マウス実験で治療のターゲットとなる遺伝子とタンパク質を同定 Mouse study IDs gene and protein that could be targets for therapy
2023-01-02 ワシントン大学セントルイス
Studying mice, researchers at Washington University School of Medicine in St. Louis have found that proteins made by stem cells to help regenerate the cornea may become new targets for treating and preventing injuries to the cornea related to dry eye disease. When eyes are dry, the cornea is more susceptible to injury. By tracking the movements of stem cells (in fluorescent green) in a mouse eye, researchers were able to trace the cells as they differentiated into corneal cells and migrated to the center of the cornea, providing clues about how the cells work to help corneal injuries heal. (Photo: Apte lab)
「ドライアイとは、眼球が自然の涙で十分な潤滑を得られない場合に起こる病気です。ドライアイにかかった人は、不足した自然の涙を補い、目の潤滑性を保つために様々な種類の目薬を使用しますが、目が乾燥すると角膜が傷つきやすくなります。」と、John F. Hardesty眼科・視覚科学科のPaul A. Cibis特別教授である主任研究員のRajendra S. Apte医師、PhDは述べています。「目の健康に重要な遺伝子を含むこの研究では、ドライアイでは健康な目とは異なる治療標的の可能性を特定しました。ドライアイに伴う合併症や傷害のために、世界中で数千万人(米国だけでも1500万人)が目の痛みやかすみに耐えており、これらのタンパク質を標的とすることで、これらの傷害をよりうまく治療、あるいは予防することができるかもしれません。」
研究者達は、ドライアイ疾患だけでなく、糖尿病やその他の疾患も含む、いくつかのモデルマウスで、角膜で発現する遺伝子を分析しました。その結果、ドライアイを発症したマウスでは、角膜がSPARCという遺伝子の発現を活性化していることがわかった。さらに、SPARCタンパク質のレベルが高いほど、治癒が良好であることも明らかにした。
<関連情報>
- https://source.wustl.edu/2023/01/dry-eye-disease-alters-how-the-eyes-cornea-heals-itself-after-injury/
- https://medicine.wustl.edu/news/dry-eye-disease-alters-how-the-eyes-cornea-heals-itself-after-injury/?_ga=2.49307429.2094597223.1672890614-531768696.1642754088
- https://www.pnas.org/doi/10.1073/pnas.2204134120
マウスのドライアイ病は、恒常的な角膜上皮の再生とは異なる適応的な角膜上皮の再生を活性化する Dry eye disease in mice activates adaptive corneal epithelial regeneration distinct from constitutive renewal in homeostasis
Joseph B. Lin ,Xiaolei Shen,Charles W. Pfeifer ,Fion Shiau ,Andrea Santeford ,Philip A. Ruzycki ,Brian S. Clark ,Qin Liu ,Andrew J. W. Huang ,Rajendra S. Apte
Proceedings of the National Academy of Sciences Published:January 3, 2023
DOI:https://doi.org/10.1073/pnas.2204134120
Significance
We resolve cell type-specific transcriptional signatures of corneal epithelial differentiation in health, injury, and disease; identify unique genes and gene networks that may be amenable to therapy for the treatment of ocular surface diseases; and create a framework for future studies of corneal limbal stem cells and other stem cell compartments.
Abstract
Many epithelial compartments undergo constitutive renewal in homeostasis but activate unique regenerative responses following injury. The clear corneal epithelium is crucial for vision and is renewed from limbal stem cells (LSCs). Using single-cell RNA sequencing, we profiled the mouse corneal epithelium in homeostasis, aging, diabetes, and dry eye disease (DED), where tear deficiency predisposes the cornea to recurrent injury. In homeostasis, we capture the transcriptional states that accomplish continuous tissue turnover. We leverage our dataset to identify candidate genes and gene networks that characterize key stages across homeostatic renewal, including markers for LSCs. In aging and diabetes, there were only mild changes with <15 dysregulated genes. The constitutive cell types that accomplish homeostatic renewal were conserved in DED but were associated with activation of cell states that comprise “adaptive regeneration.” We provide global markers that distinguish cell types in homeostatic renewal vs. adaptive regeneration and markers that specifically define DED-elicited proliferating and differentiating cell types. We validate that expression of SPARC, a marker of adaptive regeneration, is also induced in corneal epithelial wound healing and accelerates wound closure in a corneal epithelial cell scratch assay. Finally, we propose a classification system for LSC markers based on their expression fidelity in homeostasis and disease. This transcriptional dissection uncovers the dramatically altered transcriptional landscape of the corneal epithelium in DED, providing a framework and atlas for future study of these ocular surface stem cells in health and disease.
