Planarians are freshwater flatworms that have become a key model for studying regeneration and stem cells, as they can regenerate any part of their bodies, including their heads. But how does the animal know what part of the body it is missing and what type of tissue it must regenerate?
Researchers from the Department of Genetics, Microbiology and Statistics of the University of Barcelona (UB) and the Institute of Biomedicine (IB) of the UB have studied the regeneration process of these animals and have identified how the modulation of the intercellular signaling pathway Wnt modifies chromatin, the set of genetic material that cells have in the cell nucleus. Within hours of an amputation, this mechanism tells stem cells in the wound to know the fate of the new tissue.
Researchers from the Andalusian Center for Development Biology (CABD), the Pablo de Olavide University in Seville and the University of East Anglia in Norwich have also participated in the work, the first two entities in Spain and the third in the United Kingdom.
The surprising plasticity of planarians is due to the presence of a population of pluripotent adult stem cells, the neoblasts, which are capable of reproducing any type of cell in the organism. Right after an amputation, when new tissue must be regenerated, there is a window of time in which everything is possible for these pluripotent cells, and, based on the signal received by the cells where the cut has occurred, it is decided what fate they will have. One of the first steps in this process is to specify the body axis, such as the anteroposterior axis, which defines the position of the head and tail.
To understand how this phenomenon occurs, the researchers have carried out a genomic study of the cells located near the wound that occurs after amputating the head and tail. Using the ATAC-seq and Chip-seq techniques, researchers have been able to analyze the regions of the genome that are accessible or inaccessible in these tissues at a given time; in this case, twelve hours after the amputation. “Only the open regions are accessible to transcription factors, which are responsible for the expression of genes. Therefore, these studies allow us to know which set of genes is activated in the cells of the wounds twelve hours after the cut, and if they are different between the anterior and posterior part of the planaria”, explains Teresa Adell, professor at the Faculty of Biology, who has coordinated the research.
The results reveal that twelve hours after the amputation, the chromatin – the set of genetic material that cells have inside the nucleus – changes its conformation depending on whether the cells near the wound detect that they must regenerate a head or a tail. In addition, they demonstrate that the change in chromatin composition, which is what regulates gene expression in the cell, depends on whether a cell signaling pathway, the Wnt pathway, is activated. “If it is necessary to make the head, the Wnt pathway is inhibited; and if it is necessary to queue, it is activated. Furthermore, this change in chromatin composition occurs twelve hours after cutting; new tissue has not yet been made, but the cells already know what destiny will have to follow”, points out the researcher.
These freshwater worms are capable of regenerating any part of their bodies, including their heads. (Photo: Teresa Adell)
Similarities and differences with respect to other organisms
Understanding this regeneration in planarians is also important for understanding this process in other organisms, since the molecular mechanisms that allow the correct regeneration of organs and tissues are evolutionarily conserved, that is, they are very similar in all animals. In this sense, previous studies had already shown that the regulation of the Wnt pathway is responsible for specifying the anteroposterior axis of many organisms —including mammals— during embryonic development and also in regeneration in adult animals. ‘Our study reveals the mechanism by which this is the case in planarians, but also in other animals: the Wnt pathway specifies which genes are expressed and therefore cell fate, since they regulate the conformation of chromatin from the first moment of regeneration”, summarizes Teresa Adell.
On the other hand, the conclusions of the work also show the differences with other animals. “Our study corroborates the idea that organisms as plastic as planaria have very active intercellular signaling pathways, as if they were embryos, which means that any change in context can change the fate of the cells. It does not happen like in mammals, for example, in which the plasticity of the cells is much more restricted”, points out the researcher.
The risks of cell reprogramming
In the case of humans and the possible future biomedical impact of this basic research, the researcher stresses that the implications “are not direct, but conceptual”: “In this study we show that the regenerative capacity is linked to the ability to cells reprogram themselves to change fate. Therefore, a strategy to improve the regenerative capacity of humans could be to provoke cell reprogramming”, says Teresa Adell.
In any case, the researcher is prudent with respect to this strategy and warns that it could have unwanted effects, such as tumor transformation. “In animal models that do regenerate, it has been shown that the signals that must be activated to regenerate, such as the Wnt pathway that we mentioned, are also those that promote tumor processes when activated in the wrong way. As is often the case, nothing is absolutely right or wrong, it depends on the context in which we find ourselves », she concludes.
The study is titled “Wnt/β-catenin signaling is required for pole-specific chromatin remodeling during planarian regeneration.” And it has been published in the academic journal Nature Communications.
All the results of the genomic analyzes that have been carried out during the study have been integrated into the PlanExp open access platform, with the aim of sharing information and facilitating data analysis for the scientific community. (Source: UB)