regeneration in nature

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Neural progenitor cells in planarians

Planarians are really amazing creatures as they can regenerate a whole animal from a tiny piece of their bodies. Planarians can do that because they possess a population of adult pluripotent stem cells, called neoblasts. For many years one of the debates within the field has been how homogeneous or heterogeneous is this neoblast population. Thanks to a study from the laboratory of Peter Reddien we know now that at least a proportion of those neoblasts are real totipotent stem cells. But how do these neoblasts, the only proliferative cells in planarians, differentiate into the different cell-lineages? Are there cell type-specific progenitors in these animals? Recently, some studies from Peter Reddien clearly indicate that at least for some cell types, such as photoreceptors and the excretory system, specific progenitors exist.

One of most astonished abilities of planarians is that they can regenerate a complete central nervous system de novo from those undifferentiated neoblasts. For long time people have wondered whether neural progenitor cells exist in these animals and how they would behave during regeneration. Two very recent papers from the laboratories of Kerstin Bartscherer (http://www.ncbi.nlm.nih.gov/pubmed/24131630) and Bret Pearson (http://www.ncbi.nlm.nih.gov/pubmed/23903188) have shown that the transcription factors lhx175-1 and pitx were required for the regeneration of the serotonergic lineage. Importantly, these transcription factors were co-expressed in cells expressing Smedwi-1, a homologue of the PIWI proteins and a marker of planarian neoblasts, suggesting the existence of progenitor cells for the serotonergic lineage.

Now these findings have been further corroborated and expanded by the laboratory of Ricardo Zayas (http://www.ncbi.nlm.nih.gov/pubmed/24173799). In this study they carried out a genome-wide analysis of bHLH transcription factors in planarians. In other models bHLH factors play pivotal roles in neurogenesis, from fate commitment to cell migration. In planarians, the authors identified 44 genes predicted to code for a bHLH domain, of which 12 were expressed in the CNS and neoblasts. Because of their specific expression patterns they mainly focussed on three of them: coe (collier/olfactory-1/early B-cell factor), hesl-3 (hairy/enhancer of split) and sim (single-minded). By double labelling they first checked how these factors were co-expressed with different markers of specific neuronal populations: cholinergic, GABAergic, octopaminergic, dopaminergic and serotonergic neurons. Next, in intact non-regenerating animals and through elegant BrdU pulse-chase experiments, they detected proliferating cells expressing coe or sim close to the nervous system, which could be traced to the brain or ventral nerve cords. Over time, the number of such double-labelled cells increased, especially in the head region. Similarly, during anterior regeneration these populations of progenitor cells expressing coe or sim, seems to contribute to the regenerative blastema. Therefore, it seems that these transcription factors would be labelling progenitor cells for distinct neuronal populations.

In the second part of the paper the authors performed RNAi analyses of this set of bHLH transcription factors in order to determine their functions during regeneration. Remarkably, they did not find any strong phenotype after knocking-down proneural bHLH genes such as neuroD or acheate-scute. However, silencing of coe, hesl-3 and sim resulted in clear defects of the regenerating brain either in terms of its gross morphology and/or the number or localization of specific neuronal populations. On the other hand, in intact animals the silencing of hesl-3 and sim did not produced any detectable defect in the nervous system.  This was different for coe, as after RNAi in intact animals these animals displayed an aberrant external morphology and they lost specific neuropeptidergic neurons (also lost in regenerating animals after coe RNAi).

In summary, these results suggest that coe, sim and hesl-3 may define progenitor cells committed to distinct neural fates and their function would be required for the differentiation of some neuronal cell types. As coe and sim are co-expressed with specific markers of different neuronal populations, their expression could be defining a set of multipotent progenitors.

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Francesc Cebrià

Francesc Cebrià

Francesc Cebrià

I am a Biologist and Professor at the University of Barcelona. I do my research on a fascinating animal: freshwater planarians. You can cut them in as many pieces as you want and each piece will regenerate a complete new flatworm in very few days. In this blog I will keep you updated on the latest news on the field of animal regeneration. You will be able to follow the latest research on how planarians, axolotls, newts, cnidarians and other animals are able to regenerate parts of their bodies

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