Enteric neural differentiation in innervated, physiologically functional, smooth muscle constructs is modulated by bone morphogenic protein 2 secreted by sphincteric smooth muscle cells.
Enteric neural differentiation in innervated, physiologically functional, smooth muscle constructs is modulated by bone morphogenic protein 2 secreted by sphincteric smooth muscle cells.
复制标题
受神经支配的、具有生理功能的平滑肌结构中的肠神经分化受到括约肌平滑肌细胞分泌的骨形态发生蛋白2的调节。
DOI：
10.1002/term.2027
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发表时间：
2017
影响因子：
3.3
通讯作者：
Bitar,KhalilN
中科院分区：
文献类型：
--
作者：
Rego,StephenL;Raghavan,Shreya;Zakhem,Elie;Bitar,KhalilN
肠道神经系统(ENS)控制胃肠(GI)功能，包括运动和消化，这些功能在ENS疾病中受到损害。肠神经细胞的分化是由肠道间充质释放的因子介导的，包括平滑肌细胞(SMCs)。参与成人肠神经前体细胞分化的SMC来源的因子仍然难以捉摸。此外，还没有生理上相关的体外模型来研究肠道不同区域的神经支配，如幽门和下食道括约肌(LES)。本实验研究了由兔肛门内括约肌、幽门、LES和结肠的SMC组成的生物工程神经环状结构的神经分化。此外，还鉴定了可诱导神经分化的SMC衍生因子，以优化生物工程构建神经。括约肌和非括约肌的生物工程结构沿周向排列，SMC保持收缩表型。狮身人掌的构造产生了自发的基音。与非括约肌构建物相比，生物工程、神经支配的括约肌构建物具有更高的兴奋性和抑制性运动神经元分化和骨形态发生蛋白2(BMP2)的分泌水平。在非括约肌的结肠SMC结构中加入BMP2增加了氮能神经支配，而在括约肌结构中用noggin抑制BMP2会降低功能松弛。这些研究提供了：(A)第一个生物工程化的支配幽门和LES的结构；(B)生理相关的模型来研究SMC和成体NPC的相互作用；以及(C)SMC在BMP2介导的神经分化中的区域特异性效应的证据。此外，这项研究为神经化生物工程GI组织结构的开发铺平了道路，这些组织结构是针对特定的肠道疾病和位置量身定做的。版权所有©2015 John Wiley&Sons，Ltd.
The enteric nervous system (ENS) controls gastrointestinal (GI) functions, including motility and digestion, which are impaired in ENS disorders. Differentiation of enteric neurons is mediated by factors released by the gut mesenchyme, including smooth muscle cells (SMCs). SMC‐derived factors involved in adult enteric neural progenitor cells (NPCs) differentiation remain elusive. Furthermore, physiologically relevantin vitromodels to investigate the innervations of various regions of the gut, such as the pylorus and lower oesophageal sphincter (LES), are not available. Here, neural differentiation in bioengineered innervated circular constructs composed of SMCs isolated from the internal anal sphincter (IAS), pylorus, LES and colon of rabbits was investigated. Additionally, SMC‐derived factors that induce neural differentiation were identified to optimize bioengineered construct innervations. Sphincteric and non‐sphincteric bioengineered constructs aligned circumferentially and SMCs maintained contractile phenotypes. Sphincteric constructs generated spontaneous basal tones. Higher levels of excitatory and inhibitory motor neuron differentiation and secretion of bone morphogenic protein 2 (BMP2) were observed in bioengineered, innervated, sphincteric constructs compared to non‐sphincteric constructs. The addition of BMP2 to non‐sphincteric colonic SMC constructs increased nitrergic innervations, and inhibition of BMP2 with noggin in sphincteric constructs decreased functional relaxation. These studies provide: (a) the first bioengineered innervated pylorus and LES constructs; (b) physiologically relevant models to investigate SMCs and adult NPCs interactions; and (c) evidence of the region‐specific effects of SMCs on neural differentiation mediated by BMP2. Furthermore, this study paves the way for the development of innervated bioengineered GI tissue constructs tailored to specific disorders and locations within the gut. Copyright © 2015 John Wiley & Sons, Ltd.