Grafted human pluripotent stem cell-derived cortical neurons integrate into adult human cortical neural circuitry.,STEM CELLS Translational Medicine

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Grafted human pluripotent stem cell-derived cortical neurons integrate into adult human cortical neural circuitry.
STEM CELLS Translational Medicine ( IF 5.4 ) Pub Date : 2020-06-29 , DOI: 10.1002/sctm.20-0134
Marita Grønning Hansen ₁ , Cecilia Laterza _{1,

2} , Sara Palma-Tortosa _{1,

2} , Giedre Kvist _{1,

2} , Emanuela Monni _{1,

2} , Oleg Tsupykov ₃ , Daniel Tornero ₄ , Naomi Uoshima _{1,

2} , Jordi Soriano ₅ , Johan Bengzon _{1,

6} , Gianvito Martino ₇ , Galyna Skibo ₃ , Olle Lindvall _{1,

2} , Zaal Kokaia _{1,

2}

Affiliation

Several neurodegenerative diseases cause loss of cortical neurons, leading to sensory, motor, and cognitive impairments. Studies in different animal models have raised the possibility that transplantation of human cortical neuronal progenitors, generated from pluripotent stem cells, might be developed into a novel therapeutic strategy for disorders affecting cerebral cortex. For example, we have shown that human long‐term neuroepithelial‐like stem (lt‐NES) cell‐derived cortical neurons, produced from induced pluripotent stem cells and transplanted into stroke‐injured adult rat cortex, improve neurological deficits and establish both afferent and efferent morphological and functional connections with host cortical neurons. So far, all studies with human pluripotent stem cell‐derived neurons have been carried out using xenotransplantation in animal models. Whether these neurons can integrate also into adult human brain circuitry is unknown. Here, we show that cortically fated lt‐NES cells, which are able to form functional synaptic networks in cell culture, differentiate to mature, layer‐specific cortical neurons when transplanted ex vivo onto organotypic cultures of adult human cortex. The grafted neurons are functional and establish both afferent and efferent synapses with adult human cortical neurons in the slices as evidenced by immuno‐electron microscopy, rabies virus retrograde monosynaptic tracing, and whole‐cell patch‐clamp recordings. Our findings provide the first evidence that pluripotent stem cell‐derived neurons can integrate into adult host neural networks also in a human‐to‐human grafting situation, thereby supporting their potential future clinical use to promote recovery by neuronal replacement in the patient's diseased brain.

中文翻译：

移植的人类多能干细胞衍生的皮层神经元整合到成人皮层神经回路中。

几种神经退行性疾病会导致皮质神经元丢失，从而导致感觉、运动和认知障碍。对不同动物模型的研究提出了一种可能性，即由多能干细胞产生的人类皮质神经元祖细胞的移植可能会发展成为影响大脑皮质的疾病的新治疗策略。例如，我们已经证明，人类长期神经上皮样干 (lt-NES) 细胞衍生的皮层神经元，由诱导多能干细胞产生并移植到中风受伤的成年大鼠皮层中，改善神经功能缺损并建立传入和与宿主皮层神经元的传出形态和功能连接。迄今为止，所有关于人类多能干细胞衍生神经元的研究都是在动物模型中使用异种移植进行的。这些神经元是否也能整合到成人大脑回路中尚不清楚。在这里，我们展示了皮层命运的 lt-NES 细胞能够在细胞培养中形成功能性突触网络，当体外移植到成人皮层的器官型培养物中时，会分化为成熟的、层特异性皮层神经元。免疫电子显微镜、狂犬病病毒逆行单突触追踪和全细胞膜片钳记录证明，移植的神经元是有功能的，并与切片中的成人皮质神经元建立传入和传出突触。

更新日期：2020-06-29

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