Metabolic regulation of collagen gel contraction by porcine aortic valvular interstitial cells

Kamel, Peter I.; Qu, Xin; Geiszler, Andrew M.; Nagrath, Deepak; Harmancey, Romain; Taegtmeyer, Heinrich; Grande-Allen, K. Jane

doi:10.1098/rsif.2014.0852

Cited by 14 publications

(12 citation statements)

References 42 publications

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“…In the context of VICs, we have previously shown that ORR correlated with cellular proliferative potential when VICs were cultured under different media conditions 24 . We have also previously reported that an increase in pathological stretch reduced the ORR in VICs, suggesting that the involved signaling pathways and VIC pathological function are closely linked to the overall cellular metabolic state 14,19,24 . However, TPEF imaging metrics -ORR and mitochondrial clustering have not yet been shown to predict or correlate with the pathological changes in VICs during early CAVD progression.…”

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confidence: 54%

Label-free metabolic biomarkers for assessing valve interstitial cell calcific progression

Tandon

Kolenc

Cross

et al. 2020

Sci Rep

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Calcific aortic valve disease (CAVD) is the most common form of valve disease where the only available treatment strategy is surgical valve replacement. Technologies for the early detection of CAVD would benefit the development of prevention, mitigation and alternate therapeutic strategies. Two-photon excited fluorescence (TPEF) microscopy is a label-free, non-destructive imaging technique that has been shown to correlate with multiple markers for cellular differentiation and phenotypic changes in cancer and wound healing. Here we show how specific TPEF markers, namely, the optical redox ratio and mitochondrial fractal dimension, correlate with structural, functional and phenotypic changes occurring in the aortic valve interstitial cells (VICs) during osteogenic differentiation. The optical redox ratio, and fractal dimension of mitochondria were assessed and correlated with gene expression and nuclear morphology of VICs. The optical redox ratio decreased for VICs during early osteogenic differentiation and correlated with biological markers for CAVD progression. Fractal dimension correlated with structural and osteogenic markers as well as measures of nuclear morphology. Our study suggests that TPEF imaging markers, specifically the optical redox ratio and mitochondrial fractal dimension, can be potentially used as a tool for assessing early CAVD progression in vitro. Calcific aortic stenosis or calcific aortic valve disease (CAVD) is a progressive disease involving multiple signaling pathways, endothelial dysfunction, cytokine infiltration, collagen remodeling, as well as lipid and calcium deposition 1-4. The symptoms and markers for CAVD manifest via both degenerative (apoptotic) and active (osteogenic) mechanisms 5,6. Aortic valve endothelial and interstitial cells differentiate into an osteoblast-like phenotype, the extracellular matrix becomes thicker and stiffer and calcium mineralization occurs throughout the tissue 7,8. Aortic stenosis and sclerosis have an increased prevalence in the elderly and contribute to a 50% elevated risk of infarction and other potentially fatal cardiovascular pathologies 2,9,10. Currently, valve replacement is the preferred treatment method, as other strategies, such as the retardation of calcific progression, prevention and early diagnosis, are non-existent 11. Diagnostic techniques like echocardiography, cardiac MRI and cardiac CT are widely used, but are only sensitive during later stages of the disease once there is tissue mineralization, and hemodynamic and geometric impairment 12,13. Aortic valve interstitial cells (VICs) are the primary cells in the heart valves and are involved in tissue maintenance, repair and remodeling 14. VICs exist in a quiescent state under healthy conditions and are activated due to injury or disease 15 , potentially differentiating into an osteogenic-like phenotype to potentiate calcification 2. Current in vitro biochemical techniques to assess CAVD are typically destructive as they involve cell lysis or fixation and do not facilitate the longitu...

