Autophagy maintains metabolism and functional activity of a subset of aged hematopoietic stem cells [gene expression]. Mus musculus

Autophagy is critical for protecting HSCs from metabolic stress. Here, we used a genetic approach to inactivate autophagy in adult HSCs by deleting the Atg12 gene. We show that loss of autophagy causes accumulation of mitochondria and an oxidative phosphorylation (OXPHOS)-activated metabolic state, which drives accelerated myeloid differentiation likely through epigenetic deregulations rather than transcriptional changes, and impairs HSC self-renewal activity and regenerative potential. To determine how loss of autophagy affects gene expression, we conducted microarray analysis of purified control and Atg12 conditional knockout HSCs. Overall design: Atg12flox/flox:Mx1-Cre conditional knockout mice and control Atg12flox/flox mice were injected with poly(I:C) at 4 week of age, and HSCs (Lin-/c-Kit+/Sca-1+/Flk2-/CD150+/CD48-) were isolated from the bone marrow of individual mice 2-3 months later. RNA was extracted, and microarray analysis was conducted with Affymetrix Gene ST 1.0 microarrays as described in the methods.