聚焦哺乳动物眼晶状体：发育、解剖、生理、透明性、生物力学及与年龄相关的问题

Catherine Cheng; Michael P. Vu

doi:10.3791/70442

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综述文章

聚焦哺乳动物眼晶状体：发育、解剖、生理、透明性、生物力学及与年龄相关的问题

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DOI：

10.3791/70442

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2026年5月29日

Catherine Cheng¹ , Michael P. Vu¹

¹School of Optometry and Vision Science Program, Indiana University

本文内容

摘要

晶状体通过将光线聚焦到视网膜上以实现其功能，该功能依赖于组织的透明度、生物力学特性以及折射率。本文综述了晶状体的三维结构，并探讨了维持组织稳态的复杂机制。

摘要

晶状体是位于眼球前房内的透明椭球状器官，可将光线聚焦到视网膜上。该三维组织由上皮细胞和纤维细胞构成，结构高度有序，以确保光路清晰，并通过多种机制建立和维持高折射率与透明性。在人类中，晶状体通过改变形状来聚焦不同距离的光线，这一过程称为调节；晶状体的弹性与生物力学特性依赖于组织、细胞和分子层面的机制。白内障是指原本透明的晶状体出现任何混浊，仍是全球致盲的首要原因。老花眼则与年龄相关的晶状体硬化有关，已被证实与调节能力下降及需要佩戴阅读眼镜相关。本文综述将探讨哺乳动物晶状体的发育与终身生长、晶状蛋白与细胞骨架蛋白、细胞间通讯与微循环、晶状体生物力学，以及研究这一独特组织所面临的挑战与新兴方法。

引言

晶状体乍看起来是一种相对简单的组织，仅由两种细胞类型构成：上皮细胞和纤维细胞。晶状体的大部分质量由纤维细胞组成，其前半球表面覆盖着一层单层的上皮细胞¹（图1A）。整个组织被一层称为晶状体囊膜的薄基底膜包裹，该膜主要由IV型胶原蛋白和层粘连蛋白构成，如先前综述所述²。晶状体无血管和神经支配，通过连接晶状体囊膜与睫状体的弹性悬韧带纤维（又称悬韧带）悬吊于眼球前房内¹。位于晶状体前部或中央的上皮细胞呈立方形，排列成鹅卵石样结构³^,⁴^,⁵（图1A，浅蓝色细胞，顶部）。这些细胞处于静止状态，不发生增殖⁶。在晶状体赤道区前方，上皮细胞在生发区进行分裂（图1A，橙色细胞，右上角），这些赤道区细胞将向赤道迁移，并排列成高度有序的子午线状行列，细胞呈六边形⁷^,⁸^,⁹^,¹⁰（图1A，绿色细胞，右上角）。子午线行列细胞将其顶端锚定于晶状体的支点（即中轴部），随后开始伸长并分化为新的次级纤维细胞（图1A，左下角）。次级纤维细胞的顶端通过与上皮细胞顶端面相互作用，向晶状体前极迁移，形成一种特殊的顶端-顶端连接结构³（图1A，红线）。新形成的纤维细胞的后端基底端沿晶状体囊膜向后极延伸（图1A，左下角）。当伸长中的纤维细胞末端到达前极或后极时，细胞从前部上皮细胞或后部囊膜脱离，并与来自组织对侧延伸而来的细胞末端相遇，形成缝合线结构¹¹^,¹²^,¹³（图1A，左上角）。晶状体纤维细胞在横切面上呈拉长的六边形，具有两个长/宽边、四个短边以及六个三细胞连接结构（图1A，右下角）¹⁴。相邻纤维细胞之间极小的细胞间隙有助于减少光散射¹⁴。皮质区纤维细胞在周边持续添加，并叠加于先前生成的纤维层之上，从而支持晶状体终生生长¹⁴^,¹⁵。晶状体中心区域称为晶状体核，该区域的硬度高于周边部或皮质区，如先前综述所述¹⁶。

晶状体结构示意图及皮层纤维的扫描电镜图，显示纤维排列方式和上皮细胞。
图1：晶状体解剖结构与组织形态。 (A) 晶状体由覆盖前半球的单层上皮细胞（浅蓝色、橙色和浅绿色）以及大量晶状体纤维（白色和粉色）构成。一层薄的胶原膜，称为晶状体囊膜（棕褐色），包裹着整个组织。晶状体通过悬韧带纤维（悬韧带）悬挂在眼球前房内，这些纤维插入晶状体赤道部周围的囊膜中。前部/中央区的上皮细胞（顶部浅蓝色）呈立方体形，横切面呈鹅卵石状。生发区的赤道部上皮细胞（橙色）从随机排列的细胞（橙色）转变为有序的六边形细胞的经向排列（绿色）。这些经向排列的细胞伸长，成为晶状体周边部的新皮层次级纤维细胞层（白色）。新生次级纤维的顶端锚定在支点/中央柱（海螺色方框，左下角）。伸长中的次级纤维顶端沿晶状体上皮细胞的顶端侧面向前极迁移，并形成一种特殊的顶端-顶端连接（红线）。伸长纤维的基底端则沿后囊膜向后极迁移。当次级纤维完全伸长后，其顶端从前部上皮或后囊膜脱离，形成晶状体缝合线（深蓝色线条及左上图像）。晶状体纤维细胞横切面呈拉长的六边形（右下角），具有两个长/宽侧面、四个短侧面以及六个三细胞连接点。在纤维细胞成熟过程中，所有细胞器均被清除，形成无细胞器区（深绿色双向箭头），以最大限度减少光散射。最古老的晶状体纤维细胞被压缩至组织中心，形成晶状体核（粉色）。示意图未按比例绘制。(B) 不同深度晶状体纤维细胞的扫描电子显微镜图像，展示了细胞在分化与成熟过程中的形态变化。为突出显示，单个细胞以绿色标出。皮层外周纤维在长侧边具有榫卯状嵌合结构，在短侧边具有小突起。在纤维细胞成熟过程中，成熟细胞的短侧边出现带有小突起的大桨状结构以及大突起。核周纤维在整个膜上具有舌槽状嵌合结构，短侧边具有大突起。核内纤维在短侧边具有大突起，并呈现球状膜形态。比例尺：5 µm。改编自 ¹⁶^,³²⁸。请点击此处查看该图的放大版本。

