leukaemia cells with protein kinase C and protein kinase A activators induced CREB phosphorylation and upregulated the mRNA and protein levels of NALP1. Conversely, ectopic expression of a dominant negative form of CREB in TF1 cells blocked the transcriptional activity of the NALP1 promoter and significantly reduced the expression of NALP1. Thus NALP1 is transcriptionally regulated by CREB in myeloid cells, a mechanism that may contribute to modulate the response of these cells to pro-inflammatory stimuli