Metabolism and the Control of Cell Fate Decisions and Stem Cell Renewal

Abstract

Although the stem cells of various tissues remain in the quiescent state to maintain their undifferentiated state, they also undergo cell divisions as required, and if necessary, even a single stem cell is able to provide for lifelong tissue homeostasis. Stem cell populations are precisely controlled by the balance between their symmetric and asymmetric divisions, with their division patterns determined by whether the daughter cells involved retain their self-renewal capacities. Recent studies have reported that metabolic pathways and the distribution of mitochondria are regulators of the division balance of stem cells and that metabolic defects can shift division balance toward symmetric commitment, which leads to stem cell exhaustion. It has also been observed that in asymmetric division, old mitochondria, which are central metabolic organelles, are segregated to the daughter cell fated to cell differentiation, whereas in symmetric division, young and old mitochondria are equally distributed between both daughter cells. Thus, metabolism and mitochondrial biology play important roles in stem cell fate decisions. As these decisions directly affect tissue homeostasis, understanding their regulatory mechanisms in the context of cellular metabolism is critical.

Keywords: cell fate; metabolism; mitochondria; self-renewal; stem cells.

Figure 1

Stem cell metabolism. Stem cells in various tissues rely on glycolysis, and HIF-1α promotes glycolysis, which prevents pyruvate oxidation by suppressing the PDH complex. The PI3K-AKT pathway promotes ROS production by repressing FOXO. LKB1/AMPK regulates stem cell function. Fatty acid synthase, the main biosynthetic enzyme, performs the condensation of Ac-CoA and malonyl-CoA to produce the saturated fatty acid palmitate and other long-chain fatty acids. The PML-PPAR pathway promotes fatty acid oxidation through positively regulating the activity of CPT-1, which is the rate-limiting enzyme for fatty acid oxidation. The PML-PPAR pathway for fatty acid oxidation is required for hematopoietic stem cell self-renewal by controlling the fate decision. Abbreviations: Ac-CoA, acetyl-coenzyme A; Acyl-CoA, acyl-coenzyme A; AMPK, AMP-activated protein kinase; CPT, carnitine-O-palmitoyltransferase; FOXO, forkhead box O; HIF-1α, hypoxia-inducible factor 1α; LKB1, liver kinase B1; PDH, pyruvate dehydrogenase; PML, promyelocytic leukemia; PPAR-δ, peroxisome proliferator–activated receptor δ; ROS, reactive oxygen species.

Figure 2

The metabolic pathway regulates the division pattern of stem cells. (a) Division patterns of stem cells. A stem cell divides to provide one stem cell and one committed cell (asymmetric division: stem cell maintenance), two committed cells (symmetric commitment: stem cell exhaustion), or two stem cells (symmetric division: stem cell expansion). (b) The critical roles of the PML–PPAR-δ–FAO pathway in proper regulation of stem cell fate. Functional loss along this pathway reduces self-renewal of stem cells and triggers excessive commitment of stem cells, resulting in stem cell exhaustion. Abbreviations: FAO, fatty acid oxidation; PML, promyelocytic leukemia; PPAR-δ; peroxisome proliferator–activated receptor δ.

Figure 3

Asymmetric stem cell division by unequal apportionment of older mitochondria. (a) A possible model for producing two distinct daughter cells. (❶) A stem cell first produces two stem cells through symmetric division. (❷) After that, one of these daughter cells loses its stem cell properties. (❸) Similar to asymmetric division, two daughter cells with distinct fates, one stem cell and one differentiated cell, are produced after this stem cell division. (b) Asymmetric distribution of old and young mitochondria influences the cell fate of the daughter cells of a stem cell. In some mammary stem-like-cell divisions, mitochondria are split unevenly between the two daughters, and old mitochondria are apportioned primarily to the tissue-progenitor daughter, whereas newly synthesized mitochondria are apportioned to the stem cell–like daughter.