晶状体的复杂性在于其高度有序的三维（3D）细胞排列、特化的纤维细胞成熟过程（该过程会降解并清除所有细胞器），以及建立和维持组织透明性和高折射率的分子与细胞机制。大多数晶状体纤维细胞中缺乏细胞器，这增加了在整个生物体生命周期中维持所有已生成晶状体细胞健康和长寿的难度。晶状体是研究衰老及与年龄相关变化的理想组织，因为其中心最深处的细胞形成于早期胚胎发育阶段，而晶状体在整个生命过程中持续在组织周边生成新细胞，从而允许对 chronological 上较老的细胞与在老年时期生成的细胞进行比较研究。晶状体的精细聚焦功能使来自不同距离物体的清晰图像能够投射到视网膜上，这一功能依赖于晶状体改变形状或进行调节的能力。晶状体是一种非结缔组织、非肌肉组织，其正常功能依赖于特定的生物力学特性。

导致视力障碍的首要原因是衰老¹⁷。与年龄相关的变化会引起晶状体的两种主要病理状态：白内障和老视¹⁸。白内障或任何类型的晶状体混浊仍是全球致盲的首要原因¹⁹，其成因包括遗传和环境因素，如紫外线辐射、吸烟、糖尿病以及氧化应激等，这些因素会导致蛋白质聚集和/或细胞缺陷，如先前综述所述¹⁸^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵。老视是一种与年龄相关的调节能力下降，由晶状体在聚焦近处物体时改变形状的能力减弱所致，进而导致需要佩戴阅读眼镜²⁶^,²⁷^,²⁸。世界卫生组织估计，全球至少有10亿人存在未被矫正的视力障碍，其中包括6520万白内障患者和8.26亿老视患者¹⁷。随着人口老龄化加剧，迫切需要更深入地理解晶状体的生理学与生物学特性。

本文综述了哺乳动物晶状体中对功能和稳态至关重要的组织结构、细胞排列及分子机制，并简要介绍了其他脊椎动物晶状体的相关信息。旨在提供晶状体生物学与生理学的总体概述，并附有指向更详细综述的参考文献。内容涵盖胚胎期晶状体发育、出生后晶状体生长、三维细胞与组织排列、组织的生物力学特性以及微循环系统。下文将讨论主要的晶状体蛋白，即晶状体蛋白（crystallins）、细胞骨架网络以及细胞间通讯。最后，本文将总结当前研究该独特组织所面临的主要挑战及新兴的研究方法。

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综述与观点

胚胎晶状体发育与出生后晶状体生长

在脊椎动物中，晶状体由表层外胚层细胞发育而来，未来的晶状体始于视泡上方表层外胚层的增厚⁶^,²⁹^,³⁰（图2A）。随着视杯的形成，增厚的外胚层或晶状体原基向内凹陷，形成晶状体凹陷⁶^,²⁹^,³⁰（图2B）。肌动蛋白丝（F-actin）将晶状体凹陷的后部与发育中的视杯前表面相连，以协调这些发育组织的运动和形态变化³¹^,³²^,³³^,³⁴，而晶状体上皮细胞的顶端收缩是晶状体凹陷内陷所必需的³⁵^,³⁶^,³⁷^,³⁸^,³⁹^,⁴⁰（图2C）。晶状体凹陷的开口持续变窄，直至完全闭合，此过程中晶状体茎细胞发生凋亡⁴¹^,⁴²^,⁴³。晶状体泡与未来角膜外胚层分离，形成一个由上皮细胞构成的中空球体，即晶状体泡⁶^,²⁹^,³⁰（图2D）。晶状体泡中的后部上皮细胞向前列上皮延伸，并分化为初级纤维细胞，填充腔隙，形成胚胎期晶状体（图2E）。覆盖前半球的单层上皮细胞得以维持，而在完全形成的胚胎晶状体中已无后部上皮细胞（图2F）。初级纤维细胞构成晶状体核最中心的部分，其外围终生由来自晶状体周边部或皮质区的新一代次级晶状体纤维不断添加而形成⁶^,²⁹^,³⁰。尽管大多数脊椎动物的晶状体通过内陷方式形成，但在斑马鱼中，原基增厚后通过去分化形成晶状体⁴⁴。

晶状体发育阶段：示意图中的基板、凹陷、泡状结构至胚胎期晶状体。
图 2：哺乳动物眼睛中胚胎期晶状体的发育过程。 表面外胚层细胞为白色，晶状体细胞为浅蓝色，视杯/视泡细胞为沙色。(A) 胚胎期晶状体基板（浅蓝色）由表面外胚层发育而来。位于表面外胚层和晶状体基板后方的是视泡。(B) 晶状体基板内陷形成晶状体凹陷，视泡内陷形成视杯。视杯的前部将发育为虹膜和睫状体，而后部将形成视网膜和视网膜色素上皮。(C) 晶状体基板的开口逐渐变窄，直至完全闭合。(D) 晶状体泡从表面外胚层分离，形成一个由晶状体上皮细胞衬里的中空球体。(E) 晶状体泡中后部的晶状体上皮细胞开始伸长并分化为初级晶状体纤维。(F) 初级晶状体纤维填充晶状体泡腔，形成胚胎期晶状体。示意图未按比例绘制。仿照 ⁴¹¹ 绘制。请点击此处查看此图的放大版本。

