RESUMEN
Intensive efforts are focused on identifying regulators of human pancreatic islet cell growth and maturation to accelerate development of therapies for diabetes. After birth, islet cell growth and function are dynamically regulated; however, establishing these age-dependent changes in humans has been challenging. Here, we describe a multimodal strategy for isolating pancreatic endocrine and exocrine cells from children and adults to identify age-dependent gene expression and chromatin changes on a genomic scale. These profiles revealed distinct proliferative and functional states of islet α cells or ß cells and histone modifications underlying age-dependent gene expression changes. Expression of SIX2 and SIX3, transcription factors without prior known functions in the pancreas and linked to fasting hyperglycemia risk, increased with age specifically in human islet ß cells. SIX2 and SIX3 were sufficient to enhance insulin content or secretion in immature ß cells. Our work provides a unique resource to study human-specific regulators of islet cell maturation and function.
Asunto(s)
Envejecimiento/genética , Regulación del Desarrollo de la Expresión Génica , Células Secretoras de Insulina/metabolismo , Adulto , Diferenciación Celular , Separación Celular , Niño , Preescolar , Cromatina/metabolismo , Inmunoprecipitación de Cromatina , Diabetes Mellitus/genética , Código de Histonas , Proteínas de Homeodominio/metabolismo , Humanos , Lactante , Persona de Mediana Edad , Factores de Transcripción/metabolismo , Transcriptoma/genética , Adulto JovenRESUMEN
Left ventricular ejection is depressed immediately after repair of ventricular septal defect (VSD). Postrepair functional depression seen after VSD closure could result from a reduction in preload. However, other mechanisms could be at work. Functional depression could also be caused by closure of a low-impedance path for left ventricular ejection, the introduction of a stiff akinetic patch, or the operation itself. We reasoned that functional depression mediated by changes in preload or afterload should symmetrically affect end-diastole and end-systole, whereas depression resulting from changes in septal mechanics should be localized. We, therefore, performed segmental wall-motion analysis on intraoperative echocardiograms from patients undergoing VSD and atrial septal defect repair. After VSD closure, there was an asymmetric change in left ventricular end-systolic segment length and a decrease in fractional segment shortening localized to the septal and lateral walls, whereas patients with atrial septal defect had a symmetric increase in fractional shortening. These results suggest that acute functional depression after VSD repair is a result of localized impairment of septal function.