microRNA returns the ability to regenerate to the myocardium
Recent studies have demonstrated the ability of adult mammalian cardiomyocytes to proliferate. However, unfortunately, this ability is very poorly expressed and it is not enough to repair damage to the heart muscle, including those developing as a result of myocardial infarction.
Researchers at the University of Pennsylvania, working under the guidance of Professor Ed Morrissey, have found that microRNAs, which play an important role in the proliferation of cardiomyocytes at the stage of development of the body, are able to induce the proliferation of these cells in the adult heart. (For the microRNA technology developed in Morrisey's laboratory, see in the article "A new method for producing induced pluripotent stem cells").
microRNAs are not involved in protein synthesis. Their function is to suppress gene expression by binding and starting the process of cleavage of informational RNAs (mRNAs) encoding a sequence of protein molecules.
The authors found that the loss of a microRNA cluster known as miR302-367 leads to a decrease in the proliferation of cardiomycites during the development of a mouse embryo. In the adult heart, increased expression of this microRNA cluster, on the contrary, leads to reactivation of the proliferation process of cardiomycites that do not divide in a normal state.
In part, this reactivation is due to the repression of the Hippo signaling mechanism, which regulates the proliferation of cardiomyocytes and determines the size of the emerging organ. Activation of this mechanism usually suppresses cell proliferation. miR302-367 cluster microRNAs affect the three main kinase components of Hippo, which reduces its activity, allowing cardiomyocytes to resume division and start tissue regeneration. According to Professor Morrisey, in this case we are talking about the repression of the repressor.
The cardiomyocyte of an adult organism has resumed its cell cycle
as a result of the resumption of miR302-367 expression.
In experiments on adult mice with simulated myocardial infarction, the expression of the miR302-367 cluster restored using genetic methods caused reactivation of cardiomyocyte proliferation, reducing the amount of scar tissue formed in the area of damage. An increase in the number of cardiomyocytes was recorded in the same animals.
However, prolonged expression of the miR302-367 cluster for several months led to dedifferentiation and decreased functionality of mouse cardiomyocytes. Based on this observation, the researchers suggested that dedifferentiation is necessary to restore the ability of cardiomyocytes to divide, but over time it worsens their contractility.
As subsequent experiments have shown, this can be avoided by introducing artificial short-lived microRNA analogues to animals. Daily administration of such microRNAs for seven days after myocardial infarction ensured the desired effect: suppressed the formation of scar tissue and improved the functioning of the damaged myocardium. At the same time, there was no progressive extinction of cardiac function in the animals, characteristic of genetic models of increased expression of the miR302-367 cluster.
At the next stage of the work, the authors plan to develop a system for targeted delivery of microRNAs into the heart tissue and test the experimental approach on larger animal models.
Article by Ying Tian et al. A microRNA-Hippo pathway that promotes cardiomyocyte proliferation and cardiac regeneration in mice is published in the journal Science Translational Medicine.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the University of Pennsylvania:
Penn Researchers Describe New Approach to Promote Regeneration of Heart Tissue.
23.03.2015