Cited2 regulates proliferation and survival in young and old mouse cardiac stem cells

Wu, Qiong; Liu, Qin; Zhan, Jinxi; Wang, Qian; Zhang, Daxiu; He, Shuangli; Pu, Shiming; Zhou, Zuping

doi:10.1186/s12860-019-0207-2

Cited by 9 publications

(7 citation statements)

References 25 publications

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“…Recently, Cited2, a protein implicated in glucose metabolism, has been shown to be important for Sca-1+ cardiac stem cell proliferation [ 42 ]. Although the authors did not measure any metabolic parameter, Cited2 deletion in ESCs has been shown to result in aberrant mitochondrial morphology, reduced glucose oxidation, increased glycolysis, and defective differentiation [ 43 ].…”

Section: Metabolism At the Heart Of Stem Cellsmentioning

confidence: 99%

Stem Cell Metabolism: Powering Cell-Based Therapeutics

Rigaud

Hoy

Mohsin

et al. 2020

Cells

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Cell-based therapeutics for cardiac repair have been extensively used during the last decade. Preclinical studies have demonstrated the effectiveness of adoptively transferred stem cells for enhancement of cardiac function. Nevertheless, several cell-based clinical trials have provided largely underwhelming outcomes. A major limitation is the lack of survival in the harsh cardiac milieu as only less than 1% donated cells survive. Recent efforts have focused on enhancing cell-based therapeutics and understanding the biology of stem cells and their response to environmental changes. Stem cell metabolism has recently emerged as a critical determinant of cellular processes and is uniquely adapted to support proliferation, stemness, and commitment. Metabolic signaling pathways are remarkably sensitive to different environmental signals with a profound effect on cell survival after adoptive transfer. Stem cells mainly generate energy through glycolysis while maintaining low oxidative phosphorylation (OxPhos), providing metabolites for biosynthesis of macromolecules. During commitment, there is a shift in cellular metabolism, which alters cell function. Reprogramming stem cell metabolism may represent an attractive strategy to enhance stem cell therapy for cardiac repair. This review summarizes the current literature on how metabolism drives stem cell function and how this knowledge can be applied to improve cell-based therapeutics for cardiac repair.

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Section: Metabolism At the Heart Of Stem Cellsmentioning

confidence: 99%

Stem Cell Metabolism: Powering Cell-Based Therapeutics

Rigaud

Hoy

Mohsin

et al. 2020

Cells

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show abstract

“…Donated stem cells are exposed to ischemic cardiac milieu composed of near anoxia, increased ROS and pro-inflammatory factors that together push massive cell loss upon transplantation. Recent studies have shown metabolism as a critical determinant of stem cell fate regulating various processes such as cell proliferation [ 12 ], survival [ 13 ], and commitment [ 14 ]. Metabolic signaling pathways are sensitive to changes in environmental conditions allowing stem cells to adapt to fluctuating oxygen and nutrient levels [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

LIN28a induced metabolic and redox regulation promotes cardiac cell survival in the heart after ischemic injury

et al. 2021

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Rationale Cell-based therapeutics have been extensively used for cardiac repair yet underperform due to inability of the donated cells to survive in near anoxia after cardiac injury. Cellular metabolism is linked to maintenance of cardiac stem cell (CSC) renewal, proliferation and survival. Ex vivo expansion alters (CSC) metabolism increasing reliance on oxygen dependent respiration. Whether promoting ‘metabolic flexibility’ in CSCs augments their ability to survive in near anoxia and repair the heart after injury remains untested. Objective Determine the effect of LIN28a induced metabolic flexibility on cardiac tissue derived stem like cell (CTSC) survival and repair after cardiac injury. Methods and results LIN28a expression coincides during heart development but is lost in adult CTSCs. Reintroduction of LIN28a in adult CTSC (CTSC- LIN ) increased proliferation, survival, expression of pluripotency genes and reduced senescence compared to control (CTSC- GFP ). Metabolomic analysis show glycolytic intermediates upregulated in CTSC- LIN together with increased lactate production, pyruvate kinase activity, glucose uptake, ECAR and expression of glycolytic enzymes compared to CTSC- GFP . Additionally, CTSC- LIN showed significantly reduced ROS generation and increase antioxidant markers. In response to H2O2 induced oxidative stress, CTSC- LIN showed increased survival and expression of glycolytic genes. LIN28a salutary effects on CTSCs were linked to PDK1/let-7 signaling pathway with loss of PDK1 or alteration of let-7 abrogating LIN28a effects. Following transplantation in the heart after myocardial infarction (MI), CTSC- LIN showed 6% survival rate at day 7 after injection compared to control cells together with increased proliferation and significant increase in cardiac structure and function 8 weeks after MI. Finally, CSTC-LIN showed enhanced ability to secrete paracrine factors under hypoxic conditions and ability to promote cardiomyocyte proliferation following ischemic cardiac injury. Conclusions LIN28a modification promotes metabolic flexibility in CTSCs enhancing proliferation and survival post transplantation including ability to repair the heart after myocardial injury.

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“…Cellular metabolism has emerged recently as a regulator of stem cell fate as well as molecular and cellular function [21,22]. Changes in environmental conditions alter energy generation in stem cells leading to a shift from a quiescent to proliferative or differentiated state [23].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Profiling of Cardiac Cells Links Age-Dependent Changes in Acetyl-CoA Signaling to Chromatin Modifications

Kurian

Bohl

Behanan

et al. 2021

IJMS

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Metabolism has emerged as a regulator of core stem cell properties such as proliferation, survival, self-renewal, and multilineage potential. Metabolites serve as secondary messengers, fine-tuning signaling pathways in response to microenvironment alterations. Studies show a role for central metabolite acetyl-CoA in the regulation of chromatin state through changes in histone acetylation. Nevertheless, metabolic regulators of chromatin remodeling in cardiac cells in response to increasing biological age remains unknown. Previously, we identified novel cardiac-derived stem-like cells (CTSCs) that exhibit increased functional properties in the neonatal heart (nCTSC). These cells are linked to a unique metabolism which is altered with CTSC aging (aCTSC). Here, we present an in-depth, RNA-sequencing-based (RNA-Seq) bioinformatic with cluster analysis that details a distinct epigenome present in nCTSCs but not in aCTSCs. Gene Ontology (GO) and pathway enrichment reveal biological processes, including metabolism, gene regulation enriched in nCTSCs, and STRING analysis that identifies a network of genes related to acetyl-CoA that can potentially influence chromatin remodeling. Additional validation by Western blot and qRT-PCR shows increased acetyl-CoA signaling and histone acetylation in nCTSCs compared to aCTSCs. In conclusion, our data reveal that the link between metabolism and histone acetylation in cardiac cells is altered with the aging of the cardiac tissue.

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Cited2 regulates proliferation and survival in young and old mouse cardiac stem cells

Cited by 9 publications

References 25 publications

Stem Cell Metabolism: Powering Cell-Based Therapeutics

Stem Cell Metabolism: Powering Cell-Based Therapeutics

LIN28a induced metabolic and redox regulation promotes cardiac cell survival in the heart after ischemic injury

Transcriptional Profiling of Cardiac Cells Links Age-Dependent Changes in Acetyl-CoA Signaling to Chromatin Modifications

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