Metabolic regulation of cell fate

Metabolic regulation of cell fate

 

Adult tissue stem cells regulate organ homeostasis and repair, and thus are continually making decisions about whether to remain quiescent, proliferate, or differentiate into mature cell types. These decisions often integrate external cues, such as the nutritional status of the organism. From cancer studies we know that nutrients and metabolites that regulate epigenetic and signaling pathways can have instructive, rather than bystander roles in regulating cancer cell growth and migration.  However, the impact of nutrients and metabolites on tissue stem cell fate decisions is still poorly understood.  One reason for this is that tissue stem cells need to be studied within the context of the specific tissue niche, since tissue stem cells rely on cell-extrinsic cues from neighboring cells, and much of their biology cannot be recapitulated in culture.  In addition, most mainstream methods to measure metabolism cannot easily be applied to small populations of cells within the tissue niche.  Consequently, we know very little about how tissue stem cell metabolism changes when tissue stem cells transition from quiescence to activation in vivo, or whether changes in discrete nutrient levels in the diet impact tissue stem cell metabolism and fate decisions.

 

We are actively developing new isolation techniques and LC/MS-MS measurement methodologies to characterize tissue stem cell metabolism within the tissue niche, using multiple models including mice and tissue stem cell-derived organoids. We are utilizing these new methods in conjunction with genetic and pharmacologic approaches for metabolic perturbation to dissect the role that metabolism plays in regulating stem cell biology in a wide variety of contexts including nutrient regulatation of tissue stem cell fate decisions, tissue stem cell states in the developing fetus, and metabolic cross-talk that directs adult stem cell mediated tissue homeostasis and repair.

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