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.

Single-cell transcriptomic profiling reveals the tumor heterogeneity of small-cell lung cancer

Small-cell lung cancer(SCLC)is the most aggressive and lethal subtype of lung cancer,for which,better understandings of its biology are urgently needed.Single-cell sequencing technologies provide an opportunity to profile individual cells within the tumor microenvironment(TME)and investigate their roles in tumorigenic processes.Here,we performed high-precision single-cell transcriptomic analysis of~5000 individual cells from primary tumors(PTs)and matched normal adjacent tissues(NATs)from 11 SCLC patients,including one patient with both PT and relapsed tumor(RT).The comparison revealed an immunosuppressive landscape of human SCLC.Malignant cells in SCLC tumors exhibited diverse states mainly related to the cell cycle,immune,and hypoxic properties.Our data also revealed the intratumor heterogeneity(ITH)of key transcription factors(TFs)in SCLC and related gene expression patterns and functions.The non-neuroendocrine(non-NE)tumors were correlated with increased inflammatory gene signatures and immune cell infiltrates in SCLC,which contributed to better responses to immune checkpoint inhibitors.These findings indicate a significant heterogeneity of human SCLC,and intensive crosstalk between cancer cells and the TME at single-cell resolution,and thus,set the stage for a better understanding of the biology of SCLC as well as for developing new therapeutics for SCLC.