Embryonic stem cell extracellular vesicles reverse the senescence of retinal pigment epithelial cells by the p38MAPK pathway

Liu, Yurun; Gu, Simin; Su, Yangfeng; Wang, Shoubi; Cheng, Yuanrong; Sang, Xuan; Jin, Lin; Liu, Ying; Li, Chaoyang; Liu, Weiqin; Chen, Minghao; Wang, Xiaoran; Wang, Zhichong

doi:10.1016/j.exer.2022.109365

Cited by 4 publications

(3 citation statements)

References 57 publications

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“…Multiple intracellular components undergo acute ROS-triggered damage, compromising the structural and functional integrity of proteins, lipids, particularly nucleic acids (including DNA), exacerbating macromolecular damage and further promoting the SASP expression by senescent cells. All of these changes will ultimately contribute to chronic inflammation and underpin many neurodegenerative, cardiovascular and metabolic conditions 64,65 . Although PDK4 expression represents a cell non-autonomous process in senescent cells, the impact of resulting lactate on senescence through inducing superoxide generation and deteriorating DNA damage, events culminating in enhanced SASP expression, does accelerate aging and organ degeneration.…”

Section: Discussionmentioning

confidence: 99%

PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy

Dou,

Fu,

Long

et al. 2023

Nat Metab

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Senescent cells remain metabolically active, but their metabolic landscape and resulting implications remain underexplored. Here, we report upregulation of pyruvate dehydrogenase kinase 4 (PDK4) upon senescence, particularly in some stromal cell lines. Senescent cells display a PDK4-dependent increase in aerobic glycolysis and enhanced lactate production but maintain mitochondrial respiration and redox activity, thus adopting a special form of metabolic reprogramming. Medium from PDK4+ stromal cells promotes the malignancy of recipient cancer cells in vitro, whereas inhibition of PDK4 causes tumor regression in vivo. We find that lactate promotes reactive oxygen species production via NOX1 to drive the senescence-associated secretory phenotype, whereas PDK4 suppression reduces DNA damage severity and restrains the senescence-associated secretory phenotype. In preclinical trials, PDK4 inhibition alleviates physical dysfunction and prevents age-associated frailty. Together, our study confirms the hypercatabolic nature of senescent cells and reveals a metabolic link between cellular senescence, lactate production, and possibly, age-related pathologies, including but not limited to cancer.

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Section: Discussionmentioning

confidence: 99%

PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy

Dou,

Fu,

Long

et al. 2023

Nat Metab

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“…One of the biggest advantages of hPSC‐EVs is their rejuvenation or anti‐senescence effects on the aged somatic cells or structure (such as blood–brain barrier). The anti‐senescence effects of hPSC‐EVs may be through transferring AKT1 and clathrin assembly lymphoid myeloid leukemia (CALM) proteins to activate the endothelial nitric oxide synthase (eNOS)−Sirt1 axis (Li et al., 2023 ), activating lysosomes (Hu et al., 2020 ), transferring SMADs to regulate the myelin transcription factor (MYT)1‐ egl‐9 family hypoxia‐inducible factor 3 (Egln3)‐Sirt1 axis (Hu et al., 2021 ) or p38‐MAPK signalling pathway (Liu et al., 2023 ). The senescent behaviour of bone marrow and adipose tissue‐derived hMSCs have been investigated in our previous studies (Jeske et al., 2021 ; Yuan et al., 2020 ), and the Sirt1/3 family and nicotinamide adenine dinucleotide (NAD)/NAD+hydrogen (H) redox status play an important role in hMSC senescence.…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicle biogenesis of three‐dimensional human pluripotent stem cells in a novel Vertical‐Wheel bioreactor

