Effects of age-dependent changes in cell size on endothelial cell proliferation and senescence through YAP1

Mammoto, Tadanori; Torisawa, Yu-suke; Muyleart, Megan; Hendee, Kathryn; Anugwom, Charles; Gutterman, David; Mammoto, Akiko

doi:10.18632/aging.102236

Cited by 25 publications

(28 citation statements)

References 76 publications

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“…To further study age-dependent changes in vascular formation in vivo , we used the fibrin gel implantation system, in which young vs. aged human adipose ECs were mixed in the gel [ 47 ], and characterized vascular formation in the gel. Consistent with previous report [ 47 ], vessel formation derived from supplemented ECs in the gel was attenuated when gel mixed with GFP-labeled aged ECs was implanted under the skin of adult immunocompromised NSG mice. Vascular area was 23% lower than that in the gel supplemented with young ECs ( Figure 4A ).…”

Section: Resultsmentioning

confidence: 99%

“…We have reported that age-related lung diseases, such as pulmonary fibrosis and accompanied pulmonary hypertension, in which changes in mechanical environment are involved in the disease progression [ 85 – 87 ], are prevented in Twist1 fl/fl /Tie2 - cre mice [ 18 , 27 ]. Other transcription factors and co-factors (e.g., TFII-I, GATA2, YAP1) that sense mechanical forces interact with Twist1, control angiogenesis [ 47 , 50 , 71 , 75 , 88 ], and contribute to age-related lung diseases ( e.g., pulmonary fibrosis, pulmonary hypertension) [ 85 – 87 ]. Thus, Twist1 senses age-dependent changes in the mechanical forces to control angiogenesis and lung regeneration.…”

Section: Discussionmentioning

confidence: 99%

“…The samples from cancer patients were excluded. ECs were isolated and cultured as described before [ 47 , 50 ] and used between passages 1-2.…”

Section: Methodsmentioning

confidence: 99%

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Twist1 signaling in age-dependent decline in angiogenesis and lung regeneration

Hendee

Hunyenyiwa

Matus

et al. 2021

Aging

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Angiogenesis – the formation of new blood capillaries- is impaired in aging animals and contributes to the pathogenesis of age-related diseases. A transcription factor, Twist1, contributes to the pathogenesis of age- and angiogenesis-related diseases such as pulmonary fibrosis and atherosclerosis. However, the mechanism by which Twist1 controls age-dependent decline in angiogenesis remains unclear. In this report, we have demonstrated that the levels of Twist1 are higher, while the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) that stimulates angiogenesis, is lower in endothelial cells (ECs) isolated from aged human adipose tissues and mouse lungs compared to those from young tissues. Knockdown of Twist1 in aged human ECs increases the levels of PGC1α and angiogenic factor receptor, vascular endothelial growth factor receptor (VEGFR2), and restores EC proliferation and migration, while inhibition of PGC1α suppresses these effects. Knockdown of Twist1 in supplemented aged ECs also restores vascular networks in the subcutaneously implanted gel, while these effects are abrogated by knockdown of PGC1α. Age-dependent inhibition of post-pneumonectomy (PNX) lung growth is suppressed in Tie2-specific Twist1 conditional knockout mouse lungs, in which VEGFR2 expression increases after PNX. These results suggest that upregulation of endothelial Twist1 mediates age-dependent decline in angiogenesis and regenerative lung growth.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Twist1 signaling in age-dependent decline in angiogenesis and lung regeneration

Hendee

Hunyenyiwa

Matus

et al. 2021

Aging

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“…EC density also changes dynamically during vascular remodelling [7]. Though changes in density have been shown to be independent of replication [7], ECs undergo drastic changes in surface area without replicating [13,14]. A complete understanding of vascular remodelling can only be achieved by taking into account all of these interlinked factors.…”

Section: Introductionmentioning

confidence: 99%

Simulating flow induced migration in vascular remodelling

et al. 2020

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Shear stress induces directed endothelial cell (EC) migration in blood vessels leading to vessel diameter increase and induction of vascular maturation. Other factors, such as EC elongation and interaction between ECs and non-vascular areas are also important. Computational models have previously been used to study collective cell migration. These models can be used to predict EC migration and its effect on vascular remodelling during embryogenesis. We combined live time-lapse imaging of the remodelling vasculature of the quail embryo yolk sac with flow quantification using a combination of micro-Particle Image Velocimetry and computational fluid dynamics. We then used the flow and remodelling data to inform a model of EC migration during remodelling. To obtain the relation between shear stress and velocity in vitro for EC cells, we developed a flow chamber to assess how confluent sheets of ECs migrate in response to shear stress. Using these data as an input, we developed a multiphase, self-propelled particles (SPP) model where individual agents are driven to migrate based on the level of shear stress while maintaining appropriate spatial relationship to nearby agents. These agents elongate, interact with each other, and with avascular agents at each time-step of the model. We compared predicted vascular shape to real vascular shape after 4 hours from our time-lapse movies and performed sensitivity analysis on the various model parameters. Our model shows that shear stress has the largest effect on the remodelling process. Importantly, however, elongation played an especially important part in remodelling. This model provides a powerful tool to study the input of different biological processes on remodelling.

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“…Cellular senescence presents multiple cellular and molecular features [1], which may function as suitable biomarkers or therapeutic targets. Senescent cells generally demonstrate an enlarged and flattened cell morphology [27] and expanded nucleoli [28,29], enhanced senescence-associated beta-galactosidase (SA-β-gal) activity [30], telomere shortening, elevation of the cyclin-dependent kinase inhibitor p16 [11,31] or p21 [32], macromolecular damage and metabolism dysfunction [1]. The prominent characteristic of senescent cells is the senescence-associated secretory phenotype (SASP).…”

Section: Features Of Cellular Senescencementioning

confidence: 99%

Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases

Song

2020

Cells

127

115

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Senescent cells are generally characterized by permanent cell cycle arrest, metabolic alteration and activation, and apoptotic resistance in multiple organs due to various stressors. Excessive accumulation of senescent cells in numerous tissues leads to multiple chronic diseases, tissue dysfunction, age-related diseases and organ ageing. Immune cells can remove senescent cells. Immunaging or impaired innate and adaptive immune responses by senescent cells result in persistent accumulation of various senescent cells. Although senolytics—drugs that selectively remove senescent cells by inducing their apoptosis—are recent hot topics and are making significant research progress, senescence immunotherapies using immune cell-mediated clearance of senescent cells are emerging and promising strategies to fight ageing and multiple chronic diseases. This short review provides an overview of the research progress to date concerning senescent cell-caused chronic diseases and tissue ageing, as well as the regulation of senescence by small-molecule drugs in clinical trials and different roles and regulation of immune cells in the elimination of senescent cells. Mounting evidence indicates that immunotherapy targeting senescent cells combats ageing and chronic diseases and subsequently extends the healthy lifespan.

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Effects of age-dependent changes in cell size on endothelial cell proliferation and senescence through YAP1

Cited by 25 publications

References 76 publications

Twist1 signaling in age-dependent decline in angiogenesis and lung regeneration

Twist1 signaling in age-dependent decline in angiogenesis and lung regeneration

Simulating flow induced migration in vascular remodelling

Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases

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