In-depth mining of single-cell transcriptome reveals the key immune-regulated loops in age-related macular degeneration

Wencan Wang; Peng Lin; Siyu Wang; Guosi Zhang; Chong Chen; Xiaoyan Lu; Youyuan Zhuang; Jianzhong Su; Hong Wang; Liangde Xu

doi:10.3389/fnmol.2023.1173123

In-depth mining of single-cell transcriptome reveals the key immune-regulated loops in age-related macular degeneration

Front Mol Neurosci. 2023 May 19:16:1173123. doi: 10.3389/fnmol.2023.1173123. eCollection 2023.

Authors

Wencan Wang^#^{1

2

3}, Peng Lin^#^{1

2

3}, Siyu Wang^#^{1

2

3}, Guosi Zhang^{1

2

3}, Chong Chen^{1

2

3}, Xiaoyan Lu^{1

2

3}, Youyuan Zhuang^{1

2

3}, Jianzhong Su^{1

2

3

4}, Hong Wang^{1

2

3

5}, Liangde Xu^{1

2

3

5}

Affiliations

¹ National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, China.
² State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China.
³ National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, China.
⁴ Institute of PSI Genomics Co., Ltd., Wenzhou, China.
⁵ Center of Optometry International Innovation of Wenzhou, Eye Valley, Wenzhou, China.

^# Contributed equally.

Abstract

Introduction: Age-related macular degeneration (AMD), an ever-increasing ocular disease, has become one of the leading causes of irreversible blindness. Recent advances in single-cell genomics are improving our understanding of the molecular mechanisms of AMD. However, the pathophysiology of this multifactorial disease is complicated and still an ongoing challenge. To better understand disease pathogenesis and identify effective targets, we conducted an in-depth analysis of the single-cell transcriptome of AMD.

Methods: The cell expression specificity of the gene (CESG) was selected as an index to identify the novel cell markers. A computational framework was designed to explore the cell-specific TF regulatory loops, containing the interaction of gene pattern signatures, transcription factors regulons, and differentially expressed genes.

Results: Three potential novel cell markers were DNASE1L3 for endothelial cells, ABCB5 for melanocytes, and SLC39A12 for RPE cells detected. We observed a notable change in the cell abundance and crosstalk of fibroblasts cells, melanocytes, schwann cells, and T/NK cells between AMD and controls, representing a complex cellular ecosystem in disease status. Finally, we identified six cell type related and three disease-associated ternary loops and elaborated on the robust association between key immune-pathway and AMD.

Discussion: In conclusion, this study facilitates the optimization of screening for AMD-related receptor ligand pathways and proposes to further improve the interpretability of disease associations from single-cell data. It illuminated that immune-related regulation paths could be used as potential diagnostic markers for AMD, and in the future, also as therapeutic targets, providing insights into AMD diagnosis and potential interventions.

Keywords: age-related macular degeneration (AMD); cell communication; regulation loops; regulon; single cell transcriptome sequencing (scRNA-seq).

Grants and funding

This study was supported by the National Key Research and Development Program for Active Health and Aging Response (grant number 2020YFC2008200), the Key Research and Development Program of Zhejiang Province (grant numbers 2023C03031, 2021C03102, and 2020C03036), the National Natural Science Foundation of China (grant numbers 81830027 and U20A20364), the Major Scientific and Technological Innovation Projects of Wenzhou (grant number ZY2020013), and the Internal Fund Project of Eye Hospital of Wenzhou Medical University (grant number KYQD20210702).