在胚胎发育过程中，晶状体周围存在一个篮网状的血管系统⁶^,⁴⁵^,⁴⁶。这些血管起源于视网膜的玻璃体动脉，最初在晶状体凹陷的后方开始形成血管网络，最终构建出有序的晶状体血管膜（tunica vasculosa lentis），以滋养胚胎期的晶状体，直至前房结构和房水分泌系统完全发育成熟⁶^,⁴⁵。这些血管随后退化并完全消失，以确保出生前或睁眼前（取决于物种）形成清晰的光路⁶^,⁴⁵^,⁴⁶^,⁴⁷。

Pax6 对早期眼睛发育是必需的⁴⁸^,⁴⁹^,⁵⁰^,⁵¹^,⁵²，并且对晶状体发育至关重要且足以驱动其发育⁵³^,⁵⁴^,⁵⁵^,⁵⁶。Pax6 的磷酸化和 SUMO 化修饰可调控该转录因子在脑、中枢神经系统及眼睛发育过程中的功能⁵⁷^,⁵⁸^,⁵⁹^,⁶⁰。其他对胚胎眼和晶状体发育至关重要的信号通路与 Pax6 信号通路相互交汇，包括增强子 [Meis、骨形态发生蛋白（Bmp）和成纤维细胞生长因子（FGF）] 及下游蛋白 [Foxe3 和视黄酸（RA）]，如先前综述所述⁶¹。Meis1 和 Meis2 可结合至 Pax6 基因的增强子区域，并在脊椎动物中为晶状体诱导所必需⁶²。遗传学研究表明，Bmp7 通过调控 Pax6 的表达而对晶状体原基的发育至关重要⁶³^,⁶⁴。Foxe3 位于 Pax6 信号通路的下游，对晶状体发育必不可少⁶⁵^,⁶⁶，尤其是在晶状体泡形成时实现晶状体柄与表面外胚层的清晰分离。Foxe3 的缺失会导致一种称为彼得斯异常（Peters Anomaly）的先天性眼部缺陷⁶⁷。成纤维细胞生长因子受体（FGFR）信号通路与 Bmp7 协同作用，调控 Pax6 的表达，从而进一步影响发育中晶状体内 Foxe3 的水平⁶⁸。表达一种抑制性 FGFR 形式会导致晶状体原基形成延迟、晶状体柄分离不完全以及晶状体泡体积变小⁶⁸。视黄酸（RA）信号通路的破坏会导致眼部形成缺陷⁶⁹，而当 Pax6 受到干扰时，RA 的表达水平降低，提示这两条信号通路之间存在一定的交互作用⁷⁰。

胚胎晶状体完全形成后，晶状体的持续生长被认为主要由生长因子信号通路驱动，尤其是在哺乳动物晶状体中主要通过成纤维细胞生长因子（FGF）信号通路实现，如先前综述所述⁷¹。FGF在玻璃体中的含量高于房水，从而在晶状体赤道部附近形成一个促进生长和分化的浓度梯度⁷²^,⁷³。晶状体表达4种FGF受体（FGFR）中的3种，即FGFR1、FGFR2和FGFR3，且在晶状体赤道部及其后方区域表达水平逐渐升高⁷⁴^,⁷⁵。FGF的过表达可诱导原本静止的前部上皮细胞异常伸长并分化为类似纤维细胞的细胞⁷⁶^,⁷⁷^,⁷⁸。除了FGF信号通路外，抑制剂实验表明Bmp通路在纤维细胞伸长过程中也发挥作用⁷⁹^,⁸⁰，而转化生长因子β（TGFβ）受体的异常会破坏纤维细胞的正常成熟过程⁸¹。

晶状体透明度与折射率

晶状体纤维细胞在成熟过程中经历一种特化的程序，以清除所有细胞器，从而消除光路中的散射物，并形成无细胞器区（OFZ）⁸² （图1A）。当纤维细胞达到其成熟程序的特定阶段后，所有细胞器的协调性丢失会迅速发生⁸³^,⁸⁴^,⁸⁵^,⁸⁶^,⁸⁷^,⁸⁸。细胞器降解异常会导致白内障，多个基因敲除（KO）斑马鱼和小鼠模型已鉴定出一系列对OFZ形成至关重要的基因，包括参与染色质和DNA降解的基因⁸⁹^,⁹⁰^,⁹¹^,⁹²^,⁹³、细胞周期蛋白依赖性激酶⁹⁴^,⁹⁵、热休克因子4⁹¹^,⁹⁶^,⁹⁷^,⁹⁸以及PLATT磷脂酶⁹⁹。细胞膜蛋白和细胞骨架蛋白¹⁰⁰^,¹⁰¹^,¹⁰²^,¹⁰³^,¹⁰⁴、晶状体蛋白（crystallins）¹⁰⁵^,¹⁰⁶^,¹⁰⁷以及癌基因¹⁰⁸^,¹⁰⁹的异常表达或突变也会影响细胞器的清除及晶状体透明度。然而，触发纤维细胞中细胞器降解的确切信号仍不明确。近期研究揭示了RNA结合蛋白在晶状体发育和白内障形成中的重要作用，如先前综述所述¹¹⁰。RNA结合蛋白的功能障碍，包括Tdrd7¹¹¹、caprin2¹¹²、Rbm24¹¹³和Celf1¹¹⁴^,¹¹⁵^,¹¹⁶，可导致晶状体发育异常、细胞器降解受阻以及白内障的发生。

