Re: “Organ-On-A-Chip Technologies for Advanced Blood–Retinal Barrier Models,” by Ragelle et al.
Re: “Organ-On-A-Chip Technologies for Advanced Blood–Retinal Barrier Models,” by Ragelle et al.
复制标题
回复：“用于先进血液的器官芯片技术——视网膜屏障模型”，作者：Ragele 等人。
DOI：
10.1089/jop.2022.0003
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发表时间：
2022
影响因子：
2.3
通讯作者：
Vazquez, Maribel
中科院分区：
文献类型：
--
作者：
Castro, Natalia G.;Cohen, Rick;Vazquez, Maribel
亲爱的编辑，我们怀着极大的兴趣阅读了Ragelle等人的文章，题为“先进的血液视网膜屏障模型的器官芯片技术”。1作者强调了体外技术的进步和血视网膜屏障（BRB）的器官芯片建模。然而，我们写信强调将诱导多能干细胞（iPSC）衍生的Müller胶质细胞（MG）用于更合适的BRB模型以推进再生疗法的必要性和优势。正如文章中所强调的，体外BRB研究所需的一个重大进展是应用人类iPSC（hiPSC），而不是原代培养物或永生化细胞系。hiPSC减少了动物建模的伦理问题，并提供了上级生理相关性和对人类临床需求的更平滑的转化。2 hiPSC最近已用于模拟内部BRB（iBRB）的视网膜神经元和内皮细胞（EC），1表明hiPSC分化为其他视网膜细胞谱系将改善iBRB的细胞模型。此外，微流体与基于hiPSC的技术的结合为全面的iBRB模型的开发带来了巨大的希望，因为微尺度系统有助于在生理间隔和尺度上进行细胞研究。当代的微流控装置和芯片实验室技术已经产生了控制系统来检查神经退行性疾病和在一个集成系统中研究多种细胞类型。2我们自己的实验室最近开发了一种视网膜尺度上的胶质细胞系（gLL）微流体系统（图1A），以检查MG的肥大、粘附和迁移的变化，这些变化是胶质增生的标志，对iBRB的完整性具有重要意义。gLL是用商业聚二甲基硅氧烷（PDMS）制成的，并与显微镜载玻片粘合。它提供了一个受控的微环境，其中hiPSC衍生的MG和EC可以接种共培养，以检查集体细胞行为和对细胞外刺激（例如，缺氧，葡萄糖）的反应。3 iBRB最常以EC为重点进行建模，尽管这种神经血管屏障组织也受到MG的复杂调节，MG跨越视网膜层以维持稳态并启动修复（图1B）。1虽然EC对于从血流中运输氧气和营养物穿过iBRB至关重要，但MG通过充当血管系统和视网膜之间调节运输的额外屏障而对iBRB同样重要。视网膜退行性疾病，如糖尿病视网膜病变（DR），主要特征是iBRB功能障碍。DR是影响眼睛健康的最普遍的疾病之一，损害患者视力，因为升高和波动的血糖水平与通过形成iBRB的EC的紧密连接的渗漏相关。改变的紧密连接允许血液成分穿透视网膜，这可以刺激神经胶质增生，其中MG释放生长因子和细胞因子作为神经保护反应。随着时间的推移，这为视网膜创造了一个破坏性的炎症环境，可导致神经胶质瘢痕形成并最终导致视力丧失。4由于MG的过度保护反应及其进一步损害视网膜功能的潜力，MG在研究疾病和开发不引起延长的神经胶质活性的疗法时是必不可少的。尽管MG对视网膜变性的反应具有重要意义，但很少有生物医学项目将MG的行为纳入BRB的研究中。微流体与基于hiPSC的MG的组合为开发全面的BRB模型以检查DR和靶MG天然的进展带来了巨大的希望。
Dear Editor, We have read with great interest the article by Ragelle et al. entitled ‘‘Organ-on-a-chip technologies for advanced blood–retinal barrier models.’’1 The authors highlighted the advancements of in vitro technologies and organ-on-a-chip modeling for the blood–retinal barrier (BRB). However, we write to stress the need and advantages of incorporating induced pluripotent stem cell (iPSC)-derived Müller glia (MG) for more appropriate BRB models to advance regenerative therapies. As highlighted in the article, a significant advancement needed for in vitro BRB studies is the application of human iPSCs (hiPSCs), rather than primary cultures or immortalized cell lines. hiPSCs reduce ethical concerns of animal modeling as well as provide superior physiological relevance and smoother translation to human clinical needs. 2 hiPSCs have been recently used to model retinal neurons and endothelial cells (ECs) of the inner BRB (iBRB), 1 suggesting that hiPSC differentiation into other retinal cell lineages will improve cellular models of the iBRB. Moreover, the combination of microfluidics with hiPSC-based technology holds great promise for the development of comprehensive iBRB models because the microscale system facilitates cell study at physiological spacing and scale. Contemporary microfluidic devices and laboratory-on-achip technology have produced controlled systems to examine neurodegenerative diseases and the study of multiple cell types in an integrated system. 2 Our own laboratory has recently developed a glial line (gLL) microfluidic system (Fig. 1A) on the retinal scale to examine changes in hypertrophy, adhesion, and migration of MG that are hallmarks of gliosis and significant to iBRB integrity. The gLL is fabricated with commercial polydimethylsiloxane (PDMS) and bonded to a microscope slide. It provides a controlled microenvironment where hiPSC-derived MG and ECs can be seeded for coculture to examine collective cell behaviors and responses to extracellular stimuli (eg, hypoxia, glucose). 3 The iBRB is most commonly modeled with a focus on ECs, although this neurovascular barrier tissue is also intricately regulated by MG that span the retinal laminae to maintain homeostasis and initiate repair (Fig. 1B). 1 Although ECs are vital for the transport of oxygen and nutrients from blood flow across the iBRB, MG are equally essential to the iBRB by serving as an additional barrier of regulatory transport between the vasculature and the retina. Retinal degenerative diseases, such as diabetic retinopathy (DR), are largely characterized by iBRB dysfunction. DR, one of the most prevalent diseases affecting eye health, impairs patient vision, as elevated and fluctuating blood glucose levels are associated with leakage through tight junctions of the ECs that form the iBRB. The altered tight junctions allow blood-borne elements to penetrate the retina, which can stimulate gliosis, where MG release growth factors and cytokines as neuroprotective responses. Over time, this creates a destructive inflammatory environment for the retina that can result in glial scarring and ultimately vision loss. 4 Because of the overprotective response of MG and their potential to further damage retinal function, MG are essential when studying diseases and for developing therapies that do not elicit prolonged gliotic activity. Despite the significance of MG response to retinal degeneration, few biomedical projects have incorporated the behaviors of MG into studies of the BRB. The combination of microfluidics with hiPSC-based MG holds great promise for the development of comprehensive BRB models to examine the progression of DR and target MG native …