Metabolic profiling of hematopoietic stem and progenitor cells during proliferation and differentiation into red blood cells

Daud, Hasbullah; Browne, Susan M.; Al-Majmaie, Rasoul; Murphy, William G.; Al‐Rubeai, Mohamed

doi:10.1016/j.nbt.2015.05.002

Cited by 15 publications

(15 citation statements)

References 45 publications

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“…52 MSCs displayed suppressed glycolysis when driven to differentiation towards osteocytes. 53 Our study characterized the metabolic profile change of PV-ADSCs during SMC differentiation and proposed the importance of lipid metabolism in regulating the differentiation process. MiR-378-3a bears potential in regulating SMC differentiation.…”

Section: Discussionmentioning

confidence: 93%

Single-Cell RNA-Sequencing and Metabolomics Analyses Reveal the Contribution of Perivascular Adipose Tissue Stem Cells to Vascular Remodeling

Nowak

Xie

et al. 2019

ATVB

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Objective: Perivascular adipose tissue (PVAT) plays a vital role in maintaining vascular homeostasis. However, most studies ascribed the function of PVAT in vascular remodeling to adipokines secreted by the perivascular adipocytes. Whether mesenchymal stem cells exist in PVAT and play a role in vascular regeneration remain unknown. Approach and Results: Single-cell RNA-sequencing allowed direct visualization of the heterogeneous PVAT-derived mesenchymal stem cells (PV-ADSCs) at a high resolution and revealed 2 distinct subpopulations, among which one featured signaling pathways crucial for smooth muscle differentiation. Pseudotime analysis of cultured PV-ADSCs unraveled their smooth muscle differentiation trajectory. Transplantation of cultured PV-ADSCs in mouse vein graft model suggested the contribution of PV-ADSCs to vascular remodeling through smooth muscle differentiation. Mechanistically, treatment with TGF-β1 (transforming growth factor β1) and transfection of microRNA (miR)-378a-3p mimics induced a similar metabolic reprogramming of PV-ADSCs, including upregulated mitochondrial potential and altered lipid levels, such as increased cholesterol and promoted smooth muscle differentiation. Conclusions: Single-cell RNA-sequencing allows direct visualization of PV-ADSC heterogeneity at a single-cell level and uncovers 2 subpopulations with distinct signature genes and signaling pathways. The function of PVAT in vascular regeneration is partly attributed to PV-ADSCs and their differentiation towards smooth muscle lineage. Mechanistic study presents miR-378a-3p which is a potent regulator of metabolic reprogramming as a potential therapeutic target for vascular regeneration.

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Section: Discussionmentioning

confidence: 93%

Single-Cell RNA-Sequencing and Metabolomics Analyses Reveal the Contribution of Perivascular Adipose Tissue Stem Cells to Vascular Remodeling

Nowak

Xie

et al. 2019

ATVB

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“…Therefore, it was shown that the commitment of human and murine HSCs/HPCs to the erythroid lineage is dependent upon glucose and glutamine metabolism [54]. In the early and late proliferation phases of erythroid commitment, differentiating HPCs demon-strated a high metabolic rate with a mixed metabolism of both glycolysis and oxidative phosphorylation, whereas in the differentiation phase, cells displayed an increased dependence on oxidative phosphorylation activity [55].…”

