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Cell atlas of trabecular meshwork in glaucomatous non-human primates and DEGs related to tissue contraction based on single-cell transcriptomics

ABSTRACT: Dysfunction of TM, which is the main channel of aqueous humor outflow, can lead to elevated intraocular pressure (IOP) and result in primary open-angle glaucoma (POAG), but the molecular mechanism is still unclear. In this research, single-cell RNA sequencing (scRNAseq) analysis of TM were performed in spontaneous POAG and healthy macaques to compare cellular heterogeneity, thus exploring differentially expressed genes (DEGs) and pathways associated with dysfunction of TM contraction. Here, we show a comprehensive cell atlas of TM upon clustering analysis based on single-cell transcriptomics, which 14 distinct cell types were identified and some of them were associated with tissue contraction. The proportions of each cell types between spontaneous POAG and healthy macaques were different. Multiple genes associated with TM contraction were identified in Beam A, Beam B, Beam C and SMC cell types, with TPM1 and its associated ACTC1 and TNNT1 being first found. TPM1, ACTC 1 and TNNT1 were considered to be important protein in the regulation of tissue contraction, and the expressions of them were confirmed to be located in the sieve-like region of TM, which expressions in POAG models were lower than that in normal models. Altered levels of TPM1 expression have significant impact on TNNT1 and ACTC1 expression downstream of it. In addition, the microstructural alterations in TM of POAG non-human primate were observed, which was compact and collapsed. Thus, our study indicated that TPM1 may be a key target for regulating TM structure, contraction function and resistance of aqueous humor outflow.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE231749 | GEO | 2023/05/10

REPOSITORIES: GEO

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Project description:Impaired drainage of aqueous humor through the trabecular meshwork (TM) culminating in increased intraocular pressure is a major risk factor for glaucoma, a leading cause of blindness worldwide. Regulation of aqueous humor drainage through the TM, however, is poorly understood. The role of RhoA GTPase-mediated contractile activity, cell adhesive interactions, and gene expression in regulation of aqueous humor outflow was investigated using adenoviral vector-driven expression of constitutively active RhoA (RhoAV14). Organ cultured anterior segments from porcine eyes expressing RhoAV14 exhibited significant reduction of aqueous humor outflow. Cultured TM cells expressing RhoAV14 revealed strong contractile cell morphology, increased actin stress fibers and focal adhesions, along with increased levels of phosphorylated myosin II, and collagen IV, fibronectin and laminin. cDNA microarray analysis of RNA extracted from RhoAV14 expressing human TM cells revealed a significant increase in the expression of genes encoding extracellular matrix (ECM) proteins, cytokines, integrins, cytoskeletal proteins and signaling proteins. Conversely, various ECM proteins stimulated robust increases in phosphorylation of myosin II, paxillin and focal adhesion kinase, and activated Rho GTPase and actin stress fiber formation in TM cells, indicating a potential regulatory feedback interaction between ECM-induced mechanical strain and Rho GTPase-induced isometric tension in TM cells. Collectively, these data demonstrate that sustained activation of Rho GTPase signaling in the aqueous humor outflow pathway increases resistance to aqueous humor outflow through the trabecular pathway by influencing the contractile force, cell adhesive interactions, and the expression of ECM proteins and cytokines in TM cells. Keywords: Gene Expression Two condition experiment: Human trabecular mesh work cells infected with Adenivirus expressing GFP Vs Adenovirus expressing GFP and constitutively active RhoAV14

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Cell atlas of trabecular meshwork in glaucomatous non-human primates and DEGs related to tissue contraction based on single-cell transcriptomics

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