与体内大多数细胞类型相比，哺乳动物晶状体纤维细胞的蛋白质浓度极高（200–450 mg/ml）¹¹⁷^,¹¹⁸^,¹¹⁹^,¹²⁰。蛋白质占晶状体总重量的30%–35%，因此晶状体的含水量相对较低，约为65%–70%¹²¹^,¹²²。按质量计，晶状体蛋白质的90%为晶状体蛋白（crystallins）¹²³，哺乳动物晶状体中存在三类晶状体蛋白家族：α、β和γ，如先前综述所述¹²⁴^,¹²⁵。通常情况下，高蛋白含量会增加大于光波长一半的聚集体形成风险，从而导致光散射¹²⁶，但晶状体蛋白在纤维细胞胞质中以短程有序的方式排列，有助于提高折射率并维持透明性¹¹⁷^,¹²⁷。α-晶状体蛋白具有类似分子伴侣的功能，可抑制蛋白质聚集，下文将对此进行讨论。晶状体内部的梯度折射率（GRIN）有助于光线聚焦，如先前综述所述¹²⁸^,¹²⁹，晶状体中心的最大折射率与核部纤维细胞的致密排列相关¹³⁰^,¹³¹^,¹³²。在鱼类晶状体中，数据表明核部高折射率是蛋白质被运输至组织中心的结果¹³³。人们推测，沿纤维细胞膜分布的膜融合结构可能形成大分子运输通路，从而促进晶状体蛋白在细胞间及不同纤维层之间的均匀分布¹³⁴^,¹³⁵。然而，在小鼠晶状体中尚未明确观察到膜融合结构¹³⁶^,¹³⁷^,¹³⁸，且对多种物种晶状体进行的阻抗研究也未检测到膜融合的存在¹³⁹^,¹⁴⁰^,¹⁴¹^,¹⁴²。来自间隙连接通讯受损的小鼠模型的数据表明，细胞间通讯和纤维细胞的伸长也参与了大分子运输通路的形成¹⁴³。

晶状体蛋白的分子量约为 20–30 kDa，在晶状体中具有结构和折射功能。α-晶状体蛋白由 αA 和 αB 两个亚基组成，二者具有 55%–60% 的同源性¹⁴⁴^,¹⁴⁵^,¹⁴⁶。尽管 αB 在大多数细胞中广泛表达，αA-晶状体蛋白则主要在晶状体中表达，并已在脾脏和胸腺等其他组织中以低水平被检测到¹⁴⁷^,¹⁴⁸。最近的研究还表明，视网膜色素上皮细胞和视网膜神经节细胞在应激或疾病状态下可表达 αA-晶状体蛋白，推测其具有神经保护作用¹⁴⁹^,¹⁵⁰^,¹⁵¹。α-晶状体蛋白通常组装成包含 30–35 个混合 αA 和 αB 亚基的大型异源多聚体¹²³。在小鼠、牛和人晶状体上皮中，前部细胞仅检测到 αB，赤道部细胞中 αA 与 αB 的比例为 1:3；而在次级纤维细胞分化和伸长过程中，该比例转变为 3:1¹²³^,¹⁵²^,¹⁵³。α-晶状体蛋白属于小分子热休克蛋白家族，具有类似分子伴侣的功能¹⁵⁴，能够结合并隔离异常或未折叠的蛋白质，防止进一步的蛋白质聚集。如先前综述所述，小分子 α-晶状体蛋白肽段已被探索用于预防由蛋白质聚集引起的疾病，包括白内障¹⁵⁵。然而，在小鼠模型中，α-晶状体蛋白的分子伴侣样活性增强或减弱均会导致白内障严重程度增加，表明适当的分子伴侣样活性对维持晶状体透明至关重要¹⁵⁶。β-和 γ-晶状体蛋白属于其特有的 β/γ-晶状体蛋白家族，且为纤维细胞特异性表达；在哺乳动物中，β-晶状体蛋白有 7 种异构体，以二聚体、四聚体或更高阶的寡聚体形式存在，而 γ-晶状体蛋白也有 7 种异构体，均为单体形式，如先前综述所述¹²⁵。除了结构功能外，β 和 γ-晶状体蛋白还能结合钙离子，调节晶状体纤维中的钙离子可用性与储备¹⁵⁷^,¹⁵⁸^,¹⁵⁹^,¹⁶⁰^,¹⁶¹。

晶状体细胞骨架与膜蛋白

晶状体上皮细胞和纤维细胞中含有F-actin、角蛋白或波形蛋白中间丝、特化的串珠状中间丝以及微管构成的细胞骨架网络，如先前综述所述¹⁶²^,¹⁶³^,¹⁶⁴^,¹⁶⁵^,¹⁶⁶。除了在眼和晶状体发育过程中发挥功能³¹^,³²^,³³^,³⁴外，晶状体上皮细胞和纤维细胞中多样的F-actin网络对维持晶状体透明性也具有重要作用¹⁶⁷^,¹⁶⁸^,¹⁶⁹^,¹⁷⁰^,¹⁷¹^,¹⁷²。近期研究表明，F-actin网络的改变会影响晶状体的生物力学特性¹⁷³^,¹⁷⁴^,¹⁷⁵^,¹⁷⁶。由波形蛋白或角蛋白组成的中间丝分别仅存在于晶状体纤维细胞分化的早期阶段或胚胎发育期间¹⁷⁷^,¹⁷⁸^,¹⁷⁹^,¹⁸⁰^,¹⁸¹；相比之下，所有晶状体纤维细胞均含有由filensin（又称CP95/CP115，由Bsfp1编码）和CP49（又称phakinin，由Bsfp2编码）组成的异源二聚体构成的串珠状中间丝¹⁸²^,¹⁸³^,¹⁸⁴。这些异源二聚体呈现串珠状外观，是由于CP49和filensin形成的寡聚体装饰在纤维核心上¹⁸⁵^,¹⁸⁶，以及α-晶状体蛋白结合于这些特化的中间丝上所致¹⁸⁷^,¹⁸⁸^,¹⁸⁹^,¹⁹⁰^,¹⁹¹。filensin或CP49任一蛋白的缺失均会导致该网络完全丧失¹⁹²^,¹⁹³^,¹⁹⁴^,¹⁹⁵。波形蛋白中间丝或串珠状中间丝的破坏可在人类和动物模型中引发白内障¹⁹²^,¹⁹³^,¹⁹⁶^,¹⁹⁷^,¹⁹⁸^,¹⁹⁹^,²⁰⁰^,²⁰¹^,²⁰²^,²⁰³^,²⁰⁴，表明这些细胞骨架网络对晶状体透明性至关重要。近期研究提示，微管在晶状体纤维细胞的伸长²⁰⁵^,²⁰⁶以及无细胞器区域的形成过程中发挥重要作用¹⁷⁷。

