In our laboratory, multiple animal models have been used to determine the underlying causes in neurodevelopmental impairment in children with congenital heart disease. We believe that integrating the genetic, cellular and molecular approaches in animal models with novel imaging tools used on children will offer steps towards developing new therapies to improve neurological outcomes in our patients.
Recent advances in stem cell technology have opened new opportunities to model human brain development in vitro on an individual basis using inducible pluripotent stem cells (iPSCs). This powerful technique can be used to understand altered cortical development in children with congenital heart disease in a high-throughput manner by generating and studying iPSC-derived human neurons, glia cells, or organoids. It is important to note that this in vitro approach is highly amenable to several genetic and molecular techniques.
The piglet brain is a powerful model system when studying human brain development because it displays a highly evolved gyrencephalic neocortex. Furthermore, similar to humans, approximately 50% of the piglet brain volume is represented by white matter. We have previously demonstrated that the maturation pattern in porcine white matter displays a similar progression to human white matter. In addition, our studies have shown that the characteristics of neurogenic niche in the piglet brain closely resemble its human counterpart.
The piglet shares more metabolic/physiological similarities to humans than other mammals, therefore, the model is highly translational to develop new therapeutic approaches in the human patient. Finally, the piglet is large enough in the newborn period for investigation using cardiopulmonary bypass. Our team uses this model to investigate the effects of chronic hypoxia and neonatal cardiac surgery.
Mouse models provide significant advantages in our research because of large litter sizes, rapid growth, genetic and molecular manipulation, an eclectic toolkit of cutting-edge techniques, and sophisticated neurobehavioral assay. We developed a rodent brain slice model to investigate the effects of in utero hypoxia and cardiopulmonary bypass on white matter injury, respectively. Mice are reared in prolonged hypoxic conditions during a neonatal developmental time-window overlapping the period spanning third trimester to term birth in humans.
Viable brain slices are cultured in a perfusion system where circulatory arrest could be simulated by oxygen-glucose deprivation. Studies using the mouse model allow our further understanding of complex pre- and intraoperative effects on brain development.
Advances in neuroimaging technology have provided a wealth of information regarding brain development and injury in children with congenital heart disease. Future clinical imaging studies paired with neurological outcome investigations will facilitate correlation with specific developmental and behavioral disabilities in our patients. There is a clear need for animal studies incorporating clinically-relevant imaging approaches paired with histological analysis to brain insults resulting from congenital cardiac anomalies. We believe that, in conjunction with clinical research, studies of this nature will aid in acquiring a full picture of impaired brain development and neurological injury associated with congenital heart disease.