Section: Hypoxia and Hifs In Normal And Lscsmentioning

confidence: 99%

Oxidative stress and hypoxia in normal and leukemic stem cells

Testa

Labbaye

Castelli

et al. 2016

Experimental Hematology

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The main hematopoietic stem cell (HSC) functions, self-renewal and differentiation, are finely regulated by both intrinsic mechanisms such as transcriptional and epigenetic regulators and extrinsic signals originating in the bone marrow microenvironment (HSC niche) or in the body (humoral mediators). The interaction between regulatory signals and cellular metabolism is an emerging area. Several metabolic pathways function differently in HSCs compared with progenitors and differentiated cells. Hypoxia, acting through hypoxia-inducing factors, has emerged as a key regulator of stem cell biology and acts by maintaining HSC quiescence and a condition of metabolic dormancy based on anaerobic glycolytic energetic metabolism, with consequent low production reactive oxygen species (ROS) and high antioxidant defense. Hematopoietic cell differentiation is accompanied by changes in oxidative metabolism (decrease of anaerobic glycolysis and increase of oxidative phosphorylation) and increased levels of ROS. Leukemic stem cells, defined as the cells that initiate and maintain the leukemic process, show peculiar metabolic properties in that they are more dependent on oxidative respiration than on glycolysis and are more sensitive to oxidative stress than normal HSCs. Several mitochondrial abnormalities have been described in acute myeloid leukemia (AML) cells, explaining the shift to aerobic glycolysis observed in these cells and offering the unique opportunity for therapeutic metabolic targeting. Finally, frequent mutations of the mitochondrial isocitrate dehydrogenase-2 (IDH2) enzyme are observed in AML cells, in which the mutated enzyme acts as an oncogenic driver and can be targeted using specific inhibitors under clinical evaluation with promising results.

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“…22 An understanding of the metabolic profile, either to increased dependence on OXPHOS activity during differentiation or a shift to glycolytic metabolism in cell proliferation, reportedly should support the optimization of culture conditions. 23 Cultured HCECs have a tendency for cell-state transition (CST) into a senescent phenotype, epithelialmesenchymal transition (EMT), and transformed fibroblastic cell morphology. To detail molecular mechanisms underlying the impaired proliferation of HCECs, we attempted to clarify the presence of functionally heterogeneous SPs in cHCECs, distinct in their energy metabolism.…”

mentioning

confidence: 99%

Metabolic Plasticity in Cell State Homeostasis and Differentiation of Cultured Human Corneal Endothelial Cells

Hamuro

Ueno

Asada

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To clarify whether cultured human corneal endothelial cells (cHCECs), heterogeneous in their differentiation state, exhibit distinctive energy metabolism with the aim to develop a reliable method to sort cHCECs applicable for regenerative medicine.METHODS. The presence of cHCEC subpopulations (SPs) was verified via surface cluster-ofdifferentiation (CD) marker expression. Cultured HCEC metabolic extracts or corresponding culture supernatants with distinctive cellular phenotypes in regard to energy-metabolismrelated functional markers c-Myc and CD44 were prepared and analyzed via capillary electrophoresis-tandem mass spectrometry. The metabolic requirements of heterogeneous SPs of cHCECs were also investigated. RESULTS. After successfully discriminating SPs, as verified via surface CD markers in terms of their secretory metabolites, we found that the CD44þþþ SP with cell-state transition (CST) exhibited disposition for anaerobic glycolysis, whereas the CD44 À SP without CST was disposed to mitochondria-dependent oxidative phosphorylation (OXPHOS). These results raised the possibility of establishing effective culture conditions to selectively expand mature cHCECs with a hexagonal cobblestone shape and inclination for mitochondria-dependent OXPHOS.CONCLUSIONS. The findings of this study open a pathway for monitoring the disposition of cHCECs via their energy metabolism, thus leading to safe and stable regenerative medicine by use of metabolically defined cHCECs in cell-suspension form.

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Metabolic profiling of hematopoietic stem and progenitor cells during proliferation and differentiation into red blood cells

Cited by 15 publications

References 45 publications

Single-Cell RNA-Sequencing and Metabolomics Analyses Reveal the Contribution of Perivascular Adipose Tissue Stem Cells to Vascular Remodeling

Single-Cell RNA-Sequencing and Metabolomics Analyses Reveal the Contribution of Perivascular Adipose Tissue Stem Cells to Vascular Remodeling

Oxidative stress and hypoxia in normal and leukemic stem cells

Metabolic Plasticity in Cell State Homeostasis and Differentiation of Cultured Human Corneal Endothelial Cells

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