与肌动蛋白细胞骨架相互作用的黏附连接对晶状体形成²⁰⁷和晶状体纤维细胞分化具有重要意义。E-钙黏蛋白和N-钙黏蛋白均在晶状体上皮细胞中表达²⁰⁸^,²⁰⁹^,²¹⁰^,²¹¹，其中E-钙黏蛋白在纤维细胞分化起始时被关闭²¹²。N-钙黏蛋白在晶状体纤维细胞中高表达，并富集于伸长中纤维细胞基底六角形足部的中点处⁸^,²⁰⁹。在初级纤维细胞形成后若缺失N-钙黏蛋白，会导致次级纤维细胞伸长受阻，其原因是分化中纤维细胞的顶端在前部上皮细胞顶面迁移异常²¹³。晶状体中Eph-ephrin双向信号传导的破坏可导致黏附连接出现缺陷⁴^,⁷^,²¹⁴^,²¹⁵^,²¹⁶。

其他主要的晶状体膜蛋白包括水通道蛋白（aquaporins）；连接蛋白（connexins）；MP20（如先前综述所述²¹⁷）；半乳糖凝集素3（galectin 3）；半乳糖凝集素相关纤维间蛋白（galectin-related interfiber protein, GRIFIN）；整合素（integrins）（如先前综述所述²¹⁸）；以及富含半胱氨酸的酸性分泌蛋白（secreted protein acidic and rich in cysteine, SPARC）。水通道蛋白和连接蛋白将在下一节中讨论。MP20（又称MP17或Lim2）是一种晶状体特异性的膜蛋白，具有细胞间黏附功能⁸⁵^,²¹⁹，在晶状体纤维细胞中含量丰富²²⁰^,²²¹；MP20的突变可导致白内障²²²^,²²³^,²²⁴^,²²⁵^,²²⁶^,²²⁷^,²²⁸^,²²⁹^,²³⁰。近期研究发现MP20与另一种重要的细胞间黏附分子——半乳糖凝集素3之间存在相互作用²³¹^,²³²^,²³³。GRIFIN是半乳糖凝集素的一种晶状体特异性异构体，定位于纤维细胞膜，并与Pax6、晶状体蛋白（crystallins）和钙黏蛋白（cadherins）相互作用²³⁴^,²³⁵^,²³⁶^,²³⁷。整合素是连接细胞外基质（extracellular matrix, ECM）与细胞骨架的重要连接分子，对晶状体正常发育至关重要。在晶状体中表达的整合素异构体可作为晶状体囊膜组分（如层粘连蛋白、胶原蛋白或纤连蛋白）的受体⁸^,²³⁸^,²³⁹^,²⁴⁰^,²⁴¹^,²⁴²^,²⁴³^,²⁴⁴^,²⁴⁵。每种基质成分均可与多种整合素相互作用，通过整合素在晶状体发育和生长过程中的时空表达，引发多样化的信号传导²¹⁸。目前特别关注白内障手术后残余晶状体上皮细胞发生上皮-间质转化过程中TGFβ、整合素及ECM组分的变化，这些变化可导致后囊膜混浊，相关机制已在先前综述中描述²¹⁸。SPARC是一种参与细胞间黏附和增殖的分子，定位于晶状体上皮细胞，在分化中的纤维细胞中则不表达²⁴⁶。SPARC缺失可导致白内障²⁴⁶^,²⁴⁷^,²⁴⁸，近期研究表明SPARC可能具有类似分子伴侣的功能²⁴⁹，可影响整合素和ECM蛋白的表达²⁵⁰^,²⁵¹^,²⁵²，并参与调控微循环通路²⁵³。

无血管组织的微循环通路

由于缺乏血液供应，完全形成的晶状体可自主生成微循环通路以输送营养物质并清除代谢废物，如先前综述所述²⁵⁴^,²⁵⁵^,²⁵⁶^,²⁵⁷。离子电流从晶状体的前极和后极进入，并在赤道区流出²⁵⁸。内向电流依赖于钠离子沿浓度梯度从两极的晶状体细胞间细胞外间隙流入，该浓度梯度由主动运输建立；而外向电流则通过集中在晶状体赤道区附近的纤维细胞膜上的缝隙连接通道介导，使钠离子可在赤道区排出²⁵⁹。赤道部上皮细胞和周边纤维细胞高表达Na⁺/K⁺ ATP酶泵，主动将3个钠离子泵出细胞，同时将2个钾离子从晶状体外环境泵入细胞内²⁶⁰^,²⁶¹^,²⁶²。晶状体维持高钾浓度（135 mM）和低钠浓度（16 mM），从而建立钠离子在两极沿浓度梯度重新进入晶状体的条件²⁵⁹^,²⁶³。除了Na⁺/K⁺ ATP酶外，离子共转运体Na-K-2Cl共转运体1（NKCC1）也通过机械敏感通道的激活参与调节晶状体内的离子浓度，如先前综述所述²⁶⁴。

