Single-cell RNA sequencing reveals the Müller subtypes and inner blood–retinal barrier regulatory network in early diabetic retinopathy

Wang, Yan; Yang, Xiongyi; Li, Qiumo; Zhang, Yuxi; Chen, Lin; Li, Hong; Xie, Zhuohang; Yang, Siyu; Deng, Xiaoqing; Cao, Mingzhe; Yi, Guoguo; Fu, Min

doi:10.3389/fnmol.2022.1048634

Cited by 5 publications

(6 citation statements)

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“…The same analytical procedures of the pineal gland were applied to the retina datasets, which included data normalization, dimensionality reduction, and cellular clustering. Cell identities were determined by previously published papers 36,51,52 …”

Section: Methodsmentioning

confidence: 99%

“…The scRNA‐seq data of zebrafish and rat retinas were obtained from NCBI (accession numbers are GSE160140 51 and GSE209872 52 ). The snRNA‐seq dataset of monkey retina was acquired from the NHPCA 36 .…”

Section: Methodsmentioning

confidence: 99%

“…68 This observation prompted a comparative analysis to elucidate the evolutionary and functional interplay of cell types between these two tissues at the single-cell level. To this end, we first collected available daytime retinal datasets 36,51,52 for the three species and characterized the cell clusters (Figure S3 and Table S4). Overall, we identified six clusters in the retinas of the three species, including photoreceptors (cone cells and rod cells), bipolar cells, amacrine cells, retinal ganglion cells (RGC), horizontal cells, and glial cells (Müller glia cells, RPE cells, astrocytes, and microglia) (Figure 3A-C).…”

Section: Transcriptional Parallels Between Pineal and Retina Across S...mentioning

confidence: 99%

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Cross‐species single‐cell landscape of vertebrate pineal gland

Zheng,

Song,

Zhou

et al. 2023

Journal of Pineal Research

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The pineal gland has evolved from a photoreceptive organ in fish to a neuroendocrine organ in mammals. This study integrated multiple daytime single‐cell RNA‐seq datasets from the pineal glands of zebrafish, rats, and monkeys, providing a detailed examination of the evolutionary transition at single‐cell resolution. We identified key factors responsible for the anatomical and functional transformation of the pineal gland. We retrieved and integrated daytime single‐cell transcriptomic datasets from the pineal glands of zebrafish, rats, and monkeys, resulting in a total of 22 431 cells after rigorous quality filtering. Comparative analysis was then conducted to elucidate the evolution of pineal cells, their photosensitivity, their role in melatonin production, and the signaling processes within the glands of these species. Our analysis identified distinct cellular compositions of the pineal gland in zebrafish, rats, and monkeys. Zebrafish photoreceptors exhibited comprehensive phototransduction gene expression, while specific genes, including transducin (Gngt1, Gnb3, and Gngt2) and phosducin (Pdc), were consistently present in mammalian pinealocytes. We found transcriptional similarities between the pineal gland and retina, underscoring shared evolutionary and functional pathways. Zebrafish displayed unique light‐responsive circadian gene activity compared to rats and monkeys. Key ligand‐receptor interactions were identified, especially involving MDK and PTN, influencing melatonin synthesis across species. Furthermore, we observed species‐specific GPCR (G protein‐coupled receptors) expressions related to melatonin synthesis and their alignment with retinal expressions. Our findings also highlighted specific transcription factors (TFs) and regulatory networks associated with pineal gland evolution and function. Our study provides a detailed analysis of the pineal gland's evolution from fish to mammals. We identified key transcriptional changes and controls that highlight the gland's functional diversity. Notably, we found significant ligand‐receptor interactions influencing melatonin synthesis and demonstrated parallels between pineal and retinal expressions. These insights enhance our understanding of the pineal gland's role in phototransduction, melatonin production, and circadian rhythms in vertebrates.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Transcriptional Parallels Between Pineal and Retina Across S...mentioning

confidence: 99%

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Cross‐species single‐cell landscape of vertebrate pineal gland

Zheng,

Song,

Zhou

et al. 2023

Journal of Pineal Research

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“…As shown in Table 1 , the application of scRNA‐seq to the study of DR has seen significant advancements. 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 …”

