Stem Cell Differentiation Depends on the Central Metabolic Regulator AMPK

The ability of stem cells to differentiate into mature tissue depends on the activity of the central metabolic regulator AMP-activated protein kinase (AMPK).

Investigators at the Salk Institute for Biological Studies (La Jolla, CA, USA) reported in the March 2016 issue of the journal Genes & Development that although AMPK-deficient embryonic stem cells (ESCs) were normal in the pluripotent state, these cells displayed profound defects upon differentiation, failing to generate chimeric embryos and preferentially adopting an ectodermal fate at the expense of the endoderm during embryoid body (EB) formation.

EBs lacking AMPK exhibited reduced levels of Tfeb (Transcription factor EB), a master transcriptional regulator of lysosomes, which led to diminished endolysosomal function. Reintroduction of Tfeb into the dysfunctional cells restored normal development and differentiation.

"Even though there is great interest in AMPK related to diabetes and cancer, frankly nothing was known about how this fuel gauge process changes in different cell populations during development," said senior author Dr. Reuben Shaw, professor of molecular and cell biology at the Salk Institute for Biological Studies. "It was thought that lysosomes and AMPK were connected somehow, but no one had dreamed that you would get no lysosomes if you do not have this fuel gauge. Connecting the AMPK pathway to lysosomes begs the question of whether this pathway is part of anticancer pathways as well. We are decoding some of these underlying connections that might indicate when and how a cancer drugs might be useful. This work may also help up make better, more specific ways of targeting lysosomes in cancer."

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Salk Institute for Biological Studies