晶状体中的间隙连接由三种连接蛋白组成，分别为连接蛋白43（Cx43或α1）、Cx46（或α3）和Cx50（或α8）²⁶⁵^,²⁶⁶。Cx43主要在晶状体上皮细胞中表达²⁶⁷；尽管在Cx43基因敲除（KO）晶状体中纤维细胞的形成起始正常，但上皮细胞与纤维细胞之间的界面出现扩大的细胞外间隙和细胞内空泡，提示Cx43在渗透平衡中具有功能作用²⁶⁸。Cx46主要集中于晶状体纤维细胞，而Cx50则在上皮细胞和纤维细胞中均有表达²⁶⁹。Cx23也在小鼠晶状体的纤维细胞中表达，但在人晶状体中不表达²⁷⁰^,²⁷¹^,²⁷²^,²⁷³。Cx23的显性突变会导致小鼠纤维细胞缺陷²⁷⁰，但Cx23基因敲除晶状体未表现出明显异常²⁷⁴。六个连接蛋白亚基组成一个连接子（connexon）或半通道，一个细胞上的连接子与相邻细胞上的连接子对接形成间隙连接，从而在相邻细胞之间形成约10埃的孔道，允许小分子、离子和水的交换²⁷⁵^,²⁷⁶。连接蛋白半通道介导细胞内胞质与细胞外环境之间的物质转运，如先前综述所述²⁷⁷^,²⁷⁸，半通道在微循环²⁷⁹、机械敏感性营养物质和抗氧化剂的转运²⁸⁰^,²⁸¹^,²⁸²^,²⁸³以及氧化应激反应中具有重要作用²⁸⁴^,²⁸⁵^,²⁸⁶^,²⁸⁷^,²⁸⁸。间隙连接在纤维细胞膜上聚集形成较大的斑块；在晶状体中，这些斑块直径可达微米级，并沿相邻纤维细胞的长边排列²⁸⁹。在小鼠晶状体中缺失Cx46会导致致密的核性白内障，原因是晶状体微循环的流出通路受阻²⁹⁰^,²⁹¹。纤维细胞膜上大型Cx46斑块的组装和/或稳定性依赖于F-肌动蛋白和串珠状中间纤维网络²⁸⁹。Cx50基因敲除会导致小眼球、轻度核性白内障以及因上皮细胞增殖异常而导致的晶状体体积减小²⁹²^,²⁹³。缺失Cx50会影响晶状体纤维细胞中残余Cx46间隙连接斑块的门控功能¹³⁹。在内源性Cx50位点通过基因敲入表达4个拷贝的Cx46以替代Cx50，可挽救因Cx50缺失引起的白内障，并增强纤维细胞间的间隙连接耦合，但这些透明的基因敲入晶状体仍保持较小体积¹⁴²^,²⁹⁴。因此，Cx46无法替代Cx50在晶状体生长中的功能。该基因敲入策略也被用于挽救由γB-晶状体蛋白突变体引起的核性白内障，表明增强间隙连接耦合可能是改善晶状体稳态和预防白内障的一种策略²⁹⁵。

钠离子产生的离子流伴随水通过水通道蛋白通道流入晶状体细胞²⁵⁹。水通道蛋白在上皮细胞中由Aqp1组成，而在晶状体纤维细胞中则由Aqp0（又称MIP）和Aqp5构成水通道，其组成取决于细胞的成熟程度，如先前综述所述²⁶⁴^,²⁹⁶^,²⁹⁷。水通过间隙连接通道的移动在晶状体内形成静水压梯度²⁹⁸^,²⁹⁹，该梯度通过瞬时受体电位香草酸亚型1（TRPV1）和TRPV4机械敏感通道得以维持，这两种通道分别升高和降低晶状体的静水压²⁹⁹^,³⁰⁰^,³⁰¹^,³⁰²。晶状体上悬韧带张力降低会减少静水压，从而激活TRPV1，并继而激活NKCC1，增加晶状体内离子浓度，驱动水流入晶状体以恢复正常的静水压³⁰⁰^,³⁰¹。相反，悬韧带张力和晶状体体积增加会激活TRPV4，并继而激活Na⁺/K⁺ ATP酶，降低晶状体内离子浓度，从而降低静水压³⁰⁰^,³⁰¹^,³⁰²。

必需营养物质和氨基酸通过微循环通路被运输到晶状体中³⁰³，这种运输对OFZ纤维尤为重要。晶状体上皮细胞和纤维细胞中存在易化型葡萄糖转运蛋白（GLUT）；GLUT1在两种细胞类型中均有表达，而GLUT3仅在上皮细胞中表达³⁰⁴^,³⁰⁵^,³⁰⁶^,³⁰⁷。GLUT1基因敲除小鼠会发展为白内障，表明葡萄糖摄取对维持晶状体透明性至关重要³⁰⁸。谷胱甘肽（GSH）是维持晶状体透明性的重要抗氧化剂³⁰⁹^,³¹⁰，其在晶状体内合成，并可从房水中转运进入晶状体³¹¹^,³¹²^,³¹³^,³¹⁴^,³¹⁵。半胱氨酸、谷氨酸和甘氨酸是合成GSH所需的必需氨基酸，这些氨基酸在晶状体皮质和核区均有富集³¹⁴^,³¹⁵。随着年龄增长，GSH合成减少或消耗增加，可导致晶状体中特别是核区GSH含量下降³¹⁶^,³¹⁷^,³¹⁸^,³¹⁹^,³²⁰^,³²¹。谷胱甘肽过氧化物酶（GPX）以GSH作为辅酶来中和氢过氧化物，近期研究表明，由于GPX4功能受损导致毒性脂质过氧化物引发的铁死亡可导致白内障³²²^,³²³。

