The sensor protein TLR2 helps heart cells from newborn mice survive injury and divide
The sensor protein TLR2 helps heart cells from newborn mice survive injury and divide
In an article published on August 14, the authors compared genes that were active in the hearts of newborn mice after myocardial infarction with those active under pressure overload caused by aortic constriction. In cell experiments, a mixture of three proteins released mainly by cardiac immune cells both reduced cardiomyocyte death and promoted cardiomyocyte division. Both effects required TLR2, a sensor protein on the cardiomyocyte surface.
Cardiomyocytes in the adult heart rarely renew themselves. During the first few days after birth, mice retain a brief window in which these contractile muscle cells can still divide. In a 2019 study by the same group, aortic constriction on the first day of life preserved cardiac function and was accompanied by capillary growth. When the procedure was performed on the seventh day of life, cardiac function deteriorated and fibrosis developed, with scar tissue replacing muscle tissue. The new article examines the signals that initiate early cardiac repair under this type of pressure overload.
The authors compared genes that were active one day after myocardial infarction induced on the first day of life with genes that were active after two weeks of pressure overload caused by aortic constriction. Among 995 genes shared between the two conditions, they selected three proteins that cells release into the surrounding tissue: CCL4, S100A8 and C1QA. Cardiomyocytes and vascular cells carry receptors for these proteins, while tissue staining showed that cardiac immune cells produced most of them after pressure overload.
The authors added a mixture of the three proteins, called Pool3, to isolated cardiomyocytes from newborn mice. Unlike any of the individual proteins, Pool3 increased the number of cells entering the cell cycle by a factor of 1,4 and the number of cells showing signs of mitosis and cytokinesis by a factor of 1,7. Cytokinesis is the final separation of one cell into two. Anillin protein staining between two nuclei allowed the authors to confirm that this separation had occurred, rather than merely detecting nuclear duplication. Pool3 also reduced the proportion of cells showing signs of early and late cell death.
To investigate how the mixture works, the authors examined which genes it activates in cardiomyocytes and constructed a computational map of protein interactions. TLR2 was the protein at which the largest number of connections converged in this map. According to the computational model, intermediate components connect CCL4, S100A8 and C1QA to TLR2. Cardiomyocytes from mice lacking TLR2 did not respond to Pool3, and a TLR2 inhibitor eliminated the effect of the mixture in normal cells. Zymosan, a compound that activates the receptor, independently improved cell survival and increased entry into the cell cycle.
By the seventh day after aortic constriction, mice lacking TLR2 showed reduced cardiac contractility, enlarged heart chambers and increased cardiomyocyte size. Capillary network growth and cardiomyocyte division under this pressure overload also required TLR2.