Modeling human brain evolution using induced pluripotent stem cells: comparative analysis of neuronal development in humans and chimpanzees

Understanding evolutionary mechanisms underlying expansion and reorganization of the human brain represents an important aspect in analyzing the emergence of cognitive abilities typical of our species. Comparative analyses of neuronal phenotypes in closest living relatives (Pan troglodytes; the common chimpanzee) can shed the light into changes in neuronal morphology compared to the last common ancestor (LCA), opening possibilities for analyses of the timing of their appearance, and the role of evolutionary mechanisms favoring a particular type of information processing in humans. Here, we use induced pluripotent stem cell (iPSC) technology to model neural progenitor cell migration and early development of cortical pyramidal neurons in humans and chimpanzees. In addition, we provide morphological characterization of the early stages of neuronal development in human and chimpanzee transplanted cells, and examine the role of developmental mechanisms previously proposed for the evolutionary expansions of the human brain on the early development of pyramidal neurons in the two species. The strategy proposed here lay down the basis for further comparative analysis between human and non-human primates and opens new avenues for understanding cognitive capability and neurological disease susceptibility differences between species. Overall design: PolyA RNA-Seq profiling of neural progenitor cells (NPCs) and neurons differentiated from human and chimpanzee iPSCs.

解析人类大脑扩张与重塑背后的进化机制，是探究人类特有认知能力起源的重要研究方向。对现存近亲——普通黑猩猩（Pan troglodytes）的神经元表型开展比较分析，可揭示其与人类和黑猩猩的最近共同祖先（last common ancestor, LCA）相比，神经元形态所发生的演化改变，进而为解析此类改变的出现时间，以及偏向特定信息处理模式的进化机制在人类中的作用提供研究契机。本研究利用诱导多能干细胞（induced pluripotent stem cell, iPSC）技术，构建人类与黑猩猩的神经祖细胞（neural progenitor cell, NPC）迁移及皮层锥体神经元早期发育的体外模型。此外，本研究还对人类和黑猩猩的移植细胞的神经元发育早期阶段进行形态学表征，并针对此前提出的、与人类大脑进化扩张相关的发育机制，探究其在两个物种锥体神经元早期发育过程中的调控作用。本研究提出的研究策略为后续开展人类与非人灵长类动物的比较分析奠定了坚实基础，同时为解析不同物种间认知能力与神经系统疾病易感性差异开辟了全新路径。实验设计：对源自人类与黑猩猩诱导多能干细胞的神经祖细胞及分化神经元开展PolyA RNA-Seq表达谱分析。