“Goose bumps” stimulates the activity of stem cells

Researchers have found that “goosebumps” play an important role in the regulation of stem cells that regenerate hair follicles and hair.

Goosebumps are the so-called pilomotor reflex (PMR), or piloerection. This reflex in animals helps them survive in the wild: the erect hairs make the animal appear larger and more terrifying to the opponent than they really are. Another function of the PMR is additional thermal insulation, since the erect hairs retains heat better. However, humans don’t seem to benefit much from this reaction – so why has it persisted throughout evolution all this time?

In a new study, researchers at Harvard University have found the reason: The cell types that are associated with PMR are also important for the regulation of stem cells that regenerate hair follicles and hair.

Hair is lifted by contraction of a muscle located in the skin. It connects the sympathetic neuron to the stem cells of the hair follicles. The sympathetic neuron reacts to cold by contracting muscles and causing goosebumps in the short term, and stimulating stem cell activation and new hair growth over the long term.

The findings from a study in mice were published in the journal Cell. With their help, scientists expanded their understanding of the interaction of various types of cells and discovered the connection between the activity of stem cells and changes in the outside environment.

“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, Associate Professor, 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”.

Hair Regeneration Mechanism

Many organs are made up of three types of tissues: nervous, epithelial, and mesenchyme. In the skin, these three lines are organized in a special order. The sympathetic nerve, the part of the nervous system that controls the body’s homeostasis and responses to external stimuli, connects to tiny smooth muscle in the mesenchyme.

This smooth muscle, in turn connects to the stem cells of the hair follicle, a type of epithelial stem cell critical for the regeneration of the hair follicle as well as wound healing.

The connection between the sympathetic nerve and the muscle is well known because they are the cellular basis of the pilomotor reflex: cold causes the sympathetic neurons to send a signal, and the muscle responds by contracting and causing the hair to stand on end.

Though, when examining the skin at extremely high resolution using electron microscopy, the researchers found that the sympathetic neuron is not only associated with the muscle, but also forms a direct connection with the stem cells of the hair follicle. In fact, the nerve fibers are wrapped around them like a ribbon.

“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.

Researchers have also confirmed that the neuron is indeed targeted with stem cells. Usually the activity of the sympathetic nervous system is constantly kept at a low level to maintain homeostasis of the body. Scientists have found that it is also necessary to keep the stem cells ready for the regeneration process.

With prolonged exposure to cold, the neuron was activated at a much higher level and more neurotransmitters were released, which caused the stem cells to quickly activate, regenerate the hair follicle and create new hair.

Scientists also 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 neural connection to the stem cells of the hair follicle was lost, demonstrating that the muscle was a necessary building block for the sympathetic neuron to connect to the hair follicle.

System formation at early stages of development

In addition to studying the fully formed hair follicle, the researchers observed how the system develops from the very beginning – primarily how the muscles and nerves reach the hair follicle.

“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.

Reaction to the external environment

Through these experiments, the researchers discovered a two-component system that regulates the stem cells of hair follicles. A neuron is a signaling component that activates stem cells via neurotransmitters, while muscle is a structural component that allows nerve fibers to connect directly to the stem cells of hair follicles.

“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.”

In the future, the researchers plan to continue studying the influence of the external environment on skin stem cells, both under homeostasis and in regenerative situations such as wound healing.

“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.