Autophagy is a signature of a signaling network that maintains hematopoietic stem cells

• Published in: PloS one 2017-05, Vol.12 (5), p.e0177054-e0177054
• Main Authors: Nguyen-McCarty, Michelle, Klein, Peter S
• Format: Article
• Language: English
• Subjects: Acidification; Activation; Aging; Aging (artificial); AKT protein; Amino acids; Amyloid precursor protein; Annexin V; Apoptosis; Assaying; Ataxin; Autophagy; Autophagy (Cytology); Biochemistry; Biology; Biology and Life Sciences; Biosynthesis; Blood; Bone marrow; c-Kit protein; CD150 antigen; CD45 antigen; Cell culture; Cell death; Cell growth; Cell proliferation; Cell self-renewal; Cells (biology); Cellular signal transduction; Control; Cytokines; Degradation; Differentiation; Effectors; Hematology; Hematopoietic stem cells; Hematopoietic Stem Cells - metabolism; Homeostasis; Homology; Humans; Inhibition; Inhibitors; Kinases; Leukemia; Maintenance; Mammals; Medicine; Medicine and Health Sciences; Membrane potential; Membranes; Mice; Molecular biology; Neural stem cells; Nuclei; Nutrients; Organelles; Osteoprogenitor cells; Oxygen; Oxygen consumption; Pancreatic cancer; Preservation; Proteins; Quality control; Regulations; Repopulation; Research and Analysis Methods; Signal Transduction; Stem cells; Transplantation; Transplants & implants; β-Amyloid; β-Catenin
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0177054

Hematopoietic stem cells (HSCs) are able to self-renew and to differentiate into all blood cells. HSCs reside in a low-perfusion niche and depend on local signals to survive and to maintain the capacity for self-renewal. HSCs removed from the niche are unable to survive without addition of hematopoietic cytokines and rapidly lose their ability to self-renew. We reported previously that inhibition of both GSK-3 and mTORC1 is essential to maintain long-term HSCs ex vivo. Although Wnt/β-catenin signaling downstream of GSK-3 is required for this response, the downstream effectors of mTORC1 remain undefined. We now report that HSCs express a pro-autophagic gene signature and accumulate LC3 puncta only when both mTORC1 and GSK-3 are inhibited, identifying autophagy as a signature for a signaling network that maintains HSCs ex vivo. In addition, these conditions sustain HSC repopulating function despite an increased rate of global translation. Together, these findings provide new insight into the relative contributions of various mTORC1 outputs toward the maintenance of HSC function and build upon the growing body of literature implicating autophagy and tightly controlled protein synthesis as important modulators of diverse stem cell populations.