Metabolic regulation of stem cell function

Burgess, Rebecca J.; Agathocleous, Michalis; Morrison, Sean J.

doi:10.1111/joim.12247

Cited by 59 publications

(59 citation statements)

References 131 publications

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“…Emerging studies highlight the importance of metabolic state as a critical determinant regulating stem cell number and fate (Ito et al , ; Yu et al , ; Burgess et al , ; Kohli & Passegue, ; Wang et al , ). In adult BM, primitive HSCs are thought to reside in hypoxic regions and rely on low ATP generating glycolytic metabolism to maintain their quiescence.…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies have revealed multiple important HSC regulators and suggest that an orchestrated interaction among cell‐intrinsic signals (transcription factors, cell surface receptors, cell cycle regulators, and signal transducers) and extrinsic mediators (bone marrow niche components and soluble growth factors) controls HSC fate (Orkin & Zon, ; Wilson et al , ; Ehninger & Trumpp, ; Gazit et al , ). Furthermore, growing evidence suggests a link between the metabolic activity of HSCs and their capacity to preserve stem cell functions and hematopoietic differentiation potential (Yu et al , ; Burgess et al , ; Kohli & Passegue, ). Despite these advances, however, many of the molecular pathways and mechanisms that regulate the self‐renewal, survival, expansion, and regenerative functions of blood‐forming stem cells remain unknown.…”

Section: Introductionmentioning

confidence: 99%

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Attenuation of PKC δ enhances metabolic activity and promotes expansion of blood progenitors

et al. 2018

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A finely tuned balance of self‐renewal, differentiation, proliferation, and survival governs the pool size and regenerative capacity of blood‐forming hematopoietic stem and progenitor cells (HSPCs). Here, we report that protein kinase C delta (PKCδ) is a critical regulator of adult HSPC number and function that couples the proliferative and metabolic activities of HSPCs. PKCδ‐deficient mice showed a pronounced increase in HSPC numbers, increased competence in reconstituting lethally irradiated recipients, enhanced long‐term competitive advantage in serial transplantation studies, and an augmented HSPC recovery during stress. PKCδ‐deficient HSPCs also showed accelerated proliferation and reduced apoptosis, but did not exhaust in serial transplant assays or induce leukemia. Using inducible knockout and transplantation models, we further found that PKCδ acts in a hematopoietic cell‐intrinsic manner to restrict HSPC number and bone marrow regenerative function. Mechanistically, PKCδ regulates HSPC energy metabolism and coordinately governs multiple regulators within signaling pathways implicated in HSPC homeostasis. Together, these data identify PKCδ as a critical regulator of HSPC signaling and metabolism that acts to limit HSPC expansion in response to physiological and regenerative demands.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Attenuation of PKC δ enhances metabolic activity and promotes expansion of blood progenitors

et al. 2018

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“…C ellular metabolism plays a critical role in determining the fate of stem cells [1][2][3] . Haematopoietic stem cells (HSCs) are mostly retained in a quiescent non-motile state in their bone marrow niches and shift to a migratory cycling and differentiating state, replenishing the blood with mature leukocytes and red blood cells on demand 4,5 .…”

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confidence: 99%

An MTCH2 pathway repressing mitochondria metabolism regulates haematopoietic stem cell fate

et al. 2015

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The metabolic state of stem cells is emerging as an important determinant of their fate. In the bone marrow, haematopoietic stem cell (HSC) entry into cycle, triggered by an increase in intracellular reactive oxygen species (ROS), corresponds to a critical metabolic switch from glycolysis to mitochondrial oxidative phosphorylation (OXPHOS). Here we show that loss of mitochondrial carrier homologue 2 (MTCH2) increases mitochondrial OXPHOS, triggering HSC and progenitor entry into cycle. Elevated OXPHOS is accompanied by an increase in mitochondrial size, increase in ATP and ROS levels, and protection from irradiation-induced apoptosis. In contrast, a phosphorylation-deficient mutant of BID, MTCH2's ligand, induces a similar increase in OXPHOS, but with higher ROS and reduced ATP levels, and is associated with hypersensitivity to irradiation. Thus, our results demonstrate that MTCH2 is a negative regulator of mitochondrial OXPHOS downstream of BID, indispensible in maintaining HSC homeostasis.

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“…SDHD dysfunction also lead to altered metabolic properties, mainly reduced oxidative phosphorylation (OXPHOS) in vitro . These characteristics are associated with a so-called ‘stemness phenotype’ (Burgess, et al 2014; Hermann, et al 2007; Li, et al 2017; Pardal, et al 2005). We further tested if SDHD dysfunction had any impact on cellular differentiation.…”

Section: Resultsmentioning

confidence: 99%

Sdhd ablation promotes thyroid tumorigenesis by inducing a stem-like phenotype

Ashtekar

Huk

Magner

et al. 2017

Endocrine-Related Cancer

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Mutations in genes encoding enzymes in the tricarboxylic acid cycle (TCA, also known as the Krebs cycle) have been implicated as causative genetic lesions in a number of human cancers, including renal cell cancers, glioblastomas, and pheochromocytomas. In recent studies, missense mutations in the Succinate dehydrogenase (SDH) complex have also been proposed to cause differentiated thyroid cancer. In order to gain mechanistic insight into this process, we generated mice lacking the SDH subunit D (SDHD) in the thyroid. We report that these mice develop enlarged thyroid glands with follicle hypercellularity and increased proliferation. In vitro, human thyroid cell lines with knockdown of SDHD exhibit an enhanced migratory capability, despite no change in proliferative capacity. Interestingly, these cells acquire stem-like features which are also observed in the mouse tumors. The stem-like characteristics are reversed by α-ketoglutarate, suggesting that SDH-associated tumorigenesis results from dedifferentiation driven by an imbalance in cellular metabolites of the TCA cycle. The results of this study reveal a metabolic vulnerability for potential future treatment of SDH-associated neoplasia.

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Metabolic regulation of stem cell function

Cited by 59 publications

References 131 publications

Attenuation of PKC δ enhances metabolic activity and promotes expansion of blood progenitors

Attenuation of PKC δ enhances metabolic activity and promotes expansion of blood progenitors

An MTCH2 pathway repressing mitochondria metabolism regulates haematopoietic stem cell fate

Sdhd ablation promotes thyroid tumorigenesis by inducing a stem-like phenotype

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