The hair-raising reason for goosebumps

鸡皮疙瘩产生的原因

The same cell types that cause goosebumps are responsible for controlling hair growth

引起鸡皮疙瘩的细胞同时也负责控制头发的生长

If you've ever wondered why we get goosebumps, you're in good company -- so did Charles Darwin, who mused about them in his writings on evolution. Goosebumps might protect animals with thick fur from the cold, but we humans don't seem to benefit from the reaction much -- so why has it been preserved during evolution all this time?

如果你曾经思考过为什么人会产生鸡皮疙瘩，那么你有伴了，因为查尔斯•达尔文在其关于进化论的著作中也曾经思考过这一问题。

In a new study, Harvard University scientists have discovered the reason: the cell types that cause goosebumps are also important for regulating the stem cells that regenerate the hair follicle and hair. Underneath the skin, the muscle that contracts to create goosebumps is necessary to bridge the sympathetic nerve's connection to hair follicle stem cells. The sympathetic nerve reacts to cold by contracting the muscle and causing goosebumps in the short term, and by driving hair follicle stem cell activation and new hair growth over the long term.

在一项新的研究中，哈佛大学的科学家们发现了鸡皮疙瘩产生的原因：引起鸡皮疙瘩的细胞类型在调节能够产生虹毛囊和头发的干细胞中也扮演着重要的作用。在皮肤下方，通过收缩以形成鸡皮疙瘩的肌肉在将交感神经和虹毛囊干细胞连接起来发挥着必不可少的作用。在遇到寒冷时，交感神经会收缩肌肉并引起鸡皮疙瘩短期出现。此外，交感神经还会驱使虹毛囊干细胞激活并使新的头发长期生长。

Published in the journal Cell, these findings in mice give researchers a better understanding of how different cell types interact to link stem cell activity with changes in the outside environment.

根据发表于期刊《细胞》的这些论文，针对老鼠所做出的研究结果让研究人员更好地了解到不同细胞类型是如何交互作用以及是如何通过这种交互作用使干细胞的活性和外界环境的变化联系起来。

"We have always been interested in understanding how stem cell behaviors are regulated by external stimuli. The skin is a fascinating system: it has multiple stem cells surrounded by diverse cell types, and is located at the interface between our body and the outside world. Therefore, its stem cells could potentially respond to a diverse array of stimuli -- from the niche, the whole body, or even the outside environment," said Ya-Chieh Hsu, the Alvin and Esta Star Associate Professor of Stem Cell and Regenerative Biology, who led the study in collaboration with Professor Sung-Jan Lin of National Taiwan University. "In this study, we identify an interesting dual-component niche that not only regulates the stem cells under steady state, but also modulates stem cell behaviors according to temperature changes outside."

“我们一直对了解外界刺激调节干细胞的行为方式感兴趣。皮肤是一个非常迷人的系统：它有数个干细胞，干细胞周围是各种类型的细胞。而且，皮肤还位于身体和外界环境之间。因此，干细胞能够对各种类型的刺激发生反应-从小生境，到整个身体，或甚至是外界”，Ya-Chieh Hsu,干细胞和再生生物学Alvin和Esta明星副教授表示。Ya-Chieh和国立台湾大学的Sung-Jan Lin教授共同合作并是这一研究的带头人。

A system for regulating hair growth

头发生长调节系统

Many organs are made of three types of tissue: epithelium, mesenchyme, and nerve. In the skin, these three lineages are organized in a special arrangement. The sympathetic nerve, part of our nervous system that controls body homeostasis and our responses to external stimuli, connects with a tiny smooth muscle in the mesenchyme. This smooth muscle in turn connects to hair follicle stem cells, a type of epithelial stem cell critical for regenerating the hair follicle as well as repairing wounds.

许多器官都有三类组织构成：上皮细胞、间质和神经。在皮肤中，这三类组织以一种特别的方式被安排在一起。交感神经，我们神经系统（控制体内稳态和我们对外界刺激反应）中的一部分与间(充)质中一个非常微小平滑的肌肉相连。这一光滑的肌肉反过来与虹毛囊干细胞相联系。虹毛囊干细胞是一种上皮干细胞，其对于再生虹毛囊以及修复伤口具有关键作用。

The connection between the sympathetic nerve and the muscle has been well known, since they are the cellular basis behind goosebumps: the cold triggers sympathetic neurons to send a nerve signal, and the muscle reacts by contracting and causing the hair to stand on end. However, when examining the skin under extremely high resolution using electron microscopy, the researchers found that the sympathetic nerve not only associated with the muscle, but also formed a direct connection to the hair follicle stem cells. In fact, the nerve fibers wrapped around the hair follicle stem cells like a ribbon.

交感神经和肌肉之间的联系已经众所周知，因为它们构成了鸡皮疙瘩背后的细胞基础：寒冷会触发交感神经元发送神经信号，肌肉通过收缩并引起汗毛直立而做出反应。然而，当利用电子显微镜学在极其高分辨率的图像下检查皮肤时，研究人员们发现，交感神经不仅与肌肉相联系，其还与虹毛囊干细胞有直接的联系。事实上，包括在虹毛囊干细胞周围的神经纤维就像一条带子。

"We could really see at an ultrastructure level how the nerve and the stem cell interact. Neurons tend to regulate excitable cells, like other neurons or muscle with synapses. But we were surprised to find that they form similar synapse-like structures with an epithelial stem cell, which is not a very typical target for neurons," Hsu said.

