Age-associated Tissue Organization Shifts Retinal Pigmented Epithelium Actomyosin Plasticity in Phagocytosis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1265179 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33633366.fastq.gz | Fastqsanger.gz | |||
| SRR33633367.fastq.gz | Fastqsanger.gz | |||
| SRR33633368.fastq.gz | Fastqsanger.gz | |||
| SRR33633369.fastq.gz | Fastqsanger.gz | |||
| SRR33633370.fastq.gz | Fastqsanger.gz |
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Project description:Mechanical homeostasis in healthy tissues relies on a dynamic balance of mechanical properties essential for maintaining tissue integrity and function. Over time, this integrity decays due to structural reorganization from extracellular remodelling or an imbalance of cell death and proliferation. This is particularly challenging in postmitotic tissues such as the retina, where lack of proliferation requires age-dependent structural adaptation. The retinal pigment epithelium exemplifies this adaptation, compensating for apoptotic events through morphological reconfiguration and cytoskeletal remodelling. To explore the connection between age-related structural changes and mechanical homeostasis, we developed an in vitro model simulating cell density reduction observed in the human retinal pigmented epithelium during ageing. This model is characterized by reduced cell height, shortened apical microvilli, and alterations in the actin cytoskeleton. The resulting age-associated phenotype leads to significant biomechanical changes, including tissue stiffening, enhanced junctional contractility, and apical cell cortex remodelling. Transcriptional profiling revealed notable shifts in actin-associated gene expression, indicating reduced plasticity when remodelling is necessary for phagocytosis of photoreceptor outer segments. Structurally aged monolayers exhibit changes in phagocytic activity that mirror those seen in aged individuals. Additionally, we observed an impaired capacity for apico-lateral remodelling while internalizing photoreceptor outer segments. This altered activity can be partially corrected by regulating actin network remodelling capacity with inhibitors targeting the actin nucleators Arp2/3 and formins. Overall, our findings suggest that age-related structural changes in the postmitotic outer retina shift its mechanical homeostasis, impacting physiological functions that are crucial for healthy vision.
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Project description:One of the major biological functions accomplished by the retinal pigmented epithelium (RPE) is the clearance of shed photoreceptor outer segments (POS) through a multistep process referred to as phagocytosis. Phagocytosis helps maintain the viability of photoreceptors which otherwise could succumb to the high metabolic flux and photo-oxidative stress associated with visual processing. Regulatory mechanisms underlying phagocytosis in the RPE are not fully understood, although dysfunction of this process contributes to the pathogenesis of multiple human retinal degenerative disorders, including age-related macular degeneration (AMD). Here we present an integrated analysis of phagocytosing cultured-RPE cells.
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Project description:Actomyosin contractility regulates cell morphology and movement. The objective of this study was to identify whether actomyosin contractility regulates gene expression in tumour cells and whether such genes are involved in cell morphology and movement. Gene expression analysis was carried out on highly contractile melanoma cell line A375M2 plated on a deformable collagen matrix under conditions where actomyosin contractility could be altered following treatment with blebbistatin, a direct inhibitor of myosin II, or Rho-kinase inhibitors Y27632 or H1152 that interfere with signalling to myosin II. 18 samples (6 x 3 biological replicates). Cells were plated on rigid or deformable matrices. Rounded cells (A375M2 melanoma cells) plated on deformable matrices were left untreated or treated with Rho-kinase inhibitors Y27632, H1152 or blebbistatin an inhibitor of mysoin II.
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Project description:Actomyosin contractility regulates cell morphology and movement. The objective of this study was to identify whether actomyosin contractility regulates gene expression in tumour cells and whether such genes are involved in cell morphology and movement. Gene expression analysis was carried out on highly contractile melanoma cell line A375M2 plated on a deformable collagen matrix under conditions where actomyosin contractility could be altered following treatment with blebbistatin, a direct inhibitor of myosin II, or Rho-kinase inhibitors Y27632 or H1152 that interfere with signalling to myosin II.
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Project description:To assess the geome-wide similarities between primary fetal retinal pigmented epithelium (RPE) and stem-cell derived RPE, we performed whole genome microarray expression on primary RPE and both embryonic stem cell (ESC) derived RPE and induced pluripotent stem cell (iPSC) derived RPE. We found ES-derived RPE better resembles fetal RPE than iPS-derived RPE.
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Project description:Human embryonic stem cell derived retinal pigmented epithelial cells (hESC-RPE) are in clinical trials for the treatment of macular diseases. Currently, these cells take over three months to derive and subsequent months to mature and characterize. After only five to six passages the cells begin to undergo an epithelial-to-mesenchymal transition and are unsuitable for cellular therapies. We describe a novel passaging protocol and show that inhibition of Rho-associated, coiled coil containing protein kinases (ROCK1 and ROCK2) using Y-27632, allows extended passage of hESC-RPE in serum-free culture with maintenance of the RPE phenotype. After 30 population doublings, hESC-RPE at passage 13 maintain normal karyotype, display typical, polarized epithelial morphology, and continue to express RPE-specific genes. Passage 13 hESC-RPE show protein localization patterns similar to passage 2 cells, and display similar levels of growth factor secretion and phagocytosis of photoreceptor outer segments. Microarray analysis from day 2 cells shows several key pathways are altered by ROCK inhibition, including stimulation of the cell cycle and suppression of TGFβ and Wnt signaling. These findings describe a means to greatly increase the yield of functional hESC-RPE for use in research and clinical trials.
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Project description:To assess the geome-wide similarities between primary fetal retinal pigmented epithelium (RPE) and stem-cell derived RPE, we performed whole genome microarray expression on primary RPE and both embryonic stem cell (ESC) derived RPE and induced pluripotent stem cell (iPSC) derived RPE. We found ES-derived RPE better resembles fetal RPE than iPS-derived RPE. Gene expression was measured in primary fetal RPE, ES-derived RPE, iPS-derived RPE. ES cells and BJ fibroblasts were used as controls.
2010-11-10 | E-GEOD-25143 | biostudies-arrayexpress
Project description:Human embryonic stem cell derived retinal pigmented epithelial cells (hESC-RPE) are in clinical trials for the treatment of macular diseases. Currently, these cells take over three months to derive and subsequent months to mature and characterize. After only five to six passages the cells begin to undergo an epithelial-to-mesenchymal transition and are unsuitable for cellular therapies. We describe a novel passaging protocol and show that inhibition of Rho-associated, coiled coil containing protein kinases (ROCK1 and ROCK2) using Y-27632, allows extended passage of hESC-RPE in serum-free culture with maintenance of the RPE phenotype. After 30 population doublings, hESC-RPE at passage 13 maintain normal karyotype, display typical, polarized epithelial morphology, and continue to express RPE-specific genes. Passage 13 hESC-RPE show protein localization patterns similar to passage 2 cells, and display similar levels of growth factor secretion and phagocytosis of photoreceptor outer segments. Microarray analysis from day 2 cells shows several key pathways are altered by ROCK inhibition, including stimulation of the cell cycle and suppression of TGFM-NM-2 and Wnt signaling. These findings describe a means to greatly increase the yield of functional hESC-RPE for use in research and clinical trials. Two-condition experiment, Control vs Y-27632 treated hESC-RPE passage 5. Biological replicates: 4 control, 4 Y-27632. The experiments were technically carried out as dual channel (eg, Cy3 and Cy5-labeled samples hybridized to the same array) but processed as though they are single channel (Cy3 and Cy5 signals are calculated; Cy3/Cy5 ratios are not calculated). Therefore, there are 4 raw data files for total 8 samples.
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