Modeling congenital cataract in vitro using patient-specific induced pluripotent stem cells.
Modeling congenital cataract in vitro using patient-specific induced pluripotent stem cells.
复制标题
使用患者特异性诱导多能干细胞体外模拟先天性白内障
DOI：
10.1038/s41536-021-00171-x
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发表时间：
2021-10-01
影响因子：
7.2
通讯作者：
Yao K
中科院分区：
文献类型：
--
作者：
Lyu D;Zhang L;Qin Z;Ni S;Li J;Lu B;Hao S;Tang Q;Yin H;Chen Z;Yan YB;Ji J;He J;Nagy A;Fu Q;Yao K
先天性白内障是儿童失明的主要原因。迄今为止，手术切除白内障是唯一确定的治疗方法，但手术与多种并发症有关，这些并发症往往导致视力障碍。因此，机制研究和候选药物筛选已被开发新的治疗策略的目的所吸引。然而，这些研究由于缺乏合适的先天性白内障人类疾病模型而受到阻碍。在此，我们报告了通过将患者特异性诱导多能干细胞（iPSC）分化为再生晶状体来建立人类先天性白内障体外模型。与源自健康个体的晶状体样体（LB）相比，源自具有先天性白内障的已知致病突变的患者特异性iPSC的再生晶状体（LIBBB2 [p.P24T]和LIBGD [p.Q155X]）显示出明显的混浊，其在混浊严重程度和相应的病程方面与患者白内障中所见的非常相似。在患者特异性LB中观察到与患者白内障严重程度对应的蛋白质聚集增加和蛋白质溶解度降低，并通过羊毛甾醇治疗减弱。总之，本文所述的体外模型概括了先天性白内障的患者特异性临床表现和患者特异性LB中的蛋白质聚集，为研究白内障的病理机制和筛选用于白内障治疗的候选药物提供了稳健的系统。
Congenital cataracts are the leading cause of childhood blindness. To date, surgical removal of cataracts is the only established treatment, but surgery is associated with multiple complications, which often lead to visual impairment. Therefore, mechanistic studies and drug-candidate screening have been intrigued by the aims of developing novel therapeutic strategies. However, these studies have been hampered by a lack of an appropriate human-disease model of congenital cataracts. Herein, we report the establishment of a human congenital cataract in vitro model through differentiation of patient-specific induced pluripotent stem cells (iPSCs) into regenerated lenses. The regenerated lenses derived from patient-specific iPSCs with known causative mutations of congenital cataracts (CRYBB2[p. P24T] andCRYGD[p. Q155X]) showed obvious opacification that closely resembled that seen in patients’ cataracts in terms of opacification severity and disease course accordingly, as compared with lentoid bodies (LBs) derived from healthy individuals. Increased protein aggregation and decreased protein solubility corresponding to the patients’ cataract severity were observed in the patient-specific LBs and were attenuated by lanosterol treatment. Taken together, the in vitro model described herein, which recapitulates patient-specific clinical manifestations of congenital cataracts and protein aggregation in patient-specific LBs, provides a robust system for research on the pathological mechanisms of cataracts and screening of drug candidates for cataract treatment.
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DOI：
10.1242/dev.155838
发表时间：
2018-01-09
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Murphy P;Kabir MH;Srivastava T;Mason ME;Dewi CU;Lim S;Yang A;Djordjevic D;Killingsworth MC;Ho JWK;Harman DG;O'Connor MD
通讯作者：
O'Connor MD
影响因子：
3.7
作者：
Anchan RM;Lachke SA;Gerami-Naini B;Lindsey J;Ng N;Naber C;Nickerson M;Cavallesco R;Rowan S;Eaton JL;Xi Q;Maas RL
通讯作者：
Maas RL
影响因子：
13.7
作者：
Haargaard, B;Wohlfahrt, J;Melbye, M
通讯作者：
Melbye, M
影响因子：
13.6
作者：
Moreau KL;King JA
通讯作者：
King JA
DOI：
10.1126/science.aac9145
发表时间：
2015-11-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Makley LN;McMenimen KA;DeVree BT;Goldman JW;McGlasson BN;Rajagopal P;Dunyak BM;McQuade TJ;Thompson AD;Sunahara R;Klevit RE;Andley UP;Gestwicki JE
通讯作者：
Gestwicki JE