RESUMO
Cardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and therapeutic strategies require a deeper understanding of the molecular processes involved in the healthy heart. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavour. Here, using state-of-the-art analyses of large-scale single-cell and single-nucleus transcriptomes, we characterize six anatomical adult heart regions. Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes and fibroblasts, and reveal distinct atrial and ventricular subsets of cells with diverse developmental origins and specialized properties. We define the complexity of the cardiac vasculature and its changes along the arterio-venous axis. In the immune compartment, we identify cardiac-resident macrophages with inflammatory and protective transcriptional signatures. Furthermore, analyses of cell-to-cell interactions highlight different networks of macrophages, fibroblasts and cardiomyocytes between atria and ventricles that are distinct from those of skeletal muscle. Our human cardiac cell atlas improves our understanding of the human heart and provides a valuable reference for future studies.
Assuntos
Miocárdio/citologia , Análise de Célula Única , Transcriptoma , Adipócitos/classificação , Adipócitos/metabolismo , Adulto , Enzima de Conversão de Angiotensina 2/análise , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Células Epiteliais/classificação , Células Epiteliais/metabolismo , Epitélio , Feminino , Fibroblastos/classificação , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Átrios do Coração/anatomia & histologia , Átrios do Coração/citologia , Átrios do Coração/inervação , Ventrículos do Coração/anatomia & histologia , Ventrículos do Coração/citologia , Ventrículos do Coração/inervação , Homeostase/imunologia , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Miócitos Cardíacos/classificação , Miócitos Cardíacos/metabolismo , Neurônios/classificação , Neurônios/metabolismo , Pericitos/classificação , Pericitos/metabolismo , Receptores de Coronavírus/análise , Receptores de Coronavírus/genética , Receptores de Coronavírus/metabolismo , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Células Estromais/classificação , Células Estromais/metabolismoRESUMO
The channel Orai1 requires Ca2+ store depletion in the endoplasmic reticulum and an interaction with the Ca2+ sensor STIM1 to mediate Ca2+ signaling. Alterations in Orai1-mediated Ca2+ influx have been linked to several pathological conditions including immunodeficiency, tubular myopathy, and cancer. We screened large-scale cancer genomics data sets for dysfunctional Orai1 mutants. Five of the identified Orai1 mutations resulted in constitutively active gating and transcriptional activation. Our analysis showed that certain Orai1 mutations were clustered in the transmembrane 2 helix surrounding the pore, which is a trigger site for Orai1 channel gating. Analysis of the constitutively open Orai1 mutant channels revealed two fundamental gates that enabled Ca2+ influx: Arginine side chains were displaced so they no longer blocked the pore, and a chain of water molecules formed in the hydrophobic pore region. Together, these results enabled us to identify a cluster of Orai1 mutations that trigger Ca2+ permeation associated with gene transcription and provide a gating mechanism for Orai1.