Muok,

Sun,

Esmonde

et al. 2024

J of Extracellular Bio

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Extracellular vesicles (EVs) secreted by human‐induced pluripotent stem cells (hiPSCs) have great potential as cell‐free therapies in various diseases, including prevention of blood–brain barrier senescence and stroke. However, there are still challenges in pre‐clinical and clinical use of hiPSC‐EVs due to the need for large‐scale production of a large quantity. Vertical‐Wheel bioreactors (VWBRs) have design features that allow the biomanufacturing of hiPSC‐EVs using a scalable aggregate or microcarrier‐based culture system under low shear stress. EV secretion by undifferentiated hiPSCs expanded as 3‐D aggregates and on Synthemax II microcarriers in VWBRs were investigated. Additionally, two types of EV collection media, mTeSR and HBM, were compared. The hiPSCs were characterized by metabolite and transcriptome analysis as well as EV biogenesis markers. Protein and microRNA cargo were analysed by proteomics and microRNA‐seq, respectively. The in vitro functional assays of microglia stimulation and proliferation were conducted. HiPSCs expanded as 3‐D aggregates and on microcarriers had comparable cell number, while microcarrier culture had higher glucose consumption, higher glycolysis and lower autophagy gene expression based on mRNA‐seq. The microcarrier cultures had at least 17–23 fold higher EV secretion, and EV collection in mTeSR had 2.7–3.7 fold higher yield than HBM medium. Microcarrier culture with mTeSR EV collection had a smaller EV size than other groups, and the cargo was enriched with proteins (proteomics) and miRNAs (microRNA‐seq) reducing apoptosis and promoting cell proliferation (e.g. Wnt‐related pathways). hiPSC‐EVs demonstrated the ability of stimulating proliferation and M2 polarization of microglia in vitro. HiPSC expansion on microcarriers produces much higher yields of EVs than hiPSC aggregates in VWBRs. EV collection in mTeSR increases yield compared to HBM. The biomanufactured EVs from microcarrier culture in mTeSR have exosomal characteristics and are functional in microglia stimulation, which paves the ways for future in vivo anti‐aging study.

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“…Indeed, an increased ROS level can trigger a modification of cellular redox balance in favor of overall oxidation. Consequently, multiple components of the cell will undergo acute ROS-mediated damage, further promoting the generation of damaging signals, markedly compromising the structural and functional integrity of proteins, lipids, particularly nucleic acids, ultimately contributing to chronic inflammation characteristic of cellular senescence and underpinning many neurodegenerative, cardiovascular, and metabolic conditions 71,72 .…”

Section: Discussionmentioning

confidence: 99%

Senescent cells develop PDK4-dependent hypercatabolism and produce lactate to promote cancer resistance and aging

Dou

Long

et al. 2023

Preprint

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Senescent cells remain metabolically active, but their metabolic landscape and resulting implications remain underexplored. Here we highlight upregulation of pyruvate dehydrogenase kinase 4 (PDK4) upon cellular senescence, a tendency adversely correlated with cancer patient survival after chemotherapy. Senescent cells exhibit increased aerobic glycolysis and enhanced lactate production, but subject to reversal upon PDK4 inhibition. Distinct from the cancer cell-featured Warburg effect, however, senescent cells sustain mitochondrial respiration and redox activity, adopting a special form of metabolic reprogramming. Media from PDK4+ stromal cells change global expression and promote malignancy of recipient cancer cells in vitro, while targeting PDK4 causes tumor regression in vivo. The metabolite lactate causes NOX1 upregulation and ROS production in mitochondrion-disabled cells, whereas PDK4 suppression reduces DNA damage severity and restrains the senescence-associated secretory phenotype (SASP). In preclinical trials, PDK4 intervention alleviates physical dysfunction and prevents age-associated frailty, conditions frequently observed in advanced life. Together, our study substantiates the hypercatabolic nature of senescent cells, and reveals a metabolic link between cellular senescence, lactate production, chronological aging and age-related pathologies including but not limited to cancer.

show abstract

Embryonic stem cell extracellular vesicles reverse the senescence of retinal pigment epithelial cells by the p38MAPK pathway

Cited by 4 publications

References 57 publications

PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy

PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy

Extracellular vesicle biogenesis of three‐dimensional human pluripotent stem cells in a novel Vertical‐Wheel bioreactor

Senescent cells develop PDK4-dependent hypercatabolism and produce lactate to promote cancer resistance and aging

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