Stem cells reach out for help

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(Nature, Jul 2015) Scientists show that stem cells use special structures called nanotubes to receive supportive signals from their environment.

One of the most important open questions in stem cell research is how stem cells are maintained and regulated in their natural microenvironment within our organs (or as scientists call it, their niche). A research team led by Dr. Yukiko Yamashita’s at University of Michigan is tackling this very question using a particular group of stem cells in the fruit fly testis, called .

In each fly testis, 8 to 10 GSCs are organized as the petals on a flower surrounding another group of cells, called the hub, which produces important signaling molecules that allow the stem cells to . The contact between hub and stem cells is the basis for two different signaling cascades, called and , both of which lead to activating the expression the important stem cell genes.

However, researchers had long wondered how the hub signals would reach only the closest stem cells. Sometimes, solutions are well hidden, even from those who have both experience and the technology to reveal them. “I have been seeing these cells for more than a decade, essentially every day, and have missed it !” says Yamashita. It was postdoc Mayu Inaba in Yamashita’s research group who made the first coupling between an observation in the microscope and a potential answer to the riddle. In a recent article in the journal Nature [1], the team showed that GSCs have long, thin arms that reach out towards the hub cells. These arms, called nanotubes, are only 3 micrometers long, approximately 30 times thinner than a human hair.

Yamashita and her colleagues found that the Tkv receptor for the Dpp molecule was found inside the nanotubes, where they would bind each other, triggering the signaling cascade that maintains GSC identity (see illustration).

NEW ILLUSTRATION ENGLISH Nanotubes Inaba Nature 2015 Eng-01Stem cells (light gray) are organized as petals around hub cells (dark gray). The hub produces the Dpp ligand (green), while the stem cells produce the Tkv receptor (red). Cell #1 lacks nanotubes and Dpp must find its way over to the stem cell to activate Tkv. In cell #2, the receptors are placed on the nanotube, and facilitate binding of the ligand and receptor. More ligands and receptors bind, increasing the stem cell identity signal cascade in this cell. (Illustration: Åsmund Eikenes).

This mechanism would offer a very precise and tight coupling between the two cells; only cells that can project nanotubes into the hub will be able to receive the support signal, which avoids rogue signaling molecules and helps to limit the stem cell pool. Interestingly, the components of the JAK-STAT pathway components were not present in the nanotubes, and Yamashita recognizes that understanding how BMP and JAK-STAT coordinate stem cell regulation remains an important question.

“It is always difficult to prove structural-functional relationships”, explains Yamashita. But when she and her colleagues prevented the stem cells from making normal nanotubes, they eventually lost their identity. On the other hand, stem cells with overly large and chunky nanotubes showed elevated levels of stem cell identity.

It is unlikely that the machinery to make nanotubes is expressed or used exclusively in testis GSCs. Instead, this study shows that the stem cells use the nanotube machinery differently than other cells. “We need to continue investigating how the nanotubes contribute to bringing the right signal to the right cell […] We have assumed for a long time that identifying which signaling pathways and transcription networks are active or inactive in stem cells is enough to understand stem cell self-renewal”, explains Yamashita, adding that “stem cell research is no longer just about which genes are turned on or off, but how the cells behave in their environment. We have to stay open-minded!”.

Åsmund Eikenes, PhD

[1] Inaba, M., Buszczak, M., and Yamashita, Y.M. (2015). Nanotubes mediate niche-stem-cell signalling in the Drosophila testis. Nature advance online publication. doi:10.1038/nature14602

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Flies are cheap and their genes are very easy to manipulate. In addition, GSCs are easy to observe with a microscope, making this a very convenient laboratory model to understand the function and regulation of stem cells in a living organism. Just as importantly, many of the discoveries made with fly GSCs have shown to be true for human stem cells too.
When germline stem cells divide, the two daughter cells are endowed with different tasks. One of them starts specializing into sperm (or an egg cell, in female flies), whereas the other remains a stem cell tightly associated with the hub, thus replacing the original copy.
BMP (Bone morphogenetic proteins) refers to a large family of factors that cells use to communicate with one another, both in insects and vertebrates. In flies, one of these BMP factors is called Decapentaplegic (Dpp), and is recognized by a receptor on the surface of a cell receiving the message, called Thickveined (Tkv). In turn, the activation of Tkv triggers a signal relay cascade that makes its way into the nucleus to activate the expression of specific genes.
JAK-STAT (Janus Kinase – Signal Transducer and Activator of Transcription) is another signaling system that cells use to regulate cellular growth and development in animals. Binding of a factor called Unpaired (Upd) to a surface receptor called Domeless activates a similar cascade of signals inside the cell that ultimately leads to gene activation by STAT proteins.

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