Engineered Perineural Vascular Plexus for Modeling Developmental Toxicity.,Advanced Healthcare Materials

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Engineered Perineural Vascular Plexus for Modeling Developmental Toxicity.
Advanced Healthcare Materials ( IF 10.0 ) Pub Date : 2020-07-01 , DOI: 10.1002/adhm.202000825
Gaurav Kaushik ₁ , Kartik Gupta ₂ , Victoria Harms ₁ , Elizabeth Torr ₁ , Jonathan Evans ₃ , Hunter J Johnson ₃ , Cheryl Soref ₁ , Suehelay Acevedo-Acevedo ₃ , Jessica Antosiewicz-Bourget ₄ , Daniel Mamott ₄ , Peyton Uhl ₁ , Brian P Johnson ₃ , Sean P Palecek ₅ , David J Beebe _{3,

6,

7} , James A Thomson ₄ , William T Daly ₁ , William L Murphy _{1,

3}

Affiliation

There is a vital need to develop in vitro models of the developing human brain to recapitulate the biological effects that toxic compounds have on the brain. To model perineural vascular plexus (PNVP) in vitro, which is a key stage in embryonic development, human embryonic stem cells (hESC)‐derived endothelial cells (ECs), neural progenitor cells, and microglia (MG) with primary pericytes (PCs) in synthetic hydrogels in a custom‐designed microfluidics device are cocultured. The formation of a vascular plexus that includes networks of ECs (CD31+, VE‐cadherin+), MG (IBA1+), and PCs (PDGFRβ+), and an overlying neuronal layer that includes differentiated neuronal cells (βIII Tubulin+, GFAP+) and radial glia (Nestin+, Notch2NL+), are characterized. Increased brain‐derived neurotrophic factor secretion and differential metabolite secretion by the vascular plexus and the neuronal cells over time are consistent with PNVP functionality. Multiple concentrations of developmental toxicants (teratogens, microglial disruptor, and vascular network disruptors) significantly reduce the migration of ECs and MG toward the neuronal layer, inhibit formation of the vascular network, and decrease vascular endothelial growth factor A (VEGFA) secretion. By quantifying 3D cell migration, metabolic activity, vascular network disruption, and cytotoxicity, the PNVP model may be a useful tool to make physiologically relevant predictions of developmental toxicity.

中文翻译：

用于模拟发育毒性的工程神经周围血管丛。

迫切需要开发发育中的人类大脑的体外模型，以概括有毒化合物对大脑的生物学影响。为了在体外模拟神经周围血管丛 (PNVP)，这是胚胎发育的关键阶段，人类胚胎干细胞 (hESC) 衍生的内皮细胞 (EC)、神经祖细胞和具有初级周细胞 (PC) 的小胶质细胞 (MG)在定制设计的微流体装置中的合成水凝胶中进行共培养。血管丛的形成，包括 ECs（CD31+、VE-cadherin+）、MG（IBA1+）和 PCs（PDGFR β +）网络，以及包括分化神经元细胞（βIII Tubulin+, GFAP+) 和放射状胶质细胞 (Nestin+, Notch2NL+) 被表征。随着时间的推移，血管丛和神经元细胞增加的脑源性神经营养因子分泌和差异代谢物分泌与 PNVP 功能一致。多种浓度的发育毒物（致畸剂、小胶质细胞破坏剂和血管网络破坏剂）显着减少 EC 和 MG 向神经元层的迁移，抑制血管网络的形成，并减少血管内皮生长因子 A（VEGFA）的分泌。通过量化 3D 细胞迁移、代谢活动、血管网络破坏和细胞毒性，PNVP 模型可能是对发育毒性进行生理相关预测的有用工具。

更新日期：2020-08-19

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