Abstract
SummaryAutophagy is a protective cellular mechanism in response to stress conditions. However, whether autophagy is required for maintenance of the alveolar epithelium is unknown. Here, we report that the loss of autophagy-related 5 (Atg5) in AT2 cells worsened bleomycin-induced lung injury. Mechanistically, during bleomycin injury, autophagy downregulated lipid metabolism but upregulated glucose metabolism in AT2 cells for alveolar repair. Chemical blockade of fatty acid synthesis promoted organoid growth of AT2 cells and counteracted the effects of autophagy loss on bleomycin injury. However, genetic loss of glucose transporter 1, interference with glycolysis, or interference with the pentose phosphate pathway reduced the proliferation of AT2 cells. Inhibition of glucose metabolism exacerbated the effects of bleomycin injury. Failure of autophagy generated additional hydrogen peroxide, which reduced AT2 cell proliferation. These data highlight an essential role for autophagy in reprogramming the metabolism of alveolar progenitor cells to meet energy needs for alveolar epithelial regeneration.
Highlights
Tissue maintenance and successful regeneration after injury rely on healthy stem/progenitor cells
autophagy-related 5 (Atg5) mRNA expression was promoted in the surviving alveolar type 2 (AT2) cells, identified as CD31ÀCD34ÀCD45ÀSca-1ÀEpCAM+CD24À by fluorescence-activated cell sorting (FACS) as described previously (Chen et al, 2012), from Atg5f/f mice 14 days after BLM administration (Figure 1A)
(B) Representative micrographs of organoid cultures of mouse AT2 cells isolated from Atg5f/f, SftpcCreER;Atg5f/f, or Nkx2.1Cre;Atg5f/f mice 14 days after BLM injury
Summary
Tissue maintenance and successful regeneration after injury rely on healthy stem/progenitor cells. Dysfunctional stem/progenitor cells will limit regeneration, increasing vulnerability to insults at steady state or persistence of tissue injury. During bleomycin-induced injury in the adult murine lung, senescence markers are upregulated in alveolar type 2 (AT2) cells, which self-renew and differentiate into AT1 cells as stem/progenitor cells (Lehmann et al, 2017). It remains unclear how AT2 cells maintain their health during homeostasis and injury repair. Accumulating evidence suggests that the metabolic program of stem cells is critical for their maintenance through influencing the balance between self-renewal and differentiation. Lactate dehydrogenase activity increases during hair follicle stem cell activation, while deletion of this catalytic enzyme blocks hair follicle stem cell activation and the hair cell cycle (Flores et al, 2017)
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