“我们能够在超微结构层面看到神经和干细胞是如何相互作用的。神经元倾向于调节易兴奋的细胞，比如其他带有突触的神经元或肌肉。但我们很惊讶地发现，它们会形成类似的突触，就像表皮干细胞的结构一样，其并非神经元的一个典型的目标。”

Next, the researchers confirmed that the nerve indeed targeted the stem cells. The sympathetic nervous system is normally activated at a constant low level to maintain body homeostasis, and the researchers found that this low level of nerve activity maintained the stem cells in a poised state ready for regeneration. Under prolonged cold, the nerve was activated at a much higher level and more neurotransmitters were released, causing the stem cells to activate quickly, regenerate the hair follicle, and grow new hair.

接下来，研究人员们证实，神经确实以干细胞为目标。交感神经通常会在一个恒定的低水平下被激活，以维持身体的体内稳定。研究人员们发现，这种低水平的神经活性使干细胞保持在一种平衡的状态下以为再生做准备。在持续的寒冷条件下，神经会在一个更高的水平层面被激活并释放更多是神经递质，从而引起干细胞快速激活并产生虹毛囊以及生出新的头发。

The researchers also investigated what maintained the nerve connections to the hair follicle stem cells. When they removed the muscle connected to the hair follicle, the sympathetic nerve retracted and the nerve connection to the hair follicle stem cells was lost, showing that the muscle was a necessary structural support to bridge the sympathetic nerve to the hair follicle.

研究人员还调查了是什么使神经和虹毛囊干细胞之间建立联系。当把与虹毛囊有关联的肌肉移除后，交感神经收回，神经与虹毛囊干细胞之间的联系消失，这表明肌肉是必不可少的将交感神经和虹毛囊联系在一起的结构支架。

How the system develops

系统如何发展变化

In addition to studying the hair follicle in its fully formed state, the researchers investigated how the system initially develops -- how the muscle and nerve reach the hair follicle in the first place.

除了研究完全成型的虹毛囊外，研究人员们还调查了系统最初发展的方式-肌肉和神经如何在一开始到达虹毛囊。

"We discovered that the signal comes from the developing hair follicle itself. It secretes a protein that regulates the formation of the smooth muscle, which then attracts the sympathetic nerve. Then in the adult, the interaction turns around, with the nerve and muscle together regulating the hair follicle stem cells to regenerate the new hair follicle. It's closing the whole circle -- the developing hair follicle is establishing its own niche," said Yulia Shwartz, a postdoctoral fellow in the Hsu lab. She was a co-first author of the study, along with Meryem Gonzalez-Celeiro, a graduate student in the Hsu Lab, and Chih-Lung Chen, a postdoctoral fellow in the Lin lab.

“我们发现信号来自于正在形成的虹毛囊本身。它分泌出一种能够调节平滑肌肉形成的蛋白，然后再吸引交感神经。随后，在成人中，交互作用发生回转，神经和肌肉共同调节虹毛囊干细胞以产生新的虹毛囊。这时，整个循环趋于结束--正在发展的虹毛囊创建了自己的微生态”，Yulia Shwartz，Hus实验室内的博士生介绍到。Yulia和Meryem Gonzalez-Celeiro（Meryem是Hsu实验室内的研究生）还有Chih-Lung Chen（Lin实验室内的博士生）是该研究的共同第一作者。

Responding to the environment

对环境做出反应

With these experiments, the researchers identified a two-component system that regulates hair follicle stem cells. The nerve is the signaling component that activates the stem cells through neurotransmitters, while the muscle is the structural component that allows the nerve fibers to directly connect with hair follicle stem cells.

通过这些实验，研究人员发现一个拥有双成分的系统来调节虹毛囊干细胞。神经是信号成分，其可以通过神经介质激活干细胞，而肌肤是结构成分，其允许神经纤维直接与虹毛囊干细胞连接。

"You can regulate hair follicle stem cells in so many different ways, and they are wonderful models to study tissue regeneration," Shwartz said. "This particular reaction is helpful for coupling tissue regeneration with changes in the outside world, such as temperature. It's a two-layer response: goosebumps are a quick way to provide some sort of relief in the short term. But when the cold lasts, this becomes a nice mechanism for the stem cells to know it's maybe time to regenerate new hair coat."

Shwartz表示：“你可以通过很多不同方式调节虹毛囊干细胞，这些调节方式都是研究细胞再生的模型。这一特别的反应有助于将细胞再生和外界变化，如温度变化联系起来。它是一个双层应答：鸡皮疙瘩是在短期提供某种缓解手段的快速方法。但是当寒冷持续时，这将成为干细胞的一个良好机制，干细胞将知道也许现在可以产生新的毛发外层。”

In the future, the researchers will further explore how the external environment might influence the stem cells in the skin, both under homeostasis and in repair situations such as wound healing.

在未来，研究人员将继续探索外界环境将如何在体内平衡和修复情况下，比如伤口愈合方面，影响皮肤中的干细胞。

"We live in a constantly changing environment. Since the skin is always in contact with the outside world, it gives us a chance to study what mechanisms stem cells in our body use to integrate tissue production with changing demands, which is essential for organisms to thrive in this dynamic world," Hsu said.

我们生活在一个不断变化的环境中。由于皮肤往往与外界相联系，所有我们有机会研究体内的干细胞利用什么机制来将细胞生产和变化的需求结合在一起，而这是有机体在这个充满变化的世界中蓬勃发展的重要因素。

文章来源：科学日报   编辑：质控部