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miR-128 regulates non-myocyte hyperplasia, deposition of extracellular matrix and Islet1 expression during newt cardiac regeneration
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Cardiovascular disease is a global scourge to society, with novel therapeutic approaches required in order to alleviate the suffering caused by sustained cardiac damage. MicroRNAs (miRNAs) are being touted as one such approach in the fight against heart disease, acting as possible post-transcriptional molecular triggers responsible for invoking cardiac regeneration. To further ones understanding of miRNAs and cardiac regeneration, it is prudent to learn from organisms that can intrinsically regenerate their hearts following injury. Using the red-spotted newt, an adult chordate capable of cardiac regeneration, we decided to delve deeper into the role miRNAs play during this process.  RNA isolated from regenerating newt heart samples, was used in a microarray screen, to identify significantly expressed candidate miRNAs during newt cardiac regeneration. We performed quantitative qPCR analysis on several conserved miRNAs and found one in particular, miR-128, to be significantly elevated when cardiac hyperplasia is at its peak following injury. In-situ hybridisation techniques revealed a localised expression pattern for miR-128 in the cardiomyocytes and non-cardiomyocytes in close proximity to the regeneration zone and in vivo knockdown studies revealed a regulatory role for miR-128 in proliferating non-cardiomyocyte populations and extracellular matrix deposition. Finally, 3’UTR reporter assays revealed Islet1 as a biological target for miR-128, which was confirmed further through in vivo Islet1 transcriptional and translational expression analysis in regenerating newt hearts. From these studies we conclude that miR-128 regulates both cardiac hyperplasia and Islet1 expression during newt heart regeneration and that this information could be translated into future mammalian cardiac studies.

Keyword [en]
Heart, Hyperplasia, Islet1, miR-128, Newt, Regeneration
National Category
Biological Sciences
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:su:diva-93065OAI: oai:DiVA.org:su-93065DiVA: diva2:644435
Available from: 2013-08-30 Created: 2013-08-30 Last updated: 2013-09-02Bibliographically approved
In thesis
1. Heart Regeneration: Lessons from the Red Spotted Newt
Open this publication in new window or tab >>Heart Regeneration: Lessons from the Red Spotted Newt
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Unlike mammals, adult salamanders possess an intrinsic ability to regenerate complex organs and tissue types, making them an exciting and useful model to study tissue regeneration. The aims of this thesis are two fold, (1) to develop and characterize a reproducible cardiac regeneration model system in the newt, and (2) to decipher the cellular and molecular underpinnings involved in regeneration.

In Paper I of this thesis we developed a novel and reproducible heart regeneration model system in the red-spotted newt and demonstrated for the first time the newt’s ability to regenerate functional myocardial muscle, following resection injury, without scarring. The observed findings coincide with an increase in several developmental cardiac transcription factors, wide-spread cellular proliferation of cardiomyocytes and non-cardiomyocyte populations in the ventricle and reverse-remodeling at later time points during regeneration. Of further interest was the identification of functionally active Islet1+ve and GATA4+ve cardiac precursor cells in regenerating areas. The observation of such cell types further compels the similarity between mammalian cardiac development and newt cardiac regeneration and justifies these animals as suitable model organisms for studying heart regeneration. In Paper II we wanted to decipher the molecular cues possibly driving cardiac regeneration in newts. Here we used qualitative and quantitative methods to delineate the function microRNAs (miRNAs) have in this process. One interesting candidate, miR-128, a known tumor suppressor miRNA and regulator of myogenesis, was found to have a regulatory role in controlling non-cardiomyocyte hyperplasia during newt cardiac regeneration. Of further interest was the discovery of a novel binding site of miR-128 in the 3’UTR of Islet1. We speculate that the natural increase in miR-128 expression levels during cardiac regeneration functions as a fine-tuning mechanism to control cellular proliferation of precursor cells. In Paper III of my thesis we sought to explore if a link exists between RNA editing, a wide-spread post-transcriptional process and regeneration. We observed that A-to-I editing enzymes (ADARs) are present in regenerating newt tissues and the localization of ADAR1 alternates between nuclear and cytoplasmic compartments during regeneration. This activity of ADAR1 during regeneration may be partly responsible for driving the cellular plasticity that is needed during multiple phases of tissue regeneration in the red-spotted newt.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2013. 76 p.
Keyword
Heart, Regeneration, Newt, microRNAs, RNA editing
National Category
Biological Sciences
Research subject
Molecular Biology
Identifiers
urn:nbn:se:su:diva-93058 (URN)978-91-7447-726-9 (ISBN)
Public defence
2013-10-04, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
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Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 2: Manuscript.

Available from: 2013-09-12 Created: 2013-08-30 Last updated: 2013-09-04Bibliographically approved

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