3D 晶状体结构与生物力学

晶状体纤维排列成有序的六边形细胞行，起源于赤道部上皮细胞排列成子午线行（图1A）。促使随机排列、鹅卵石状的赤道部上皮细胞组织为六边形子午线行细胞的机制，主要围绕肌动蛋白细胞骨架展开。受体酪氨酸激酶EphA2的信号传导可促进六边形子午线行细胞顶点处F-肌动蛋白的聚集，从而推动细胞有序排列⁷^,³²⁴。肌球蛋白IIA是一种可与F-肌动蛋白结合的收缩蛋白，对维持六边形细胞形态也具有重要作用⁸^,³²⁵^,³²⁶。长期以来，人们认为纤维细胞高度有序的排列是晶状体透明所必需的；然而，EphA2缺失导致的排列紊乱⁷^,³²⁴、肌球蛋白IIA突变³²⁵^,³²⁶，或老年时期形成的畸形细胞¹³⁰等现象提示，六边形细胞排列并非透明所必需。

从晶状体前极延伸至后极的纤维细胞，其长度可达数毫米，具体取决于动物种类及晶状体大小³²⁷。通常，纤维细胞的横截面仅为 4–7 µm³²⁷，这些细长的细胞通过动态的细胞间交错结构相互连接，在相邻纤维细胞之间形成一种三维拉链样结构，如先前综述所述³²⁸。晶状体纤维细胞的交错结构具有复杂的形态模式，并随着细胞的分化和成熟过程而发生改变：1）周边新形成的纤维细胞，其短边具有较小的突起，长边则具有球窝状突起；2）正在经历细胞器丢失的成熟纤维细胞，其短边具有较大的桨状结构及小型互锁突起；3）核周纤维细胞，其短边具有大型互锁突起，整个膜表面呈现舌与沟样交错结构；4）核区纤维细胞，其短边具有大型突起，整个膜表面呈现球状膜形态¹³⁷^,³²⁸^,³²⁹^,³³⁰^,³³¹^,³³²^,³³³^,³³⁴^,³³⁵^,³³⁶^,³³⁷^,³³⁸^,³³⁹（图1B）。近期研究提供了直接证据，表明依赖F-actin网络的晶状体纤维细胞间交错结构对组织刚度具有重要作用¹⁷⁴，支持了一个长期存在的假说。ARVCF（黏附连接的一个组分）的缺失会导致纤维细胞交错结构异常、细胞外间隙扩大以及早发性皮质性白内障³⁴⁰。晶状体核的刚度和大小缺陷与舌与沟样交错结构的变化以及向球状膜形态转变的延迟相关¹³¹。

系统发育树图解，进化关系，比较分析。
图 3：晶状体缝合线的模式形成。 每条彩色线条代表一个单一的纤维细胞。（A） 胚胎期人晶状体中的纤维细胞形成 Y 形缝合线。Y 形缝合线在前极和后极呈镜像对称。（B） 随着人晶状体的持续发育和生长，缝合线将变得更加分支。此处为简化起见，展示了一个四分支的缝合线模式。两个极之间的缝合线模式存在偏移。示意图未按比例绘制。改编自⁴⁵。请点击此处查看此图的放大版本。

晶状体的整体形状因物种而异，纤维细胞的曲率和缝合类型被认为决定了晶状体的形状³⁴¹^,³⁴²。缝合结构由前极和后极处伸长的纤维细胞尖端相遇形成，并且两个极的缝合呈镜像对称¹¹^,¹²^,¹³^,³⁴³（图3）。小鼠晶状体的缝合呈Y形，而灵长类和人类晶状体的缝合起初为Y形，随着年龄增长逐渐变得更加分支化¹¹^,¹²^,⁴⁵。有趣的是，小鼠晶状体中的Y形缝合在机械负荷移除后限制了晶状体的弹性或回弹能力，而在Eph-ephrin信号通路受损的基因敲除（KO）晶状体中，分支状缝合与增强的回弹性相关³⁴⁴。晶状体缝合的正常形成需要间隙连接通讯³⁴⁵，小鼠晶状体中与年龄相关的前极白内障是由于缝合形成不完全所致¹³⁰。

晶状体的生物力学特性可受到多种分子、细胞和组织因素的影响，如先前的综述所述¹⁶。与年龄相关的晶状体硬度增加被认为是老视的主要成因之一³⁴⁶。在人类中，当注视远处物体时，睫状肌松弛，使附着在晶状体囊上的悬韧带纤维被拉伸，从而导致晶状体变扁平¹。当聚焦近处物体时，睫状肌收缩，使悬韧带松弛，晶状体随之变凸，以聚焦来自近处物体的光线¹。这一调节过程依赖于晶状体的生物力学特性、睫状肌的收缩以及悬韧带的张力。随着年龄增长，研究表明睫状肌的收缩能力以及悬韧带的柔韧性和张力几乎没有或没有明显变化³⁴⁷^,³⁴⁸^,³⁴⁹^,³⁵⁰。多项研究提示，晶状体整体尺寸、晶状体核尺寸的增大及其硬度的增加，共同导致了晶状体随年龄增长而整体硬化²⁶^,³⁵¹^,³⁵²^,³⁵³^,³⁵⁴。然而，在小鼠中对晶状体硬度随年龄变化的研究表明，晶状体和晶状体核的尺寸与整体晶状体硬度之间相关性较弱¹³⁰^,¹³²，提示其他因素在年龄相关的晶状体硬化中起重要作用。最近的研究表明，细胞骨架网络的变化会影响晶状体硬度；Tropomyosin 3.5（一种F-肌动蛋白稳定蛋白）的缺失会影响晶状体纤维细胞膜上F-肌动蛋白网络的组成和排列，并降低晶状体硬度¹⁷³。类似地，多个近交系野生型小鼠品系中的自发突变可导致CP49的自发敲除¹⁹²^,³⁵⁵，并产生更柔软的晶状体³⁵⁶^,³⁵⁷。晶状体纤维细胞膜具有异常高的胆固醇含量³⁵⁸^,³⁵⁹^,³⁶⁰^,³⁶¹^,³⁶²^,³⁶³，这可能调节膜的弹性³⁶⁴。随着年龄增长，膜胆固醇含量的变化以及α-晶状体蛋白与纤维细胞膜的结合，被认为会增加晶状体硬度³⁶⁵^,³⁶⁶^,³⁶⁷^,³⁶⁸^,³⁶⁹^,³⁷⁰^,³⁷¹^,³⁷²。

