Autophagy Impairment Is Less Recoverable In Stem Cells Than In Somatic Cells Of The Hematopoietic System

Autophagy maintains hemostasis for all types of mammalian cells. Whether andhow autophagy differs between stem and somatic cells remains largely unclear. Usingconditional mouse models for autophagy defects in the hematopoietic hierarchy, weshow that when impaired, autophagy recovery capacity in stem cells and somatic cells isdifferent. An in vivo atg7deletion in hematopoietic stem cells completely ablates theautophagy response, leading to irreversible hematopoiesis failure and animal death. Incontrast, atg7deleted myeloid cells in vivo do not show this phenotype but maintainactive autophagy which can be inhibited by BFA that specifically targets Golgi-derivedmembranes for autophagosome formation in alternative autophagy. Atg7-dependentcanonical autophagy in hematopoietic stem cells and myeloid cells is physiologicallyfunctional. Its impairment was only found to be rescued in myeloid cells by alternativeautophagy in which ULK1, PI3KC3, Beclin1and Rab9are upregulated. These resultsindicate that hematopoietic stem cells solely rely on atg7-dependent canonicalautophagy, whereas somatic cells acquire alternative autophagy when atg7-mediatedautophagy is dysfunctional. We thus propose that autophagy machinery is morevulnerable in stem cells，which provides a new lens for our understanding of stem celltransformation in hematopoietic system.