Thursday, 7 June 2018

Hematopoietic stem cell fate through metabolic control

Kyoko Ito and Keisuke Ito

  •  Hematopoitic stem cells (HSCs) exist in bone marrow and give rise to a number of different cell types, see here. These stem cells are usually non-dividing (quiescent) until there is a need to i) renew the pool of HSCs or ii) generate new differentiated cells. HSCs can divide symetrically (giving rise to two new HSCs), divide asymmetrically (creating 1 differentiated cell and 1 HSC) and divide to generate 2 differentiated cells (symmetric commitment).
  • The authors discuss a study where single HSCs were purified. They found that activation of the PPAR (peroxisome proliferator-activated receptor)- fatty acid oxidation pathway promotes HSC symmetric division through enhanced Parkin recruitment in mitochondria. This pathway activates enhanced mitophagy in HSCs. The authors suggest that enhanced mitophagic clearance of damaged mitochondria is necessary for self-renewing expansion of HSCs.
  • Impaired autophagy has been shown to result in HSC exhaustion, and conditional depletion of Atg7 can lead to lethal anemia
  • Defective autophagy by the ablation of Atg12 accelerates blood aging phenotypes
  • The authors discuss another study which found that loss of authophagy in HSCs causes accumulation of mitochondria and an activated metabolic state, which drives differentiation. These features are shown in HSCs from aged mice. They suggest that autophagy actively suppresses HSC metabolism by clearing active, healthy mitochondria, to maintain quiescence and stemness. [Thought. The idea of actively degrading healthy mitochondria for the purpose of slowing metabolism seems drastic/wasteful?]
  • Excessive mitophagy is associated with enlarged HSC pools and blocked lineage commitment. The authors argue that mitophagy levels must be controlled to ensure maintenance of HSCs and appropriate differentiation.

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