Dietary interventions as regulators of stem cell behavior in homeostasis and disease

Abstract

Stem cells maintain tissues by balancing self-renewal with differentiation. A stem cell's local microenvironment, or niche, informs stem cell behavior and receives inputs at multiple levels. Increasingly, it is becoming clear that the overall metabolic status of an organism or metabolites themselves can function as integral members of the niche to alter stem cell fate. Macroscopic dietary interventions such as caloric restriction, the ketogenic diet, and a high-fat diet systemically alter an organism's metabolic state in different ways. Intriguingly, however, they all converge on a propensity to enhance self-renewal. Here, we highlight our current knowledge on how dietary changes feed into stem cell behavior across a wide variety of tissues and illuminate possible explanations for why diverse interventions can result in similar stem cell phenotypes. In so doing, we hope to inspire new avenues of inquiry into the importance of metabolism in stem cell homeostasis and disease.

Keywords: caloric restriction; cell fate; cellular metabolism; fasting; high-fat diet; ketogenic diet; organismal metabolism; self-renewal; stem cells.

Figure 1.

Disparate dietary interventions converge on stem cell self-renewal. Macroscopic dietary interventions have been shown to influence stem cell behavior across a wide array of tissue types. Here, we summarize the major findings across these tissue types and propose possible explanations for why disparate dietary interventions converge on similar phenotypes. (SC) Stem cell, (ISC) intestinal stem cell, (HSC) hematopoietic stem cell, (EpdSC) epidermal stem cells, (HFSC) hair follicle stem cell, (MuSC) muscle stem cell (satellite cell), (NSPC) neural stem/progenitor cell.

Figure 2.

Integration of diet-induced metabolic changes into stem cell fate decisions. Macroscopic dietary interventions such as caloric restriction, prolonged fasting, the ketogenic diet, and a high-fat diet systemically alter an organism's metabolic state and the availability of key metabolic substrates. Interestingly, these interventions converge on pro-self-renewal phenotypes across stem cells in several different tissues. Stem cells integrate locally available metabolites such as fatty acids, ketone bodies (β-OHB and acetone), and microbiota-derived butyrate to enact changes in stem cell fate, skewing them toward a greater propensity for stemness as well as carcinogenesis. (β-OHB) β-Hydroxybutyrate, (CD36) cluster of differentiation 36 (fatty acid translocase), (HDAC) histone deacetylase, (MCT1) monocarboxylate transporter 1, (PPARδ) peroxisome proliferator-activated receptor δ.