A novel human iPSC model of COL4A1/A2 small vessel disease unveils a key pathogenic role of matrix metalloproteinases.
A novel human iPSC model of COL4A1/A2 small vessel disease unveils a key pathogenic role of matrix metalloproteinases.
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DOI：
10.1016/j.stemcr.2023.10.014
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发表时间：
2023-12-12
影响因子：
5.9
通讯作者：
Granata, Alessandra
中科院分区：
文献类型：
--
作者：
Al-Thani, Maha;Goodwin-Trotman, Mary;Bell, Steven;Patel, Krushangi;Fleming, Lauren K.;Vilain, Catheline;Abramowicz, Marc;Allan, Stuart M.;Wang, Tao;Cader, M. Zameel;Horsburgh, Karen;Van Agtmael, Tom;Sinha, Sanjay;Markus, Hugh S.;Granata, Alessandra
脑小血管病（SVD）影响大脑中的小血管，是中风和痴呆的主要原因。新出现的证据支持细胞外基质（ECM）在血液和脑之间的界面处在SVD病理学进展中的作用，但这仍然缺乏表征。为了解决ECM在SVD中的作用，我们使用来自具有COL 4A 1/A2 SVD相关突变的患者的人诱导多能干细胞开发了壁细胞和内皮细胞的共培养模型。该模型揭示了这些突变诱导壁细胞的凋亡、迁移缺陷、ECM重塑和转录组变化。重要的是，这些壁细胞缺陷通过旁分泌作用对内皮细胞紧密连接产生不利影响。COL 4A 1/A2模型还表达高水平的基质金属蛋白酶（MMP），并且抑制MMP活性部分地挽救ECM异常和壁细胞表型变化。这些数据为靶向MMP作为SVD的治疗机会提供了基础。由于胶原IV突变导致的遗传SVD的新型人iPSC衍生模型SVD壁细胞显示ECM异常并导致内皮缺陷ECM和内皮细胞异常可以通过MMP抑制来挽救。本文描述了用于胶原IV突变的新型人iPSC模型的开发，所述胶原IV突变是引起中风和痴呆的小血管疾病的遗传形式。作者使用该模型通过Transwell共培养系统探索血脑屏障异常和壁细胞中细胞外基质的变化，从而导致屏障功能障碍，并确定MMPs作为潜在的治疗方法。
Cerebral small vessel disease (SVD) affects the small vessels in the brain and is a leading cause of stroke and dementia. Emerging evidence supports a role of the extracellular matrix (ECM), at the interface between blood and brain, in the progression of SVD pathology, but this remains poorly characterized. To address ECM role in SVD, we developed a co-culture model of mural and endothelial cells using human induced pluripotent stem cells from patients with COL4A1/A2 SVD-related mutations. This model revealed that these mutations induce apoptosis, migration defects, ECM remodeling, and transcriptome changes in mural cells. Importantly, these mural cell defects exert a detrimental effect on endothelial cell tight junctions through paracrine actions. COL4A1/A2 models also express high levels of matrix metalloproteinases (MMPs), and inhibiting MMP activity partially rescues the ECM abnormalities and mural cell phenotypic changes. These data provide a basis for targeting MMP as a therapeutic opportunity in SVD. A novel human iPSC-derived model of genetic SVD due to collagen IV mutations SVD mural cells show ECM abnormalities and contribute to endothelial defects ECM and endothelial cells abnormalities can be rescued by MMP inhibition This paper describes the development of a novel human iPSC model for collagen IV mutations, which are a hereditary form of small vessel disease causing stroke and dementia. The authors use this model to explore blood-brain-barrier abnormalities by Transwell co-culture system and extracellular matrix changes in the mural cells, contributing to barrier dysfunction, and identify MMPs as potential therapeutic approach.
