TGF-β signaling controls neural crest developmental plasticity via SMAD2/3 [hiNCC RNA-seq]

The neural crest is a highly plastic stem cell population that represents a notable exception to the germ layer theory. Despite being of ectodermal origin, these cells can differentiate into skeletal derivatives like cartilage and bone, tissues that are typically formed by mesoderm. The inductive program that endows the neural crest with these unique properties is still poorly understood. Here, we report that Smad2/3-mediated TGFβ signaling endows cranial neural crest cells with enhanced developmental potential. Our results show that TGFβ signaling modulates neural crest axial identity and directly activates the gene circuits that support skeletal differentiation. Cooperation between TGFβ and low levels of WNT-signaling in the embryonic head activates cranial-specific cis-regulatory elements of anterior genes. Activation of the TGFβ pathway allowed reprogramming of trunk neural crest cells to adopt an anterior identity and led to the development of an improved protocol for the generation of human cranial neural crest cells. Our findings indicate TGFβ signaling is required for the specification of cranial neural crest cells, endowing them with the potential to give rise to the craniofacial skeleton. Examination of transcriptome of human embryonic stem cells and human induced neural crest cells under different differentiation conditions

神经嵴（neural crest）是一类具有高度可塑性的干细胞群，是胚层理论（germ layer theory）的显著例外。尽管起源于外胚层，这类细胞却可分化为软骨、骨等骨骼相关衍生物——这类组织通常由中胚层（mesoderm）发育形成。赋予神经嵴此类独特特性的诱导程序（inductive program）目前仍不甚明晰。本研究发现，由Smad2/3介导的转化生长因子β（TGFβ）信号通路可增强颅神经嵴细胞（cranial neural crest cells）的发育潜能。研究结果显示，TGFβ信号通路可调控神经嵴的轴向属性，并直接激活支持骨骼分化的基因环路。在胚胎头部中，TGFβ与低水平WNT信号通路的协同作用，可激活前部基因的颅特异性顺式调控元件（cis-regulatory elements）。激活TGFβ通路能够实现躯干神经嵴细胞的重编程，使其获得前部属性，并助力优化人类颅神经嵴细胞的体外生成方案。本研究结果表明，TGFβ信号通路对于颅神经嵴细胞的特化至关重要，可赋予其形成颅面骨骼的潜能。此外，本研究还对不同分化条件下人类胚胎干细胞与人类诱导神经嵴细胞的转录组（transcriptome）进行了分析。