Hypercholesterolemia Accelerates the Aging Phenotypes of Hematopoietic Stem Cells by a Tet1-Dependent Pathway

Tie, Guodong; Yan, Jinglian; Khair, Lyne; Tutto, Amanda A.; Messina, Louis M.

doi:10.1038/s41598-020-60403-w

Cited by 9 publications

(4 citation statements)

References 52 publications

(70 reference statements)

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“…High cholesterol levels, induced by ApoE -deficiency or high cholesterol diet, downregulated TET1 gene expression in HPSCs. In agreement with this, Tet1-/- deficiency increased total HPSC but decreased HSPC subpopulation with reconstituted stem cell capacity and induced aging characteristics [ 79 ]. The mechanism of TET1 deficiency augmented cell cycle inhibitors p19 and p21 through histone H3K27me3 modification and induced telomere shortening.…”

Section: Cholesterol Metabolism In Immune Cellssupporting

confidence: 57%

Impact of Cholesterol Metabolism in Immune Cell Function and Atherosclerosis

et al. 2020

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Cholesterol, the most important sterol in mammals, helps maintain plasma membrane fluidity and is a precursor of bile acids, oxysterols, and steroid hormones. Cholesterol in the body is obtained from the diet or can be de novo synthetized. Cholesterol homeostasis is mainly regulated by the liver, where cholesterol is packed in lipoproteins for transport through a tightly regulated process. Changes in circulating lipoprotein cholesterol levels lead to atherosclerosis development, which is initiated by an accumulation of modified lipoproteins in the subendothelial space; this induces significant changes in immune cell differentiation and function. Beyond lesions, cholesterol levels also play important roles in immune cells such as monocyte priming, neutrophil activation, hematopoietic stem cell mobilization, and enhanced T cell production. In addition, changes in cholesterol intracellular metabolic enzymes or transporters in immune cells affect their signaling and phenotype differentiation, which can impact on atherosclerosis development. In this review, we describe the main regulatory pathways and mechanisms of cholesterol metabolism and how these affect immune cell generation, proliferation, activation, and signaling in the context of atherosclerosis.

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Section: Cholesterol Metabolism In Immune Cellssupporting

confidence: 57%

Impact of Cholesterol Metabolism in Immune Cell Function and Atherosclerosis

et al. 2020

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“…39 Hyperlipidemia has also been implicated in accelerating the aging phenotype of hematopoietic stem cells by downregulating ten-eleven translocation 1 and upregulating several key cell cycle regulators such as p19 and p21. 40 In this study, we found that HDL, TG, and TC could be used as predictive indicators of impaired limbal stem cell function in diabetic patients. It was notable that all 3 cutoff points (1.215 mmol/L for HDL, 1.59 mmol/L for TG, and 4.75 mmol/L for TC) were within the normal range of the indicators: HDL ≥ 1.0 mmol/L, TG < 1.7 mmol/L, or TC < 5.2 mmol/L.…”

Section: Discussionmentioning

confidence: 70%

Evaluation of Limbal Stem Cells in Patients With Type 2 Diabetes: An In Vivo Confocal Microscopy Study