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血脑屏障破坏：正常衰老和痴呆中认知障碍的新兴生物标志物。
影响因子：
4.3
作者：
Hussain B;Fang C;Chang J
通讯作者：
Chang J
影响因子：
8.3
作者：
Candelario-Jalil E;Thompson J;Taheri S;Grossetete M;Adair JC;Edmonds E;Prestopnik J;Wills J;Rosenberg GA
通讯作者：
Rosenberg GA
DOI：
10.1073/pnas.2016950118
发表时间：
2021-02-23
影响因子：
11.1
作者：
Lu TM;Houghton S;Magdeldin T;Durán JGB;Minotti AP;Snead A;Sproul A;Nguyen DT;Xiang J;Fine HA;Rosenwaks Z;Studer L;Rafii S;Agalliu D;Redmond D;Lis R
通讯作者：
Lis R
影响因子：
30.8
作者：
Malik R;Chauhan G;Traylor M;Sargurupremraj M;Okada Y;Mishra A;Rutten-Jacobs L;Giese AK;van der Laan SW;Gretarsdottir S;Anderson CD;Chong M;Adams HHH;Ago T;Almgren P;Amouyel P;Ay H;Bartz TM;Benavente OR;Bevan S;Boncoraglio GB;Brown RD Jr;Butterworth AS;Carrera C;Carty CL;Chasman DI;Chen WM;Cole JW;Correa A;Cotlarciuc I;Cruchaga C;Danesh J;de Bakker PIW;DeStefano AL;den Hoed M;Duan Q;Engelter ST;Falcone GJ;Gottesman RF;Grewal RP;Gudnason V;Gustafsson S;Haessler J;Harris TB;Hassan A;Havulinna AS;Heckbert SR;Holliday EG;Howard G;Hsu FC;Hyacinth HI;Ikram MA;Ingelsson E;Irvin MR;Jian X;Jiménez-Conde J;Johnson JA;Jukema JW;Kanai M;Keene KL;Kissela BM;Kleindorfer DO;Kooperberg C;Kubo M;Lange LA;Langefeld CD;Langenberg C;Launer LJ;Lee JM;Lemmens R;Leys D;Lewis CM;Lin WY;Lindgren AG;Lorentzen E;Magnusson PK;Maguire J;Manichaikul A;McArdle PF;Meschia JF;Mitchell BD;Mosley TH;Nalls MA;Ninomiya T;O'Donnell MJ;Psaty BM;Pulit SL;Rannikmäe K;Reiner AP;Rexrode KM;Rice K;Rich SS;Ridker PM;Rost NS;Rothwell PM;Rotter JI;Rundek T;Sacco RL;Sakaue S;Sale MM;Salomaa V;Sapkota BR;Schmidt R;Schmidt CO;Schminke U;Sharma P;Slowik A;Sudlow CLM;Tanislav C;Tatlisumak T;Taylor KD;Thijs VNS;Thorleifsson G;Thorsteinsdottir U;Tiedt S;Trompet S;Tzourio C;van Duijn CM;Walters M;Wareham NJ;Wassertheil-Smoller S;Wilson JG;Wiggins KL;Yang Q;Yusuf S;AFGen Consortium;Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium;International Genomics of Blood Pressure (iGEN-BP) Consortium;INVENT Consortium;STARNET;Bis JC;Pastinen T;Ruusalepp A;Schadt EE;Koplev S;Björkegren JLM;Codoni V;Civelek M;Smith NL;Trégouët DA;Christophersen IE;Roselli C;Lubitz SA;Ellinor PT;Tai ES;Kooner JS;Kato N;He J;van der Harst P;Elliott P;Chambers JC;Takeuchi F;Johnson AD;BioBank Japan Cooperative Hospital Group;COMPASS Consortium;EPIC-CVD Consortium;EPIC-InterAct Consortium;International Stroke Genetics Consortium (ISGC);METASTROKE Consortium;Neurology Working Group of the CHARGE Consortium;NINDS Stroke Genetics Network (SiGN);UK Young Lacunar DNA Study;MEGASTROKE Consortium;Sanghera DK;Melander O;Jern C;Strbian D;Fernandez-Cadenas I;Longstreth WT Jr;Rolfs A;Hata J;Woo D;Rosand J;Pare G;Hopewell JC;Saleheen D;Stefansson K;Worrall BB;Kittner SJ;Seshadri S;Fornage M;Markus HS;Howson JMM;Kamatani Y;Debette S;Dichgans M
通讯作者：
Dichgans M
影响因子：
7.8
作者：
Nitta, T;Hata, M;Tsukita, S
通讯作者：
Tsukita, S