Center for Neuroscience Research, Children's National Health System, Washington, DC 20010, USA.
Children's National Heart Institute, Children's National Health System, Washington, DC 20010, USA.
Sci Transl Med. 2017 Jan 25;9(374). doi: 10.1126/scitranslmed.aah7029.
Long-term neurological deficits due to immature cortical development are emerging as a major challenge in congenital heart disease (CHD). However, cellular mechanisms underlying dysregulation of perinatal corticogenesis in CHD remain elusive. The subventricular zone (SVZ) represents the largest postnatal niche of neural stem/progenitor cells (NSPCs). We show that the piglet SVZ resembles its human counterpart and displays robust postnatal neurogenesis. We present evidence that SVZ NSPCs migrate to the frontal cortex and differentiate into interneurons in a region-specific manner. Hypoxic exposure of the gyrencephalic piglet brain recapitulates CHD-induced impaired cortical development. Hypoxia reduces proliferation and neurogenesis in the SVZ, which is accompanied by reduced cortical growth. We demonstrate a similar reduction in neuroblasts within the SVZ of human infants born with CHD. Our findings demonstrate that SVZ NSPCs contribute to perinatal corticogenesis and suggest that restoration of SVZ NSPCs' neurogenic potential is a candidate therapeutic target for improving cortical growth in CHD.
由于皮质发育不成熟导致的长期神经功能缺陷，正在成为先天性心脏病 (CHD) 的一个主要挑战。然而，CHD 中皮质发生调节紊乱的细胞机制仍不清楚。侧脑室下区 (SVZ) 是成年后神经干细胞/祖细胞 (NSPCs) 的最大来源。我们发现仔猪 SVZ 与人类 SVZ 相似，具有强大的出生后神经发生能力。我们提供的证据表明，SVZ NSPCs 以特定的区域方式迁移到额叶皮质并分化为中间神经元。旋曲脑的仔猪大脑缺氧重现 CHD 引起的皮质发育障碍。缺氧会减少 SVZ 中的增殖和神经发生，从而导致皮质生长减少。我们在患有 CHD 的人类婴儿的 SVZ 中也发现了类似的神经母细胞减少。我们的研究结果表明，SVZ NSPCs 有助于围产期皮质发生，并表明恢复 SVZ NSPCs 的神经发生潜能是改善 CHD 中皮质生长的候选治疗靶点。
