Mechanisms of the Metabolic Shift during Somatic Cell Reprogramming

Nishimura, Ken; Fukuda, Aya; Hisatake, Koji

doi:10.3390/ijms20092254

Cited by 63 publications

(74 citation statements)

References 106 publications

(222 reference statements)

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“…Our recent mechanistic studies confirmed that mitochondria enter cells and directly penetrate the nuclei of PB-IPCs after treatment with platelet-derived mitochondria, where they can produce profound epigenetic changes [21]. Due to the essential role of mitochondria in the reprogramming of somatic cells to iPS cells [32], additional molecular mechanisms underlying the mitochondrial reprogramming of PB-IPCs need to be determined. In conclusion, innovative reprogramming of adult PB-IPCs by treatment with platelet-derived mitochondria may overcome the limitations and safety concerns associated with using conventional transgenic technologies to reprogram ES and iPS cells in the clinical setting.…”

Section: Discussionmentioning

confidence: 80%

Generation of Hematopoietic-Like Stem Cells from Adult Human Peripheral Blood Following Treatment with Platelet-Derived Mitochondria

Song

et al. 2020

IJMS

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Adult stem cells represent a potential source for cellular therapy to treat serious human diseases. We characterized the insulin-producing cells from adult peripheral blood (designated PB-IPC), which displayed a unique phenotype. Mitochondria are normally located in the cellular cytoplasm, where they generate ATP to power the cell’s functions. Ex vivo and in vivo functional studies established that treatment with platelet-derived mitochondria can reprogram the transformation of adult PB-IPC into functional CD34+ hematopoietic stem cells (HSC)-like cells, leading to the production of blood cells such as T cells, B cells, monocytes/macrophages, granulocytes, red blood cells, and megakaryocytes (MKs)/platelets. These findings revealed a novel function of mitochondria in directly contributing to cellular reprogramming, thus overcoming the limitations and safety concerns of using conventional technologies to reprogram embryonic stem (ES) and induced pluripotent stem (iPS) cells in regenerative medicine.

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Section: Discussionmentioning

confidence: 80%

Generation of Hematopoietic-Like Stem Cells from Adult Human Peripheral Blood Following Treatment with Platelet-Derived Mitochondria

Song

et al. 2020

IJMS

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“…BJ fibroblasts pre-treated with lactate medium exhibited a significantly greater glycolytic reserve and significantly lower spare respiratory capacity compared to fibroblasts pre-treated with pyruvate medium. Recent studies using primary human dermal fibroblasts showed that mitochondrial spare respiratory capacity negatively correlates with somatic cell reprogramming efficiency as well as pluripotency 37,49 . Interestingly, we found that lactate pre-treatment resulted in greater BJ cell basal respiration compared to pyruvate pre-treatment.…”

Section: Discussionmentioning

confidence: 99%

“…During early somatic cell reprogramming, elevated OXPHOS promotes a ROS burst which subsequently activates the transcription factor Nuclear factor erythroid 2-related factor 2 (NRF2) which, in turn, promotes increased transcription of HIF-1α 34 . HIF-1α facilitates increased glycolytic metabolism by upregulating transcription of genes encoding glycolytic enzymes such as PDK1, PKM2 and LDHA 37 . Under normoxic conditions, HIF-1α is rapidly synthesized and degraded in the cytosol 42 .…”

Section: Discussionmentioning

confidence: 99%

“…To this end, BJ fibroblasts were initially cultured in medium containing 20 mM glucose, pyruvate, or lactate as the sole metabolite fuel source for 24 h. We first examined the impact of metabolite restriction on the protein and transcript abundance of metabolic enzymes. Pyruvate dehydrogenase (PDH) catalyses the conversion of pyruvate to acetyl-CoA, ultimately facilitating ATP production by OXPHOS 37 . Phosphorylation of PDH by PDK1 results in inhibition of PDH activity and renders cells more dependent on glycolysis to meet their energy needs 38 .…”

Section: Defined Metabolite Treatment Alters the Metabolism Of Normalmentioning

confidence: 99%

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Lactate preconditioning promotes a HIF-1α-mediated metabolic shift from OXPHOS to glycolysis in normal human diploid fibroblasts

