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MicroRNAs – the saviours of stem cells

Life means almost permanent renewal. Layers of skin and the blood cells of animals are replenished on a life-long basis, while plants can even grow whole new leaves, flowers and branches. All this is due to stem cells, the all-rounders of the cell kingdom. In plants and animals, stem cells have the potential to give rise to many types of cells, thereby giving plants the ability to grow throughout their life cycle. But how does a cell know that it is a stem cell and must not differentiate into a specialised organ cell? Prof. Dr. Thomas Laux and his colleagues from the Department of Developmental Biology and Plant Biotechnology at the Institute of Biology III at the University of Freiburg have been able to show that tiny molecules – i.e. microRNAs – play an important role in regulating stem cell self-renewal and differentiation.

“Strictly speaking, there is nothing unique about them,” says Prof. Dr. Thomas Laux of the University of Freiburg when asked to describe stem cells. Stem cells are all-rounders; they can differentiate into all kinds of specialised cells, they can also form leaves, fruit and branches, replace damaged cells and maintain their undifferentiated state by replenishing the stem cell pool. “The public perceives stem cells as miracle cells,” said Laux. “The reason for this is their pluripotency. This means that stem cells can theoretically differentiate into any type of cell whatsoever. This is a completely normal process that takes place every day in specific body regions where stem cells are kept in a quiescent state and their differentiation is repressed. These regions are referred to as stem cell niches, where the fate of stem cells is regulated through interactions with neighbouring, differentiated cells. Undifferentiated stem cells are located in the root and shoot apical meristems of plants and in the trunks of trees (cambium). The potential of stem cells is exploited in the field of regeneration biology, which provides researchers with the attractive possibility of producing any cell type they want from stem cells. “Plant stem cells can form organs in plants. Humans are unable to grow new arms, but the growth of new organs is perfectly normal for plants,” said the plant biotechnologist. One of the issues Laux was specifically interested in was the signals that ensure that stem cells recognise their position and task within organisms as well as knowing which developmental programmes they have to switch on and when.

Signalling substances from the environment determine cell fate

Stem cell formation in the apical shoot meristem of Arabidopsis thaliana. © Prof. Dr. Thomas Laux, University of Freiburg

The thale gress (Arabidopsis thaliana) provided the scientists with the answer they were seeking. Back in 1998, Laux and his colleagues discovered an area below the stem cells of the shoot meristem, which is termed organising centre (OC). These OC cells express the WUSCHEL (WUS) homeobox gene, which results in a signal (transcription factor) to maintain the overlying stem cells in a pluripotent state. The OC in turn receives a signal from the stem cells in the form of a small peptide that restricts the size of the OC by repressing WUS transcription. 

Plant shoots and roots have meristematic tissues where active stem cells provide a steady supply of cells that facilitate plant growth. While the root and shoot meristems differ in the way the division of daughter cells is regulated, both have a centre that sends out specific signals to the stem cells. Similar to the OC in the plant shoot, the plant root also has a quiescent centre whose stem cells do not undergo division. 

Shoot meristems also give rise to cells from which leaves, branches and flowers are formed. The fate of individual daughter cells is determined by their relative positions, i.e. daughter cells that are displaced from the most apical position of the shoot meristem, i.e. stem cell niche, differentiate into specialised tissue as they are unable to perceive the signal that would tell them to remain in an undifferentiated state.

Laux came across a signal that is released by the quiescent centres in root meristem stem cell niches. This signal originates from the WOX5 gene, which encodes a WUS homologue. The researchers also identified another WUSCHEL gene, i.e. WOX4, in the cambium (tissue in tree trunks where new cells are supplied). “When you find stem cells in plants, you can be sure that you will also come across a gene of the WUS family, which the plants need in order to keep their cells in an undifferentiated state,” said Laux. Laux is a biochemist by training and member of the Centre for Biological Signalling Studies (BIOSS) in Freiburg.

How are the boundaries maintained?

Root meristem: quiescent centre (QC): green; stem cells (SC): pink; differentiated cells (purple). © Prof. Dr. Thomas Laux, University of Freiburg

In theory, one would expect the distance between the apical shoot stem cell niche and the organising centre to increase gradually with every cell division round, with the result that OC stem cell pluripotency would no longer be maintained. However, this is not the case. “How is it that boundaries and structures can be maintained and the fate of individual cells determined in an area where all cells divide?” was the question to which Laux wanted to find an answer. It was already known that a particular microRNA (miRNA) signalled to some meristematic cells to differentiate into specialised cells. In addition to this miRNA, Laux and his co-workers found another miRNA that seemed to neutralise the miRNAs found in the stem cell niche.

MicroRNAs are rather small ribonucleic acid (RNA) molecules that do not encode proteins, but prevent other RNAs from being turned into proteins. Their small size enables them to move from one cell to another, a property that makes them excellent signalling substances.

In the root meristem, the miRNA that acts as the “saviour of stem cells” is only produced in the surface cell layer (epidermis). It is a mobile signal that migrates through the three apical cell layers and makes the stem cells underneath susceptible to WUSCHEL, a signal that comes from the organising centre underneath the stem cell layer. “Even though the signal might reach other cells, it is only able to trigger stem cell production in these three apical cell layers,” said Laux, going on to explain “WUSCHEL then tells these cells what task they have as stem cells and which genes they need to switch on.”

MicroRNA 394 at work

Why does the stem cell saviour miR394 (microRNA 394) not migrate further than these three cell layers? Laux speculates that this is a quantity issue. The miRNAs do their job, which means that they are used up, and their quantity drops. As the miRNAs move from one cell to another, the signal weakens and at some stage it will no longer be strong enough. “Alternatively, it could be that the channels through which the miRNAs migrate are absent,” reasons the expert. “Some cells come into contact with only a few miRNA molecules despite being relatively close to each other.” Laux compares the finely regulated communication among cells with that of social animals: “People do not always talk to each other either. And this is just the same with cells: some exchange information and some leave each other in peace.”

The miRNAs do a reliable job in the cells that they enter; it is their job to render an inhibitor protein harmless. This inhibitor, called “leaf curling responsibleness” (LCR), is expressed in almost all plant cells and inhibits WUSCHEL. As a result, stem cell identity can no longer be maintained and the cells differentiate. In the stem cell niche, LCR is blocked by miR394; it binds to LCR mRNA and cuts it into pieces, thereby preventing it from being translated into protein. Inhibition of LCR by miRNA thus leads to the activation of the WUSCHEL transcription factor, which in turn transforms cells into stem cells.

Further information:

Prof. Dr. Thomas Laux
Institute of Biology III
University of Freiburg
Schänzlestr. 1
79104 Freiburg
Phone: +49 (0)761/203-2943
Fax: +49 (0)761-203-2745
E-mail: laux(at)biologie.uni-freiburg.de

 

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/micrornas-the-saviours-of-stem-cells