Homeostasis of Glial Cells in the Mammalian Gut

哺乳动物肠道神经胶质细胞的稳态

• 批准号: BB/L022974/1
• 负责人: Vassilis Pachnis
• 金额: $ 53.2万
• 依托单位: The Francis Crick Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL022974%2F1
• 关键词: Homeostasis; Glial; Cells; Mammalian; Gut

The gastrointestinal tract is a vital organ that converts our diet into useful digestible nutrients, contributes to the maintenance of water balance and protects our body from pathogenic microorganisms that are present within the lumen of the gut, along with large numbers of beneficial bacteria. In order for the gut to carry out its essential functions, it contains exquisitely specialised cells, including epithelial cells, immune cells, nerve cells and muscle cells. Intestinal epithelial cells are tightly connected to each other to form a sophisticated gatekeeping system that allows the selective transport of nutrients and water but keeps away harmful toxins or pathogenic bacteria. Immune cells constantly monitor the lumen and the wall of the gut and respond in case the essential intestinal barrier is breached. Finally, complex networks of nerve cells within the gut wall are responsible for generating intestinal movements that are essential for proper digestive function by activating the musculature of the gut wall. Since the intestinal epithelium is constantly exposed to harmful substances and pathogenic microorganisms, it is quite vulnerable and is often damaged. Normally this does not have detrimental consequences for an organism since all cells of the intestinal epithelium are continuously replenished by stem cells that are dedicated to producing constantly fresh epithelial cells. Although the continuous regeneration of the intestinal epithelium is essential for maintaining it in good working order, other cell types play a major role in keeping them healthy. In particular, glial cells, which normally accompany and support nerve cells in all parts of the nervous system, are also found in the vicinity of intestinal epithelial cells and release substances that are essential for maintaining the intestinal epithelial barrier; if these enteric glial cells are eliminated in experimental conditions, the barrier breaks down and animals die from acute inflammation of the small intestine. In addition, several studies have suggested that the inflammation that accompanies common gut diseases, such as Crohn's disease or ulcerative colitis, may also involve the abnormal interaction of glial cells with intestinal epithelial cells and immune cells. These observations support the idea that despite their specialised functions, the different cell types that make up the gut wall (and indeed any organ) need to work in concert in order to support its physiological roles.Despite the important roles of the intestinal glial cells in supporting the critical functions of the nerve cells and the epithelium of the gut, very little is known about their biology in healthy individuals and in disease situations. In this proposal we will aim at filling this knowledge gap by building on some of our own recent observations. In particular, we will identify and characterise the properties of the gliogenic stem cells which generate new glial cells throughout life. We will also identify conditions and signals that modulate the behaviour of intestinal glial cells. Finally, we plan to characterise molecules which are located within the nucleus and are important for these cells to maintain their properties and continue to generate new glial cells throughout adult life.Normal digestive function depends on the fine balance between the loss of old and the production of new cells in the different gut tissues and the optimal cross talk between the different cell types. Breakdown of such an equilibrium results in uncontrolled growth of cells (cancer), severe inflammation of the gut wall (inflammatory bowel disease-IBD) or inability of the gut wall to protect the internal environment of an organisms from toxic substances or pathogenic bacteria. Understanding how local glial cells contribute to the integrity and normal function of gut tissues, we can ultimately use these cells as a means to alter the course of common debilitating gastrointestinal disorders.

