Restoration of Aqueous Humor Outflow Following Transplantation of iPSC-Derived Trabecular Meshwork Cells in a Transgenic Mouse Model of Glaucoma.
Restoration of Aqueous Humor Outflow Following Transplantation of iPSC-Derived Trabecular Meshwork Cells in a Transgenic Mouse Model of Glaucoma.
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DOI：
10.1167/iovs.16-20672
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发表时间：
2017-04-01
影响因子：
4.4
通讯作者：
Kuehn MH
中科院分区：
文献类型：
--
作者：
Zhu W;Jain A;Gramlich OW;Tucker BA;Sheffield VC;Kuehn MH
原发性开角型青光眼（POAG）在老年人中特别常见，并与小梁网（TM）的病理性变性有关。我们以前已经表明，诱导多能干细胞（iPSC）衍生的TM细胞移植恢复年轻的转基因小鼠表达的致病形式的人myocilin（Tg-MYOCY 437 H）的房水动力学。这项研究旨在确定这种方法在TM功能障碍更明显的老年小鼠中是否可行。使小鼠iPSC向TM细胞表型分化（iPSC-TM）并注射到6个月大的Tg-MYOCY 437 H或对照小鼠的前房中。记录3个月内的IOP和房水流出功能。进行透射电子显微镜、蛋白质印迹和免疫组织化学分析TM形态、定量内质网（ER）应激和评估TM细胞构成。移植后12周，与未治疗的对照组相比，iPSC-TM受体的IOP在统计学上较低，流出道功能显著改善。内源性TM细胞的数量在iPSC-TM受体中显著增加，沿着出现对细胞分裂标志物呈免疫阳性的TM细胞。在形态学上，iPSC-TM的移植在移植后12周保留了ER结构。然而，在这些9个月大的Tg-MYOCY 437 H小鼠的移植眼中，肌钙蛋白和钙连接蛋白的表达水平仍然升高，表明ER应激在TM内持续存在。iPSC-TM移植可恢复老年Tg-MYOCY 437 H小鼠的IOP和流出道功能。这种类型的基于干细胞的治疗是一个有希望的可能性，在一些青光眼患者的IOP控制恢复。
Primary open-angle glaucoma (POAG) is particularly common in older individuals and associated with pathologic degeneration of the trabecular meshwork (TM). We have shown previously that transplantation of induced pluripotent stem cell (iPSC) derived TM cells restores aqueous humor dynamics in young transgenic mice expressing a pathogenic form of human myocilin (Tg-MYOCY437H). This study was designed to determine if this approach is feasible in older mice with more pronounced TM dysfunction. Mouse iPSC were differentiated toward a TM cell phenotype (iPSC-TM) and injected into the anterior chamber of 6-month-old Tg-MYOCY437H or control mice. IOP and aqueous humor outflow facility were recorded for up to 3 months. Transmission electron microscopy, Western blot, and immunohistochemistry were performed to analyze TM morphology, quantify endoplasmic reticulum (ER) stress, and assess TM cellularity. A 12 weeks after transplantation, IOP in iPSC-TM recipients was statistically lower and outflow facility was significantly improved compared to untreated controls. The number of endogenous TM cells increased significantly in iPSC-TM recipients along with the appearance of TM cells immmunopositive for a marker of cellular division. Morphologically, transplantation of iPSC-TM preserves ER structure 12 weeks after transplantation. However, myocilin and calnexin expression levels remain elevated in transplanted eyes of these 9-month-old Tg-MYOCY437H mice, indicating that ER stress persists within the TM. Transplantation of iPSC-TM can restore IOP and outflow facility in aged Tg-MYOCY437H mice. This type of stem cell–based therapy is a promising possibility for restoration of IOP control in some glaucoma patients.
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影响因子：
46.9
作者：
Lane, Steven W.;Williams, David A.;Watt, Fiona M.
通讯作者：
Watt, Fiona M.
影响因子：
3.9
作者：
Kim, C. Y.;Kuehn, M. H.;Kwon, Y. H.
通讯作者：
Kwon, Y. H.
DOI：
10.1196/annals.1354.010
发表时间：
2006-01-01
期刊：
UNDERSTANDING AND MODULATING AGING
影响因子：
--
作者：
Demetrius, Lloyd
通讯作者：
Demetrius, Lloyd
影响因子：
0.6
作者：
Gessesse, Girum W;Damji, Karim F
通讯作者：
Damji, Karim F
影响因子：
3.8
作者：
Johnson TV;Tomarev SI
通讯作者：
Tomarev SI