How does oligodendrocyte transcriptional heterogeneity change biological function?

100年前首次描述的少突胶质细胞是大脑和脊髓中的细胞，在神经周围形成髓鞘。髓鞘的作用就像电线上的绝缘层，保护并加速电脉冲沿着神经的传导。少突胶质细胞还通过将代谢物穿过髓鞘传递到神经来供养下面的神经，维持神经。这些细胞对大脑和脊髓的功能非常重要，髓鞘的形成对于发育、学习和发育至关重要。（即使在成年期）和髓鞘结构的下降与正常衰老有关。虽然所有少突胶质细胞广泛显示这些功能，我们现在知道它们实际上并不完全相同。最近的技术表明，与脊髓相比，如果少突胶质细胞来自大脑，则它们中活跃的基因会有所不同，但大脑和脊髓相同区域内的少突胶质细胞之间甚至存在差异，并且这些差异会随着年龄的增长而变化。这些不同的基因活性模式表明，这些少突胶质细胞亚型的功能也各不相同，从而预测有些可能更擅长制造髓鞘，有些更擅长提供营养支持。这些少突胶质细胞亚型在不同物种的动物之间存在差异，其中一些仅存在于人类中，这表明少突胶质细胞功能的某些方面可能是人类特异性的。我们也不知道这些少突胶质细胞亚型是否是静态的，或者细胞中基因活性的亚型和模式是否可以根据需要改变功能。为了了解不同的人类少突胶质细胞是如何工作的，我们必须在实验室中对这些不同功能的预测进行生物学测试。本项目将在人类少突胶质细胞中测试这些预测，我们将在培养皿中从干细胞（胚胎干细胞）中产生大脑和脊髓亚型模式。我们将首先制作遗传工具，用荧光标记不同亚型的少突胶质细胞。然后，我们可以在培养皿中培养这些细胞（二维或三维），并将其移植到小鼠体内，以了解大脑和脊髓少突胶质细胞的不同之处，不同亚型的产生方式以及它们是否会发生变化。我们将发现哪些基因需要被激活以产生不同亚型的少突胶质细胞，并利用这些基因来制造更多的不同亚型。然后，我们将在我们的培养物和小鼠中测试每种类型制造髓鞘和提供营养支持的能力，这将使我们了解人类少突胶质细胞亚型在制造髓鞘和为神经提供营养支持方面的根本差异。

Oligodendrocytes, first described 100 years ago, are cells in the brain and the spinal cord that form myelin sheaths around nerves. Myelin sheaths act like the insulation on wires, protecting and speeding up the conduction of electrical impulses along nerves. Oligodendrocytes also feed the underlying nerves by passing metabolites though the myelin sheath to the nerve, sustaining it. These cells are very important to the function of the brain and spinal cord, and formation of myelin is essential for development, learning (even in adulthood) and the decline in the myelin structure is associated with normal ageing.Although all oligodendrocytes broadly show these functions, we now know that they are actually not all the same. Recent technology shows that the genes that are active in oligodendrocytes vary if they come from the brain compared to the spinal cord, but there are even differences between oligodendrocytes within the same areas of the brain and spinal cord and these differences change with ageing. These different patterns of gene activity suggest that the functions of these oligodendrocyte subtypes also vary, leading to the prediction that some may be better at making myelin and some better at providing nutritional support. These oligodendrocyte subtypes vary between different species of animals, with some only existing in humans, suggesting that some aspects of oligodendrocyte function may be human-specific. We also do not know whether these oligodendrocyte subtypes are static or whether the subtype and pattern of gene activity in a cell can change as needed to alter function. To find out how different human oligodendrocytes work, we must test these predictions of different function biologically in the laboratory.This project will test these predictions in human oligodendrocytes that we will generate in the dish from stem cells (embryonic stem cells) making both brain and spinal cord subtype patterns. We will first make genetic tools tagging the different subtypes of oligodendrocytes with fluorescent colours. We can then grow these in the dish (in 2 or 3-dimensions) and after transplanted into the mouse, to find out how brain and spinal cord oligodendrocytes are different, how different subtypes are generated, and whether they can change. We will discover which genes need to be activated to generate the different subtypes of oligodendrocytes and use these to make more of the different subtypes. We will then test the ability of each type to make myelin and provide nutritional support in our cultures and in the mouse.This will give us an understanding of the fundamental differences between human oligodendrocyte subtype in making myelin and providing nutritional support to nerves.