Section: Introductionmentioning

confidence: 99%

Single‐cell RNA sequencing in exploring the pathogenesis of diabetic retinopathy

Zhang,

2024

Clinical & Translational Med

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Diabetic retinopathy (DR) is a leading cause of irreversible blindness in the working‐age populations. Despite decades of research on the pathogenesis of DR for clinical care, a comprehensive understanding of the condition is still lacking due to the intricate cellular diversity and molecular heterogeneity involved. Single‐cell RNA sequencing (scRNA‐seq) has made the high‐throughput molecular profiling of cells across modalities possible which has provided valuable insights into complex biological systems. In this review, we summarise the application of scRNA‐seq in investigating the pathogenesis of DR, focusing on four aspects. These include the identification of differentially expressed genes, characterisation of key cell subpopulations and reconstruction of developmental ‘trajectories’ to unveil their state transition, exploration of complex cell‒cell communication in DR and integration of scRNA‐seq with genome‐wide association studies to identify cell types that are most closely related to DR risk genetic loci. Finally, we discuss the future challenges and expectations associated with studying DR using scRNA‐seq. We anticipate that scRNA‐seq will facilitate the discovery of mechanisms and new treatment targets in the clinical care landscape for patients with DR.Key points Progress in scRNA‐seq for diabetic retinopathy (DR) research includes studies on DR patients, non‐human primates, and the prevalent mouse models. scRNA‐seq facilitates the identification of differentially expressed genes, pivotal cell subpopulations, and complex cell‐cell interactions in DR at single‐cell level. Future scRNA‐seq applications in DR should target specific patient subsets and integrate with single‐cell and spatial multi‐omics approaches.

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“…MGCs are sensitive to photochemical signals acting as naturally optimized optic fibers guiding signals to photoreceptors (Bringmann et al 2006). In addition, both neuronal and glial cells are in close contact with the vascular components of the retina and regulate the formation and properties of the blood retina barrier (BRB) (Wang et al 2022).…”

Section: Introductionmentioning

confidence: 99%

CCN–Hippo YAP signaling in vision and its role in neuronal, glial and vascular cell function and behavior

Chaqour

2023

J. Cell Commun. Signal.

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The retina is a highly specialized tissue composed of a network of neurons, glia, and vascular and epithelial cells; all working together to coordinate and transduce visual signals to the brain. The retinal extracellular matrix (ECM) shapes the structural environment in the retina but also supplies resident cells with proper chemical and mechanical signals to regulate cell function and behavior and maintain tissue homeostasis. As such, the ECM affects virtually all aspects of retina development, function and pathology. ECM‐derived regulatory cues influence intracellular signaling and cell function. Reversibly, changes in intracellular signaling programs result in alteration of the ECM and downstream ECM‐mediated signaling network. Our functional studies in vitro, genetic studies in mice, and multi omics analyses have provided evidence that a subset of ECM proteins referred to as cellular communication network (CCN) affects several aspects of retinal neuronal and vascular development and function. Retinal progenitor, glia and vascular cells are major sources of CCN proteins particularly CCN1 and CCN2. We found that expression of the CCN1 and CCN2 genes is dependent on the activity of YAP, the core component of the hippo‐YAP signaling pathway. Central to the Hippo pathway is a conserved cascade of inhibitory kinases that regulate the activity of YAP, the final transducer of this pathway. Reversibly, YAP expression and/or activity is dependent on CCN1 and CCN2 downstream signaling, which creates a positive or negative feedforward loop driving developmental processes (e.g., neurogenesis, gliogenesis, angiogenesis, barriergenesis) and, when dysregulated, disease progression in a range of retinal neurovascular disorders. Here we describe mechanistic hints involving the CCN–Hippo–YAP regulatory axis in retina development and function. This regulatory pathway represents an opportunity for targeted therapies in neurovascular and neurodegenerative diseases.

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Single-cell RNA sequencing reveals the Müller subtypes and inner blood–retinal barrier regulatory network in early diabetic retinopathy

Cited by 5 publications

References 47 publications

Cross‐species single‐cell landscape of vertebrate pineal gland

Cross‐species single‐cell landscape of vertebrate pineal gland

Single‐cell RNA sequencing in exploring the pathogenesis of diabetic retinopathy

CCN–Hippo YAP signaling in vision and its role in neuronal, glial and vascular cell function and behavior

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