Collagen Crosslinking for Keratoconus: Cellular Signaling Mechanisms.
Collagen Crosslinking for Keratoconus: Cellular Signaling Mechanisms.
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DOI：
10.3390/biom13040696
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发表时间：
2023-04-20
期刊：
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
胶原蛋白交联(CXL)是一种广泛使用的治疗方法，用于阻止圆锥角膜(KC)的进展。不幸的是，相当数量的进展性KC患者将不符合CXL的条件，包括那些角膜厚度小于400微米的患者。本研究旨在通过体外模型研究CXL的分子效应，模拟正常的KC以及KC中可见的较薄的角膜基质。原代培养的人角膜基质细胞来自健康供者(HCFS)和圆锥角膜供者(HKCs)。培养细胞，并用稳定的维生素C刺激，形成3D自组装细胞外基质(ECM)，细胞包埋，构建。对(A)薄ECM加CXL组和(B)正常ECM加CXL组在第4周进行CXL治疗，未加CXL组作为对照。所有构建物都被处理以进行蛋白质分析。结果表明，用Wnt7b和Wnt10a的蛋白水平来衡量，CXL对Wnt信号的调节与α-平滑肌肌动蛋白的表达有关。此外，最近发现的KC候选生物标志物催乳素诱导蛋白(PIP)在HKCs中的表达受到CXL的积极影响。研究还发现，CXL诱导的PGC-1表达上调，SRC和Cyclin D1下调。尽管对CXL的细胞/分子影响研究还很少，但我们的研究为KC和CXL的复杂机制提供了一个近似值。有必要进行进一步的研究以确定影响CXL预后的因素。
Collagen crosslinking (CXL) is a widely used treatment to halt the progression of keratoconus (KC). Unfortunately, a significant number of patients with progressive KC will not qualify for CXL, including those with corneas thinner than 400 µm. The present study aimed to investigate the molecular effects of CXL using in vitro models, mirroring the normal, as well as thinner corneal stroma seen in KCs. Primary human corneal stromal cells were isolated from healthy (HCFs) and keratoconus (HKCs) donors. Cells were cultured and stimulated with stable Vitamin C resulting in 3D self-assembled extracellular matrix (ECM), cell-embedded, constructs. CXL was performed on (a) thin ECM with CXL performed at week 2 and (b) normal ECM with CXL performed at week 4. Constructs without CXL served as controls. All constructs were processed for protein analysis. The results showed modulation of Wnt signaling, following CXL treatment, as measured by the protein levels of Wnt7b and Wnt10a, correlated to the expression of α-smooth muscle actin (SMA). Further, the expression of a recently identified KC biomarker candidate, prolactin-induced protein (PIP), was positively impacted by CXL in HKCs. CXL-driven upregulation of PGC-1 and the downregulation of SRC and Cyclin D1 in HKCs were also noted. Although the cellular/molecular impacts of CXL are largely understudied, our studies provide an approximation to the complex mechanisms of KC and CXL. Further studies are warranted to determine factors influencing CXL outcomes.
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