Kozlov

Lone

Betts

et al. 2020

Sci Rep

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Recent evidence has emerged that cancer cells can use various metabolites as fuel sources. Restricting cultured cancer cells to sole metabolite fuel sources can promote metabolic changes leading to enhanced glycolysis or mitochondrial OXPHOS. However, the effect of metabolite-restriction on non-transformed cells remains largely unexplored. Here we examined the effect of restricting media fuel sources, including glucose, pyruvate or lactate, on the metabolic state of cultured human dermal fibroblasts. Fibroblasts cultured in lactate-only medium exhibited reduced PDH phosphorylation, indicative of OXPHOS, and a concurrent elevation of ROS. Lactate exposure primed fibroblasts to switch to glycolysis by increasing transcript abundance of genes encoding glycolytic enzymes and, upon exposure to glucose, increasing glycolytic enzyme levels. furthermore, lactate treatment stabilized HIF-1α, a master regulator of glycolysis, in a manner attenuated by antioxidant exposure. our findings indicate that lactate preconditioning primes fibroblasts to switch from OXPHOS to glycolysis metabolism, in part, through ROS-mediated HIF-1α stabilization. interestingly, we found that lactate preconditioning results in increased transcript abundance of MYC and SNAI1, key facilitators of early somatic cell reprogramming. Defined metabolite treatment may represent a novel approach to increasing somatic cell reprogramming efficiency by amplifying a critical metabolic switch that occurs during ipSc generation. The preferential use of glycolysis even in the presence of oxygen is known as aerobic glycolysis or the Warburg effect, a unique form of metabolism originally identified in cancer cells, but also found in many non-transformed cells 1,2. By shuttling glucose primarily through glycolysis, cancer cells fuel their proliferation by accumulating glycolytic intermediates required for fatty acid and nucleic acid synthesis. As lactate is a by-product of glycolysis, cancer cells exist in an acidic microenvironment which serves to facilitate angiogenesis and tumour invasion 3. Research examining the relationship between cancer cells and their microenvironment has revealed a novel phenomenon known as the reverse Warburg effect 4. The reverse Warburg effect is based on the theory that cells within a tumour can switch between glycolysis and oxidative phosphorylation (OXPHOS) 5-7. The reverse Warburg effect postulates that oxidative cancer cells secrete reactive oxygen species (ROS) which induce oxidative stress in surrounding stromal cells such as cancer-associated fibroblast (CAF) cells 8,9. To respond to this stress, CAFs adopt aerobic glycolysis as their primary form of metabolism 8,9. Glycolytic CAFs secrete lactate and precursors for nucleic acid and fatty acid synthesis, which are then taken up by adjacent cancer cells to fuel OXPHOS and support proliferation, thereby continuing the cycle 8,9. Long considered merely a by-product of glycolysis, lactate is emerging as an important signalling molecule and energy source 10-15. In addition to promoti...

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“…Moreover, c-Myc and either of the other factors can bind simultaneously to specific genetic elements, resulting in chromatin decondensation followed by enhanced gene expression [39]. The reprogramming transcription factors also induce a switch in the metabolic network of the cells, which enhances the efficiency of cellular reprogramming [40,41].…”

Section: Cellular Reprogramming and Ips Cellsmentioning

confidence: 99%

Cellular Reprogramming—A Model for Melanoma Cellular Plasticity

Granados

Poelchen

Novak

et al. 2020

IJMS

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Cellular plasticity of cancer cells is often associated with phenotypic heterogeneity and drug resistance and thus remains a major challenge for the treatment of melanoma and other types of cancer. Melanoma cells have the capacity to switch their phenotype during tumor progression, from a proliferative and differentiated phenotype to a more invasive and dedifferentiated phenotype. However, the molecular mechanisms driving this phenotype switch are not yet fully understood. Considering that cellular heterogeneity within the tumor contributes to the high plasticity typically observed in melanoma, it is crucial to generate suitable models to investigate this phenomenon in detail. Here, we discuss the use of complete and partial reprogramming into induced pluripotent cancer (iPC) cells as a tool to obtain new insights into melanoma cellular plasticity. We consider this a relevant topic due to the high plasticity of melanoma cells and its association with a strong resistance to standard anticancer treatments.

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Mechanisms of the Metabolic Shift during Somatic Cell Reprogramming

Cited by 63 publications

References 106 publications

Generation of Hematopoietic-Like Stem Cells from Adult Human Peripheral Blood Following Treatment with Platelet-Derived Mitochondria

Generation of Hematopoietic-Like Stem Cells from Adult Human Peripheral Blood Following Treatment with Platelet-Derived Mitochondria

Lactate preconditioning promotes a HIF-1α-mediated metabolic shift from OXPHOS to glycolysis in normal human diploid fibroblasts

Cellular Reprogramming—A Model for Melanoma Cellular Plasticity

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