Zhou Bin's group cooperates to reveal the source and formation process of myofibroblasts after heart injury

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In the past 20 years, there has been controversy about the source of myofibroblasts in the process of adult cardiac fibrosis.
A representative study found that endothelial cells in adult cardiac fibrosis would transdifferentiate into mesenchymal cells through EndoMT (Zeisberg et al.
, Nature).
Medicine 2007), the formation of a large number of myofibroblasts to promote cardiac fibrosis has become an important target for the treatment of cardiac fibrosis
.

This conclusion is mainly based on the lineage tracing technology of Cre-loxP single homologous recombinase, which has low temporal and spatial resolution and may have technical problems of false positive tracing

Based on the double homologous recombinase-mediated lineage tracing technology (He et al.
, Nature Medicine 2017), researchers have established a technology that seamlessly captures the activation of mesenchymal genes—EndoMTracer
.

αSMA is a characteristic protein of myofibroblasts and one of the most commonly used molecular markers to indicate mesenchymal cells (Tallquist et al.

Researchers first used EndoMTracer technology to capture the process of embryonic endocardial transition to mesenchymal cells
.

Tamoxifen was used to induce the EndoMTracer system to turn on the mother mouse 8.
5 days after pregnancy, and a 17.

Next, the researchers used EndoMTracer technology to capture the EndoMT process in adult cardiac fibrosis
.

After the adult mice were induced with tamoxifen, the researchers used different injury models to induce the process of cardiac fibrosis: coarctation of the aorta and myocardial infarction

　　After the body is injured, fibroblasts are activated to transform into myofibroblasts, express αSMA , and promote fibrosis in the injured area
.

The researchers used the same strategy to capture the activated expression of αSMA in fibroblasts

　　The researchers then used another mesenchymal characteristic gene Zeb1 to capture the activated expression of Zeb1 in the heart endothelium
.

EndoMTracer endothelial cells expressing Zeb1 in the endocardium of the embryonic endocardium are permanently marked as tdTomato positive

　　In summary, this work established a technology that seamlessly captures the transcriptional activation of specific genes, revealing the process of transition from endothelial cells to mesenchymal cells during early embryonic heart development, but transient EndoMT does not occur in endothelial cells during adult cardiac fibrosis.
Nor does it form myofibroblasts
.

Fibroblasts in the heart will be activated during the injury process, express mesenchymal genes, and promote fibrosis in the injured area, suggesting that the therapeutic target for cardiac fibrosis should be focused on fibroblasts

　　Zhang Shaohua, a PhD student at the Center of Molecular Cell Excellence, is the first author of the paper.
Researcher Bin Zhou from the Center of Molecular Cell Excellence, Professor Sun Kun from Xinhua Hospital of Shanghai Jiaotong University, and Professor Lv Ailan from the Chinese University of Hong Kong are the co-corresponding authors of the paper
.

This work was strongly supported by Professor Qing-dong Wang from AstraZeneca in the United Kingdom and Professor Fengyuan Chen from Shanghai Jiaotong University
.
I would like to thank the animal platform of the Molecular Cell Center of Excellence and the cell analysis technology platform for their strong support of this research, and the Chinese Academy of Sciences, the National Natural Science Foundation of China, the Ministry of Science and Technology, and the Shanghai Municipal Science and Technology Commission for their financial support
.

　　Article link: https:// align="center">

　　Figure: Researchers use EndoMTracer technology to reveal that EndoMT exists in the process of embryonic endocardial transition to mesenchymal cells, but EndoMT does not occur in endothelial cells after adult heart injury.
Fibroblast activation and transformation form a large number of injured areas Myofibroblasts transiently express the genes of mesenchymal cells and promote cardiac fibrosis and pathological remodeling
.