Fedorova Veronika, Vanova Tereza, Elrefae Lina, Pospisil Jakub, Petrasova Martina, Kolajova Veronika, Hudacova Zuzana, Baniariova Jana, Barak Martin, Peskova Lucie, Barta Tomas, Kaucka Marketa, Killinger Michael, Vecera Josef, Bernatik Ondrej, Cajanek Lukas, Hribkova Hana, Bohaciakova Dasa
Department of Histology and Embryology, Faculty of Medicine, Masaryk University Brno, Czech Republic.
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden; Department of Molecular Neurosciences, Medical University of Vienna, Austria.
Stem Cell Res. 2019 Oct;40:101563. doi: 10.1016/j.scr.2019.101563. Epub 2019 Aug 29.
Development of neural tube has been extensively modeled in vitro using human pluripotent stem cells (hPSCs) that are able to form radially organized cellular structures called neural rosettes. While a great amount of research has been done using neural rosettes, studies have only inadequately addressed how rosettes are formed and what the molecular mechanisms and pathways involved in their formation are. Here we address this question by detailed analysis of the expression of pluripotency and differentiation-associated proteins during the early onset of differentiation of hPSCs towards neural rosettes. Additionally, we show that the BMP signaling is likely contributing to the formation of the complex cluster of neural rosettes and its inhibition leads to the altered expression of PAX6, SOX2 and SOX1 proteins and the rosette morphology. Finally, we provide evidence that the mechanism of neural rosettes formation in vitro is reminiscent of the process of secondary neurulation rather than that of primary neurulation in vivo. Since secondary neurulation is a largely unexplored process, its understanding will ultimately assist the development of methods to prevent caudal neural tube defects in humans.
利用能够形成称为神经玫瑰花结的径向组织细胞结构的人类多能干细胞（hPSC），神经管的发育已在体外得到广泛建模。虽然使用神经玫瑰花结进行了大量研究，但对于玫瑰花结如何形成以及其形成过程中涉及的分子机制和途径，研究仍不够充分。在这里，我们通过详细分析hPSC向神经玫瑰花结分化早期多能性和分化相关蛋白的表达来解决这个问题。此外，我们表明BMP信号可能有助于神经玫瑰花结复杂簇的形成，其抑制会导致PAX6、SOX2和SOX1蛋白表达改变以及玫瑰花结形态改变。最后，我们提供证据表明体外神经玫瑰花结的形成机制让人联想到继发性神经管形成过程，而不是体内原发性神经管形成过程。由于继发性神经管形成在很大程度上是一个未被探索的过程，对其的理解最终将有助于开发预防人类尾部神经管缺陷的方法。
