Single-cell analysis reveals an Angpt4-initiated EPDC-EC-CM cellular coordination cascade during heart regeneration

Mammals exhibit limited heart regeneration ability, which can lead to heart failure after myocardial infarction. In contrast, zebrafish exhibit remarkable cardiac regeneration capacity. Several cell types and signaling pathways have been reported to participate in this process. However, a comprehensive analysis of how different cells and signals interact and coordinate to regulate cardiac regeneration is unavailable. We collected major cardiac cell types from zebrafish and performed high-precision single-cell transcriptome analyses during both development and post-injury regeneration. We revealed the cellular heterogeneity as well as the molecular progress of cardiomyocytes during these processes, and identified a subtype of atrial cardiomyocyte exhibiting a stem-like state which may transdifferentiate into ventricular cardiomyocytes during regeneration. Furthermore, we identified a regeneration-induced cell (RIC) population in the epicardium-derived cells (EPDC), and demonstrated Angiopoietin 4 (Angpt4) as a specific regulator of heart regeneration. angpt4 expression is specifically and transiently activated in RIC, which initiates a signaling cascade from EPDC to endocardium through the Tie2-MAPK pathway, and further induces activation of cathepsin K in cardiomyocytes through RA signaling. Loss of angpt4 leads to defects in scar tissue resolution and cardiomyocyte proliferation, while overexpression of angpt4 accelerates regeneration. Furthermore, we found that ANGPT4 could enhance proliferation of neonatal rat cardiomyocytes, and promote cardiac repair in mice after myocardial infarction, indicating that the function of Angpt4 is conserved in mammals. Our study provides a mechanistic understanding of heart regeneration at single-cell precision, identifies Angpt4 as a key regulator of cardiomyocyte proliferation and regeneration, and offers a novel therapeutic target for improved recovery after human heart injuries.

Study on Composition of Drug Property of Hot-natured Herb Euodiae Fructus / 中国中医药信息杂志

Objective To study the material basis of hot-natured herb Euodiae Fructus. Methods Euodiae Fructus extract was separated into the chloroform fraction, ethyl acetate fraction, n-butanol fraction and water fraction. With cold syndrome rat model by reserpine, the study confirmed that n-butanol fraction of Euodiae Fructus has influence on energy metabolism in rats. With the modified magnetic polymer microspheres, Euodiae Fructus n-butanol was divided into alkaloids, phenolic acid, fat soluble and water-soluble components, and the component of Euodiae Fructus influencing energy metabolism of model rats was further confirmed.Results The Euodiae Fructus extracts and alkaloids elevated rats temperature, reduced the Na+-K+-ATP activity, increased SDH activity, the content of ATP in liver tissue, the energy charge (EC) value and body heat production, and improve the level of energy metabolism.Conclusion The alkaloid is the material basis of hot-natured herb Euodiae Fructus.