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confidence: 54%

Label-free metabolic biomarkers for assessing valve interstitial cell calcific progression

Tandon

Kolenc

Cross

et al. 2020

Sci Rep

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“…Collagen gels for contraction assays were prepared by using of Rat tail collagen I (Serva, Germany), 10× DMEM, 1 M NaOH (final pH 7.4) and mixed with cells (1 × 10 6 /ml) in 8:1:1:1 ratio previously described in Kamel et al (), with final concentration 2 mg/ml. Gel–cells suspension (triplicates) was pipetted into 96 wells pre‐coated with BSA and allowed polymerized in 5% CO 2 at 37°C for at least 30 min.…”

Section: Methodsmentioning

confidence: 99%

RASSF 1A controls tissue stiffness and cancer stem‐like cells in lung adenocarcinoma

et al. 2019

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Lung cancer remains the leading cause of cancer‐related death due to poor treatment responses and resistance arising from tumour heterogeneity. Here, we show that adverse prognosis associated with epigenetic silencing of the tumour suppressor RASSF1A is due to increased deposition of extracellular matrix (ECM), tumour stiffness and metastatic dissemination in vitro and in vivo. We find that lung cancer cells with RASSF1A promoter methylation display constitutive nuclear YAP1 accumulation and expression of prolyl 4‐hydroxylase alpha‐2 (P4HA2) which increases collagen deposition. Furthermore, we identify that elevated collagen creates a stiff ECM which in turn triggers cancer stem‐like programming and metastatic dissemination in vivo. Re‐expression of RASSF1A or inhibition of P4HA2 activity reverses these effects and increases markers of lung differentiation (TTF‐1 and Mucin 5B). Our study identifies RASSF1A as a clinical biomarker associated with mechanical properties of ECM which increases the levels of cancer stemness and risk of metastatic progression in lung adenocarcinoma. Moreover, we highlight P4HA2 as a potential target for uncoupling ECM signals that support cancer stemness.

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“…Additionally, the metabolism of circulating tumor cells is different than that of primary tumor cells, with a predilection for increased oxidative phosphorylation in circulating tumor cells (Lebleu et al, 2014). Cellular metabolism is a key first responder to changes in the chemical and mechanical environment (Kamel et al, 2014). Despite this small but growing data, the direct effect of collagen density on cellular metabolism has not been well established.…”

Section: Introductionmentioning

confidence: 99%

Collagen Matrix Density Drives the Metabolic Shift in Breast Cancer Cells

et al. 2016

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Increased breast density attributed to collagen I deposition is associated with a 4–6 fold increased risk of developing breast cancer. Here, we assessed cellular metabolic reprogramming of mammary carcinoma cells in response to increased collagen matrix density using an in vitro 3D model. Our initial observations demonstrated changes in functional metabolism in both normal mammary epithelial cells and mammary carcinoma cells in response to changes in matrix density. Further, mammary carcinoma cells grown in high density collagen matrices displayed decreased oxygen consumption and glucose metabolism via the tricarboxylic acid (TCA) cycle compared to cells cultured in low density matrices. Despite decreased glucose entry into the TCA cycle, levels of glucose uptake, cell viability, and ROS were not different between high and low density matrices. Interestingly, under high density conditions the contribution of glutamine as a fuel source to drive the TCA cycle was significantly enhanced. These alterations in functional metabolism mirrored significant changes in the expression of metabolic genes involved in glycolysis, oxidative phosphorylation, and the serine synthesis pathway. This study highlights the broad importance of the collagen microenvironment to cellular expression profiles, and shows that changes in density of the collagen microenvironment can modulate metabolic shifts of cancer cells.

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Metabolic regulation of collagen gel contraction by porcine aortic valvular interstitial cells

Cited by 14 publications

References 42 publications

Label-free metabolic biomarkers for assessing valve interstitial cell calcific progression

Label-free metabolic biomarkers for assessing valve interstitial cell calcific progression

RASSF 1A controls tissue stiffness and cancer stem‐like cells in lung adenocarcinoma

Collagen Matrix Density Drives the Metabolic Shift in Breast Cancer Cells

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