What comes first, the niche or the stem cell?

Written by Elena Conroy

Researchers at The Rockefeller University (NY, USA) identify a niche independent mechanism for stem cell specification and regulation.

Researchers at The Rockefeller University (NY, USA) have identified a new mechanism of stem cell regulation during development. The results help explain how communication between cells mediates the process by which early stem cells are formed, and how these may have implications for skin cancer treatments.

“While adult stem cells are increasingly well-characterized, we know little about their origins. Here, we show that in the skin, stem cell progenitors of the hair follicle are specified as soon as the cells within the single-layered embryonic epidermis begin to divide downward to form an embryonic hair bud,” explained Elaine Fuchs from the Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development. “This timing was much earlier than previously thought, and gives us new insights into the establishment of these very special cells.”

Clusters of stem cells receive signals from neighboring cells that instruct them to either remain a stem cell, or differentiate into a specific cell type. These instructive groups of cells, called the ‘niche’, are known to maintain adult stem cell populations. Less well understood is how the niche forms, or when and where stem cells first appear during embryonic development.

“Adult stem cells are dependent on the niche for instructions on both how to become a stem cell, and how to control stem cell population size,” stated first author Tamara Ouspenskaia. “The question was, does the niche appear first and call other cells over to become stem cells? Or is it the other way around? Stem cells could be appearing elsewhere first and then recruiting the niche.”

Fuchs and colleagues investigated the cell divisions that occur in mouse hair follicles, a region known to contain an active population of stem cells.

When it is first developing, the hair follicle begins as a small bud called a placode, and develops into a tissue of multiple layers, comprised of different cell types. By labeling cells within the placode and tracing their progeny, the researchers determined that from each division, one daughter cell stayed put, while the other migrated to a different layer.

Further experiments revealed that the migrated cell became a stem cell. This finding is significant as it’s the earliest point in development that stem cells have been detected in this system, and indicates that stem cells may exist before the niche is formed.

How cells differentiate depends on a number of factors, including molecular signaling from other cells that help turn specific genes on or off. Fuchs and colleagues observed that the signaling activity was different between the two daughter cells that ended up in different locations, and aimed to characterize how signaling helped seal their ultimate cell fate.

They demonstrated that the environment to which the migrated daughter cell moved to had low levels of WNT signaling, known to play a role in embryonic development. In contrast, WNT signaling was high in the environment where the other daughter remained. The level of WNT affected how the cells responded to another signal known as SHH — only those in the low-WNT environment responded to SHH signaling, which instructed the cells to become stem cells.

“These cells must leave home, they must leave the environment with high WNT signaling, to become stem cells,” continued Ouspenskaia. “We observed that SHH, which actually comes from the cells with high WNT signaling, is essential in helping the cells leave. So in order for this escapee cell to become a stem cell, it needs to receive an SHH signal from its sister cell at home telling it ‘you’re the stem cell.'”

The research team believes that antagonism between WNT and SHH signaling may help to control the number of stem cells produced during this stage of development. “This newly identified signaling crosstalk provides insights into why these two signals have such a profound impact on skin cancers, where the numbers of cancerous tissue-propagating stem cells are excessive,” concluded Fuchs. “This work now paves the way for future research into the fascinating and clinically important relation between tumor-propagating and normal stem cells”.

Sources: Ouspenskaia T, Matos I, Mertz AF, Fiore VF, Fuchs E. WNT-SHH antagonism specifies and expands stem cells prior to niche formation. Cell 164, 156—169 (2016); http://newswire.rockefeller.edu/2016/01/14/signals-that-make-early-stem-cells-identified/