RESUMO
Hematopoietic stem cells (HSCs) produce all essential cellular components of the blood. Stromal cell lines supporting HSCs follow a vascular smooth muscle cell (vSMC) differentiation pathway, suggesting that some hematopoiesis-supporting cells originate from vSMC precursors. These pericyte-like precursors were recently identified in the aorta-gonad-mesonephros (AGM) region; however, their role in the hematopoietic development in vivo remains unknown. Here, we identify a subpopulation of NG2+Runx1+ perivascular cells that display a sclerotome-derived vSMC transcriptomic profile. We show that deleting Runx1 in NG2+ cells impairs the hematopoietic development in vivo and causes transcriptional changes in pericytes/vSMCs, endothelial cells and hematopoietic cells in the murine AGM. Importantly, this deletion leads also to a significant reduction of HSC reconstitution potential in the bone marrow in vivo. This defect is developmental, as NG2+Runx1+ cells were not detected in the adult bone marrow, demonstrating the existence of a specialised pericyte population in the HSC-generating niche, unique to the embryo.
Assuntos
Células Endoteliais , Músculo Liso Vascular , Camundongos , Animais , Músculo Liso Vascular/metabolismo , Células Endoteliais/metabolismo , Diferenciação Celular , Células-Tronco Hematopoéticas/metabolismo , Hematopoese/genética , Mesonefro , Gônadas/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismoRESUMO
Introducción: la 5, 10-metilentetrahidrofolato reductasa (MTHFR) es una enzima clave en el metabolismo del folato; sus polimorfismos se han asociado al aumento de riesgo de padecer enfermedad coronaria, problemas obstétricos en mujeres gestantes, desarrollo de fetos con defectos de cierre del tubo neural y susceptibilidad a algunos tipos de cáncer. Este gen presenta una variación polimórfica de nucleótido único, que consiste en un cambio de C por T en la posición 677 el cual afecta de manera notable su actividad enzimática. Objetivo: Dada la importancia de esta enzima y la heterogeneidad genética de la población colombiana se realizó un estudio para determinar las frecuencias alélicas y genotípicas del polimorfismo C677T de MTHFR en individuos sanos, debido a que en el país sólo se han realizado estudios que involucran metodología de casos y controles. Materiales y métodos: Este polimorfismo se estudió a partir de ADN de una muestra poblacional de 206 estudiantes. Adicionalmente, se calcularon las frecuencias globales de Colombia utilizando los datos de controles sanos reportados en otros estudios. Resultados: En la muestra evaluada se detectó un desequilibrio Hardy-Weinberg, mientras que en los datos globales colombianos se encontró que la población está en equilibrio. Conclusión: la frecuencia poblacional del alelo T parece estar sometida a una presión de selección positiva, dado su incremento en la población a pesar de su efecto deletéreo. Un estudio español reporta resultados similares y argumenta como causa probable de este cambio en la frecuencia alélica de T la suplementación con ácido fólico a futuras madres.
Introduction: the 5, 10-methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in folate metabolism; their polymorphisms have been associated with heart disease risk increase, obstetric problems, neural tube defects in fetuses and cancer susceptibility. This gene has a single nucleotide polymorphism, a C-T change at nucleotide 677, which affects significantly its enzymatic activity. Objective: because of the biological importance of this enzyme and the Colombian population genetic heterogeneity characteristic, a study was performed to determine allele and genotype frequencies of MTHFR C677T polymorphism in healthy individuals, taking into account that in Colombia there are only studies that have involved case-control methodology. Methods: we analyzed this polymorphism trough the amplification of the DNA of a 206 students sample population. Additionally, Colombian overall frequencies were calculated, using data from healthy controls reported in other studies. Results: a Hardy-Weinberg disequilibrium was found in the sample tested. For the Colombian data, we found that the global population was in equilibrium. Conclusion: T allele population frequency seems to be under positive selection pressure, which is reflected in the population allele increase, despite its deleterious effect. A Spanish study reported similar results and identified folic acid supplementation on expectant mothers as a probably cause of this change.