Institute of Genetic Medicine, Newcastle University, UK.
Institute of Neuroscience, Newcastle University, UK; Interdisciplinary Computing and Complex Biosystems (ICOS) Research Group, Newcastle University, UK.
Acta Biomater. 2018 Jul 1;74:207-221. doi: 10.1016/j.actbio.2018.05.023. Epub 2018 May 17.
The extracellular matrix (ECM) plays an important role in numerous processes including cellular proliferation, differentiation, migration, maturation, adhesion guidance and axonal growth. To date, there has been no detailed analysis of the ECM distribution during retinal ontogenesis in humans and the functional importance of many ECM components is poorly understood. In this study, the expression of key ECM components in adult mouse and monkey retina, developing and adult human retina and retinal organoids derived from human pluripotent stem cells was studied. Our data indicate that basement membrane ECMs (Fibronectin and Collagen IV) were expressed in Bruch's membrane and the inner limiting membrane of the developing human retina, whilst the hyalectins (Versican and Brevican), cluster of differentiation 44 (CD44), photoreceptor-specific ECMs Interphotoreceptor Matrix Proteoglycan 1 (IMPG1) and Interphotoreceptor Matrix Proteoglycan 2 (IMPG2) were detected in the developing interphotoreceptor matrix (IPM). The expression of IMPG1, Versican and Brevican in the developing IPM was conserved between human developing retina and human pluripotent stem cell-derived retinal organoids. Blocking the action of CD44 and IMPG1 in pluripotent stem cell derived retinal organoids affected the development of photoreceptors, their inner/outer segments and connecting cilia and disrupted IPM formation, with IMPG1 having an earlier and more significant impact. Together, our data suggest an important role for IMPG1 and CD44 in the development of photoreceptors and IPM formation during human retinogenesis.
The expression and the role of many extracellular matrix (ECM) components during human retinal development is not fully understood. In this study, expression of key ECM components (Collagen IV, Fibronectin, Brevican, Versican, IMPG1 and IMPG2) was investigated during human retinal ontogenesis. Collagen IV and Fibronectin were expressed in Bruch's membrane; whereas Brevican, Versican, IMPG1 & IMPG2 in the developing interphotoreceptor matrix (IPM). Retinal organoids were successfully generated from pluripotent stem cells. The expression of ECM components was examined in the retinal organoids and found to recapitulate human retinal development in vivo. Using functional blocking experiments, we were able to highlight an important role for IMPG1 and CD44 in the development of photoreceptors and IPM formation.
细胞外基质（ECM）在许多过程中发挥着重要作用，包括细胞增殖、分化、迁移、成熟、黏附导向和轴突生长。迄今为止，人们尚未对人类视网膜发生过程中 ECM 分布进行详细分析，而且许多 ECM 成分的功能重要性也知之甚少。在这项研究中，研究了成年小鼠和猴子视网膜、发育中和成年人类视网膜以及源自人类多能干细胞的视网膜类器官中关键 ECM 成分的表达。我们的数据表明，基膜 ECM（纤连蛋白和胶原 IV）在发育中人类视网膜的布鲁赫膜和内界膜中表达，而透明质酸（Versican 和 Brevican）、分化群 44（CD44）、光感受器特异性 ECM 间视网膜基质蛋白聚糖 1（IMPG1）和间视网膜基质蛋白聚糖 2（IMPG2）在发育中的间视网膜基质（IPM）中被检测到。在发育中的 IPM 中，IMPG1、Versican 和 Brevican 的表达在人类发育中的视网膜和人类多能干细胞衍生的视网膜类器官之间是保守的。在多能干细胞衍生的视网膜类器官中阻断 CD44 和 IMPG1 的作用会影响光感受器的发育、它们的内外节和连接纤毛，并破坏 IPM 的形成，其中 IMPG1 的影响更早且更显著。总之，我们的数据表明，IMPG1 和 CD44 在人类视网膜发生过程中对光感受器的发育和 IPM 的形成起着重要作用。
许多细胞外基质（ECM）成分在人类视网膜发育过程中的表达和作用尚不完全清楚。在这项研究中，研究了关键 ECM 成分（胶原 IV、纤连蛋白、Brevican、Versican、IMPG1 和 IMPG2）在人类视网膜发生过程中的表达。胶原 IV 和纤连蛋白在布鲁赫膜中表达；而 Brevican、Versican、IMPG1 和 IMPG2 在发育中的间视网膜基质（IPM）中表达。成功地从多能干细胞中生成了视网膜类器官。在视网膜类器官中检查 ECM 成分的表达，发现它们重现了体内人类视网膜的发育。通过功能阻断实验，我们能够突出 IMPG1 和 CD44 在光感受器发育和 IPM 形成中的重要作用。