胃肠道是一个重要的器官，它将我们的饮食转化为有用的可消化的营养物质，有助于维持水分平衡，保护我们的身体免受肠道内存在的病原微生物和大量有益细菌的侵害。为了使肠道发挥其基本功能，它包含了精致的特化细胞，包括上皮细胞、免疫细胞、神经细胞和肌肉细胞。肠上皮细胞彼此紧密相连，形成一个复杂的把关系统，允许营养物质和水的选择性运输，但防止有害毒素或致病菌。免疫细胞不断地监测肠腔和肠壁，并在必要的肠道屏障被破坏时作出反应。最后，肠壁内复杂的神经细胞网络负责产生肠道运动，通过激活肠壁的肌肉组织来维持正常的消化功能。由于肠道上皮经常接触有害物质和病原微生物，因此非常脆弱，经常受到损伤。通常情况下，这不会对生物体产生有害的后果，因为肠道上皮的所有细胞都是由干细胞不断补充的，干细胞致力于不断产生新鲜的上皮细胞。尽管肠上皮的持续再生对于维持其良好的工作秩序至关重要，但其他类型的细胞在保持肠上皮健康方面也起着重要作用。特别是，在神经系统各个部位通常伴随和支持神经细胞的神经胶质细胞，也在肠上皮细胞附近发现，并释放维持肠上皮屏障所必需的物质；如果这些肠胶质细胞在实验条件下被清除，屏障就会破裂，动物就会死于小肠的急性炎症。此外，一些研究表明，伴随常见肠道疾病（如克罗恩病或溃疡性结肠炎）的炎症也可能涉及神经胶质细胞与肠上皮细胞和免疫细胞的异常相互作用。这些观察结果支持了这样一种观点，即尽管它们具有特殊的功能，但组成肠壁（实际上是任何器官）的不同细胞类型需要协同工作，以支持其生理作用。尽管肠胶质细胞在支持肠道神经细胞和上皮的关键功能方面发挥着重要作用，但对其在健康个体和疾病情况下的生物学特性知之甚少。在本建议中，我们将以我们自己最近的一些观察结果为基础，力求填补这一知识空白。特别是，我们将识别和表征在整个生命中产生新的神经胶质细胞的胶质干细胞的特性。我们还将确定调节肠胶质细胞行为的条件和信号。最后，我们计划表征位于细胞核内的分子，这些分子对这些细胞保持其特性并在整个成年生命中继续产生新的胶质细胞很重要。正常的消化功能取决于不同肠道组织中旧细胞的流失和新细胞的产生之间的良好平衡，以及不同细胞类型之间的最佳串扰。这种平衡的破坏导致细胞不受控制的生长（癌症），肠壁的严重炎症（炎症性肠病ibd）或肠壁无法保护生物体的内环境免受有毒物质或致病菌的侵害。了解局部神经胶质细胞如何促进肠道组织的完整性和正常功能，我们最终可以利用这些细胞作为一种手段来改变常见的使人衰弱的胃肠道疾病的进程。

项目成果

Transplantation of Chemogenetically Engineered Cortical Interneuron Progenitors into Early Postnatal Mouse Brains.

将化学基因工程改造的皮质中间神经元祖细胞移植到出生后早期小鼠大脑中。

• DOI: 10.3791/59568
• 发表时间: 2019
• 期刊: JoVE
• 作者: Denaxa M

A branching model of lineage differentiation underpinning the neurogenic potential of enteric glia.

• DOI: 10.1038/s41467-023-41492-3
• 发表时间: 2023-09-22
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Laddach, Anna;Chng, Song Hui;Lasrado, Reena;Progatzky, Franze;Shapiro, Michael;Erickson, Alek;Castaneda, Marisol Sampedro;Artemov, Artem V.;Bon-Frauches, Ana Carina;Amaniti, Eleni-Maria;Kleinjung, Jens;Boeing, Stefan;Ultanir, Sila;Adameyko, Igor;Pachnis, Vassilis
• 通讯作者: Pachnis, Vassilis

Homeostatic Regulation of Interneuron Apoptosis During Cortical Development.

• DOI: 10.1177/1179069518784277
• 发表时间: 2018
• 期刊: Journal of experimental neuroscience
• 作者: Denaxa M;Neves G;Burrone J;Pachnis V
• 通讯作者: Pachnis V

Geminin prevents DNA damage in vagal neural crest cells to ensure normal enteric neurogenesis.

• DOI: 10.1186/s12915-016-0314-x
• 发表时间: 2016-10-24
• 期刊: BMC biology
• 影响因子: 5.4
• 作者: Konstantinidou C;Taraviras S;Pachnis V
• 通讯作者: Pachnis V

Modulation of Apoptosis Controls Inhibitory Interneuron Number in the Cortex.

• DOI: 10.1016/j.celrep.2018.01.064
• 发表时间: 2018-02-13
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Denaxa M;Neves G;Rabinowitz A;Kemlo S;Liodis P;Burrone J;Pachnis V
• 通讯作者: Pachnis V