Chen

Wang

Guo

et al. 2023

Cornea

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Purpose: This study aimed to investigate corneal limbus changes in patients with type 2 diabetes mellitus (DM) using in vivo confocal microscopy (IVCM) and explore the correlation between their ocular manifestations and systemic status. Methods: Fifty-five patients with type 2 DM and 20 age-matched controls were included. The following IVCM parameters were compared between the 2 groups: palisades of Vogt (POV), corneal epithelial thickness (CET), basal cell density (BCD), subbasal nerve plexus, and dendritic cell density. All subjects underwent blood and urine sampling for laboratory analysis, including fasting blood glucose, glycated hemoglobin, total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, C-reactive protein, urinary albumin-to-creatinine ratio, urine albumin, and urine creatinine. The correlations between IVCM parameters and blood biomarkers were detected. Receiver operating characteristic curve was used for selecting the cutoff value of risk factors for corneal stem cell injury in patients with DM. Results: Compared with controls, patients with DM displayed a significant reduction of POV (superior region, P = 0.033; inferior region, P = 0.003; nasal region, P < 0.001; temporal region, P < 0.001), central CET (44.8 ± 3.6 μm vs. 51.9 ± 3.6 μm, P < 0.001), central corneal BCD (7415.5 ± 563.2 cells/mm2 vs. 9177.9 ± 977.8 cells/mm2, P < 0.001), and peripheral corneal BCD (6181.3 ± 416.5 cells/mm2 vs. 8576.3 ± 933.2 cells/mm2, P < 0.001). Dendritic cell density (41.0 ± 33.7 cells/mm2 vs. 24.6 ± 7.8 cells/mm2, P = 0.001) was significantly higher in the DM group. The following weak correlations were shown between IVCM parameters and blood biomarkers: central corneal BCD was negatively correlated with DM duration (r = −0.3, P = 0.024), TC (r = −0.36, P = 0.007), and LDL (r = −0.39, P = 0.004). The presence of POV in the superior region was negatively correlated with TC (r = −0.34, P = 0.011) and LDL (r = −0.31, P = 0.022). Cutoff values of 1.215 mmol/L for HDL, 1.59 mmol/L for TG, or 4.75 mmol/L for TC were established to distinguish patients with a high risk from a low risk for stem cell damage. Conclusions: Patients with type 2 DM displayed a lower positive rate of typical POV and a decrease in BCD, CET, and subbasal nerve density. The most relevant indicators for stem cell phenotypes were DM duration, TC, and LDL. Lipid status in diabetic patients could be a predictor of risk for developing corneal limbal stem cell deficiency. Further studies with larger sample sizes or basic research are needed to verify the results.

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“…Ten-eleven translocation (Tet) family proteins including Tet1, Tet2, and Tet3 induce DNA demethylation[ 34 ]. Tet1 is also known to promote histone methylation[ 35 ]; Tet1 deficiency leads to loss of quiescence, which depletes the HSC population and causes HSC exhaustion in Tet1 −/− mice, through decreasing histone H3 Lysine 27 trimethylation (H3K27me3) and thereby increasing the levels of the cell cycle regulators p19 and p21 in HSCs[ 35 ]. Additionally, the polycomb complex protein BMI1 suppressed multiple developmental programs in BM stromal cells (BMSCs).…”

Section: Intrinsic Mechanisms Regulating Adult Sc Quiescencementioning

confidence: 99%

Stem cell quiescence and its clinical relevance

Luo

Yang

et al. 2020

WJSC

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Quiescent state has been observed in stem cells (SCs), including in adult SCs and in cancer SCs (CSCs). Quiescent status of SCs contributes to SC self-renewal and conduces to averting SC death from harsh external stimuli. In this review, we provide an overview of intrinsic mechanisms and extrinsic factors that regulate adult SC quiescence. The intrinsic mechanisms discussed here include the cell cycle, mitogenic signaling, Notch signaling, epigenetic modification, and metabolism and transcriptional regulation, while the extrinsic factors summarized here include microenvironment cells, extracellular factors, and immune response and inflammation in microenvironment. Quiescent state of CSCs has been known to contribute immensely to therapeutic resistance in multiple cancers. The characteristics and the regulation mechanisms of quiescent CSCs are discussed in detail. Importantly, we also outline the recent advances and controversies in therapeutic strategies targeting CSC quiescence.

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Hypercholesterolemia Accelerates the Aging Phenotypes of Hematopoietic Stem Cells by a Tet1-Dependent Pathway

Abstract: HSCs, and accordingly improves the reconstitution capacity of HSCs from ApoE −/− mice after the second and third competitive transplantations.

Cited by 9 publications

References 52 publications

Impact of Cholesterol Metabolism in Immune Cell Function and Atherosclerosis

Impact of Cholesterol Metabolism in Immune Cell Function and Atherosclerosis

Evaluation of Limbal Stem Cells in Patients With Type 2 Diabetes: An In Vivo Confocal Microscopy Study

Stem cell quiescence and its clinical relevance

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