晶状体研究的挑战与新方法

晶状体的三维结构为理解细胞间的排列方式以及构建合适的模型带来了挑战体外能够重现组织结构的模型。尽管利用永生化细胞或原代培养细胞已揭示了有关信号传导和突变蛋白定位的宝贵信息，但分离的晶状体上皮细胞并不具备天然晶状体上皮细胞特有的立方柱状形态，也不具有相同的基因表达或细胞骨架结构³⁷³. 体外如先前综述所述的晶状体样体³⁷⁴ 和透镜阵列模型³⁷⁵ 分别形成类似纤维细胞的结构和类似微型晶状体的细胞团。这些模型可产生透明的、类似晶状体的结构，可用于快速药物筛选，但均无法重现晶状体纤维细胞的正常排列或晶状体的三维结构。已有多种实验方案用于在晶状体组织切片中进行蛋白质定位和免疫染色，该方法仍是了解蛋白质是否在特定细胞区室中表达的最有效手段。然而，由于晶状体固定不完全，对组织进行组织学切片和免疫染色在操作上可能较为困难，尤其是在来自年长哺乳动物的样本中。¹³⁷；在二维切片中研究三维结构会丢失对理解细胞形态、细胞间相互作用以及蛋白质定位至关重要的细节。尽管电子显微镜（EM）仍是研究纤维细胞形态的金标准，但在EM样品中进行蛋白质定位仍具有挑战性³⁷⁶^,³⁷⁷^,³⁷⁸. 上皮细胞单层扁平铺片的近期研究⁴^,⁷^,³²⁴^,³⁷³单纤维细胞染色⁸⁵^,¹⁷³^,¹⁷⁴^,³⁷⁹以及全晶状体成像⁴^,⁷^,³²⁴^,³⁴⁴^,³⁸⁰^,³⁸¹ 揭示了有关晶状体纤维中细胞间黏附、晶状体生物力学以及细胞骨架网络动态变化的重要信息。

晶状体上皮细胞与纤维细胞具有不同的功能、转录组和蛋白质组，以往在比较不同细胞区室时存在困难，原因是覆盖晶状体前半球的上皮细胞仅为单层结构，若不合并大量样本，难以获取足够的RNA或蛋白质。随着RNA提取技术、实时PCR以及自动化毛细管电泳Western blot技术的进步，现已能够对从小鼠一对眼球中分离的晶状体上皮细胞样本进行基因和蛋白质分析¹³⁰^,¹³²^,³⁷³^,³⁸² 晶状体上皮、皮质纤维和核纤维的显微解剖区域³⁸³单细胞转录组学可对斑马鱼胚胎与幼虫以及鸡胚胎的晶状体细胞进行深入分析³⁸⁴^,³⁸⁵这些新方法为揭示在正常衰老及病理状态下维持晶状体各细胞区室的分子机制提供了可能。

随着该领域的进展，需要牢记小鼠的遗传背景可能在晶状体病理学³⁸⁶^,³⁸⁷和生物力学³⁵⁵^,³⁵⁶^,³⁵⁷中发挥重要作用，因此实验中使用同窝出生的对照小鼠对于数据分析至关重要。突变型和基因敲除（KO）小鼠模型为研究年龄相关性白内障以及晶状体硬度增加提供了系统支持¹³⁰^,³⁵⁶^,³⁵⁷^,³⁸⁸^,³⁸⁹^,³⁹⁰^,³⁹¹^,³⁹²^,³⁹³^,³⁹⁴^,³⁹⁵^,³⁹⁶^,³⁹⁷，由于小鼠寿命相对较短，衰老相关研究应在老年动物上进行，而不应从年轻动物的数据外推得出结论。

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结论

转录组学、蛋白质组学、成像技术以及生物力学检测技术的进步，加深了我们对晶状体生物学、生理学和病理学的理解。我们对晶状体上皮细胞和纤维细胞不同群体之间差异的认识不断扩展，这对于理解衰老过程中的变化以及蛋白质和细胞长寿的机制具有重要意义。目前，人们越来越关注开发用于预防或延缓白内障和/或老视的药物干预手段，以及白内障手术后天然晶状体再生的可能性。为预防或延缓白内障或老视而向晶状体递送药物时，需要将滴眼液配制成具有特定化学性质，以提高药物通过晶状体囊膜的递送效率，同时必须仔细研究药物在晶状体不同深度的渗透量和蓄积量³⁹⁸^,³⁹⁹^,⁴⁰⁰^,⁴⁰¹^,⁴⁰²。爬行动物中晶状体的再生已取得显著成功，有助于阐明晶状体重生所需的关键信号通路⁴⁰³^,

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披露

作者无任何利益冲突需要披露。

致谢

本工作由美国国立眼科研究所资助（项目编号 R01 EY032056，授予 CC）。作者感谢 Isaiah J. Innis 和 Gryffin M. Flowers 提出的有益意见。

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