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A fundamental challenge in understanding cardiac biology and disease is that the remarkable heterogeneity in cell type composition and functional states have not been well characterized at single-cell resolution in maturing and diseased mammalian hearts. Massively parallel single-nucleus RNA sequencing (snRNA-seq) has emerged as a powerful tool to address these questions by interrogating the transcriptome of tens of thousands of nuclei isolated from fresh or frozen tissues. snRNA-seq overcomes the technical challenge of isolating intact single cells from complex tissues, including the maturing mammalian hearts; reduces biased recovery of easily dissociated cell types; and minimizes aberrant gene expression during the whole-cell dissociation. Here we applied sNucDrop-seq, a droplet microfluidics-based massively parallel snRNA-seq method, to investigate the transcriptional landscape of postnatal maturing mouse hearts in both healthy and disease states. By profiling the transcriptome of nearly 20,000 nuclei, we identified major and rare cardiac cell types and revealed significant heterogeneity of cardiomyocytes, fibroblasts, and endothelial cells in postnatal developing hearts. When applied to a mouse model of pediatric mitochondrial cardiomyopathy, we uncovered profound cell type-specific modifications of the cardiac transcriptional landscape at single-nucleus resolution, including changes of subtype composition, maturation states, and functional remodeling of each cell type. Furthermore, we employed sNucDrop-seq to decipher the cardiac cell type-specific gene regulatory network (GRN) of GDF15, a heart-derived hormone and clinically important diagnostic biomarker of heart disease. Together, our results present a rich resource for studying cardiac biology and provide new insights into heart disease using an approach broadly applicable to many fields of biomedicine.

Single-nucleus transcriptomic survey of cell diversity and functional maturation in postnatal mammalian hearts