RESUMO
Functional tissue regeneration is required for the restoration of normal organ homeostasis after severe injury. Some organs, such as the intestine, harbour active stem cells throughout homeostasis and regeneration; more quiescent organs, such as the lung, often contain facultative progenitor cells that are recruited after injury to participate in regeneration. Here we show that a Wnt-responsive alveolar epithelial progenitor (AEP) lineage within the alveolar type 2 cell population acts as a major facultative progenitor cell in the distal lung. AEPs are a stable lineage during alveolar homeostasis but expand rapidly to regenerate a large proportion of the alveolar epithelium after acute lung injury. AEPs exhibit a distinct transcriptome, epigenome and functional phenotype and respond specifically to Wnt and Fgf signalling. In contrast to other proposed lung progenitor cells, human AEPs can be directly isolated by expression of the conserved cell surface marker TM4SF1, and act as functional human alveolar epithelial progenitor cells in 3D organoids. Our results identify the AEP lineage as an evolutionarily conserved alveolar progenitor that represents a new target for human lung regeneration strategies.
Assuntos
Células Epiteliais/citologia , Evolução Molecular , Alvéolos Pulmonares/citologia , Regeneração , Células-Tronco/citologia , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/cirurgia , Animais , Antígenos de Superfície/metabolismo , Proteína Axina/metabolismo , Biomarcadores/metabolismo , Ciclo Celular , Linhagem da Célula , Cromatina/genética , Cromatina/metabolismo , Epigenômica , Células Epiteliais/metabolismo , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Masculino , Camundongos , Proteínas de Neoplasias/metabolismo , Organoides/citologia , Organoides/metabolismo , Células-Tronco/metabolismo , Transcriptoma , Via de Sinalização WntRESUMO
Invariant natural killer T (iNKT) cell development in the thymus depends on T cell receptor recognition of CD1d ligand on CD4/CD8 double-positive thymocytes. We previously reported that B7-CD28 co-stimulation is required for thymic iNKT cell development, but the cellular and molecular mechanisms underlying this co-stimulatory requirement are not understood. Here we report that CD28 expression on CD1d-expressing antigen-presenting T cells is required for thymic iNKT cell development. Mechanistically, antigen-presenting T cells provide co-stimulation through an unconventional mechanism, acquiring B7 molecules via CD28-dependent trogocytosis from B7-expressing thymic epithelial cells, dendritic cells, and B cells and providing critical B7 co-stimulation to developing iNKT cells. Thus, the present study demonstrates a mechanism of B7 co-stimulation in thymic T cell development by antigen-presenting T cells.