“Our skin is a part of us and how we express ourselves, how the world perceives us and how we want to be perceived,” said Maria Kasper of the Department of Cell and Molecular Biology at the Karolinska Institute, Sweden. “There’s so much about skin I’d like to tell you. It’s hard to pick.”
“When I started working on skin about 15 years ago, I thought skin is just a simple organ that protects us – but it isn’t. I’ve found out many very interesting things.”
“I invite you to explore the fascinating world of skin biology with me — a realm where cells collaborate in communities to execute incredibly diverse tasks, such as producing hair, rendering our skin waterproof, regulating our body temperature, and enabling us to feel the breeze or a gentle touch,” she continued. “To grasp the diversity of cells and cell communities in the skin, my laboratory has spent the last decade mapping the skin’s cellular landscape during its formation, in adult health during phases of hair growth and rest, and throughout the process of wound healing.”
Kasper explained that so far they have identified 56 different types of cells in skin each containing thousands of mRNA molecules. These cells have diverse functions – “an organ is like a human society running a village by interaction and collaboration”.
Our skin renews every three weeks – “lots of dust in our houses is just the skin we shed”. It’s comprised of many layers starting with the basal layer, which includes the stem cells, and moving up to the thick layer of surface cells that protect us. Skin is different across the body depending on its function. “For example,” explained Kasper, “we need thick skin on our feet (palmoplantar skin) because we walk on our soles. There are more than 60 dead cell layers on the feet.”
The skin also contains melanocytes – pigment-producing cells which pass melanin pigments to neighbouring cells where they act like “a hat to protect the cells’ DNA against UV radiation”.
Every living cell also needs nutrients and oxygen which is provided via the vascular network.
The deepest layer of the skin’s epidermis is where the stem cells reside. “Adult stem cells serve as the cornerstone for our tissues’ ability to perform essential functions throughout our lifetime,” explained Kasper. “The health of our organs hinges on the critical decisions made by each stem cell: to either self-renew and preserve their stem-cell identity or to differentiate into specialised cells.”
Defects in the stem cells also cause various diseases.
The diverse functions of the skin are maintained by the tissue stem cells within small and large cell communities – so called stem-cell niches. Each function requires its own niche – the body barrier generated in the epidermis, hair production in the hair follicle, thermoregulation via sweat glands, or sensation of touch in touch domes.
Not just hair
Kasper also introduced what she described as her “favourite mini-organ” – the hair follicle. “Hair follicles do not only generate hair in an assortment of shapes and colours but also showcase the remarkable efforts of stem cells to maintain organ function.”
We are born with all the hair follicles we will ever have. The same hair follicle goes through cycles of renewal and self-maintenance with hair growing about a centimetre a month. Each follicle also contains a network of nerves allowing us to experience for example a light breeze.
Kasper explained that the hair follicle looks like an onion with many layers. The stem cells build up different layers by moving from the signalling hub to create the next layer with the micro-niches telling the stem cells what to do.
She also explained the process of hair loss or balding which is typically caused by a signalling dysfunction in the follicles which means they cannot produce hair anymore. “This is different to hair loss due to a burn or deep wound where the hair follicles are often completely destroyed,” she explained.
Kasper’s work is focused around four areas: skin health, cancer formation, wound repair, and development. Some of the questions she and her colleagues try to address include: how cancers start to form; how cells look and behave in healthy skin; which cells are stem cells and where do they sit; how do the skin niches differ; how do cells behave differently and adapt to their new environment when there is a wound; and, what is the cellular landscape of early skin development?
She described some of her early work looking at basal cell carcinoma in a mouse model, where she aimed to answer the question why the same mutation sometimes gives rise to cancers and sometimes doesn’t. Initially, they used a quite advanced method to mark individual cells in different colours and track what they do. They observed that behaviour of individual cells was indeed strikingly different, but the study overall did not resolve their original question. The advent of single-cell RNA sequencing first published in 2009 gave a new unique possibility to look at single cells and their respective signals in detail. She and her team realized that single-cell RNA sequencing of skin could be the key, thus they pioneered it’s use in skin and generated single-cell atlases of hair follicles and their surrounding skin cells. This made it possible to look at skin and hair follicles in unprecedented resolution and sparked the idea that the different environments may have a great impact on cells, and thus cancer development.
The critical niche
This work in mice led to a number of important findings including understanding the important role of the niche in telling stem cells what to do. Stem cells are flexible and depending on the signals supplied by the niche the cell performs different tasks including forming hair cells. “We can control epithelial stem-cell fate by adapting the niche,” said Kasper. “If we give a different signal, we adapt the task.”
An almost-chance discovery of a hair follicle within a tumour led to some fascinating results.
“We managed in a tumour mouse model to create a niche under the forming tumours,” continued Kasper. “This new signalling hub pushed tumour cells to produce hair follicles instead of tumours. This meant we could ask the bigger question whether it’s possible to induce hair follicles in adult skin that hasn’t made hair.”
“Over the past ten years we have looked at skin and hair follicle cells in health, how they work together to heal a wound, as well as when stem cells decide to specialize (differentiate) in adult skin,” said Kasper. “Our latest focus is to control the decisions of tissue stem cells. Not only when to self-renew or differentiate, but also how to steer a stem cell of non-haired skin into making a hair.”
She explained that deep wounds or burns often result in the permanent loss of hair follicles, leaving a rigid, touch-impaired, hairless, disfiguring scar. For those patients there is currently no treatment modality available to regrow new hair. The ability to generate new hair follicles in adult skin therefore has great potential to ameliorate some of these deficits.
“Overall, we have learnt that the niche cells are critical; all the skin compartments have their own stem cells which are all different; that wound repair has a major influence on cell fate and the cell’s future function; and, that fully understanding stem cell fates and hair follicle generation, the study of skin development is crucial.”
The long-term aim is to re-activate skin stem cells in a controlled manner which would substantially modernise skin-regenerative medicine.
Michelle Galloway: Part-time media officer at STIAS
Photograph: Noloyiso Mtembu