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.

Mitigation of Iron Irradiation-Induced Genotoxicity and Genomic Instability by Postexposure Dietary Restriction in Mice

“…DR could decrease circulating levels of growth factors, anabolic hormones, inflammatory cytokines, and oxidative stress markers associated with various malignancies, exerting multiple suppressive effects on both target cells and microenvironments during carcinogenesis [ 83 ]. It is well known that dietary intervention was a regulator of stem cell behavior [ 84 ]. DR was able to restrict increase in hematopoietic stem and progenitor cells and formation of myeloid colony in mouse bone marrow [ 85 ].…”

Role of Diet in Stem and Cancer Stem Cells

“…On the other hand, intracellular metabolites, such as acetyl-CoA, regulate both metabolic pathways and epigenetic processes [ 48 ], thus connecting diet and metabolism with SC functions. This connection is particularly relevant in fate determination for different types of SCs, as SC self-renewal can be achieved by modifying calories or nutrients [ 16 ] and skeletal MuSCs from calorie-restricted mice are more efficient in inducing muscle regeneration than those from ad-libitum-fed mice in transplantation experiments [ 12 ]. Similarly, induced pluripotent stem cells (iPSCs) can be reprogrammed by manipulating metabolic pathways [ 14 ]; whereas MuSC activation requires the shift from fatty acid oxidation (FAO) to glycolysis [ 49 ], the upregulation of glycolytic pathways, as well as the inhibition of mitochondrial activity, may be sufficient to induce stemness features in iPSCs and ESCs [ 50 , 51 , 52 ].…”

“…Given the pivotal role of SCs in cancer onset and the well-recognized effect of CR on SC self-renewal [ 16 ], it is worth mentioning that CR and CR mimetics (CRMs) have been studied in the context of CSC generation [ 66 ]. Indeed, it has been demonstrated that CR reduces tumorigenesis in breast tissues and inhibits mammary SC self-renewal, thus reducing progenitor cell number [ 178 ].…”

“…In doing so, tissue SCs not only utilize nutrients for their metabolic needs but also adapt their functions, such as self-renewal, autophagy, or differentiation, to the metabolic environment and nutrient availability [ 12 , 13 , 14 ]. On the other hand, their relatively long lifespan, whereas indispensable to fulfill their function in tissue turnover, holds the back of the coin of continuously being exposed to environmental factors, including diet, and progressively accumulating cell damage at the genetic and epigenetic level, with significant consequences on gene and protein expression and molecular pathways [ 15 , 16 ]. The consequent perturbation in the balance between maintenance and loss of SCs characteristics can be further propagated in the offspring cells, thus inducing alterations in their functionality.…”

Beneficial and Therapeutic Potential of Ketone Bodies (KB) in Clinical Practice

“…From human medical point of view, nutritional changes may influence to several aspects. They include macroscopic dietary interventions such as Low Carbohydrate Diet (LCD), Ketogenic Diet (KD), Calorie Restriction (CR), a high-fat meal [1]. LCD and KD bring elevated ketone bodies (KB) in the blood, hyperketonemia [2].…”