The regulation of cystogenesis in a tissue engineered kidney disease system by abnormal matrix interactions.
The regulation of cystogenesis in a tissue engineered kidney disease system by abnormal matrix interactions.
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DOI：
10.1016/j.biomaterials.2012.08.020
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发表时间：
2012-11
期刊：
影响因子：
14
通讯作者：
Kaplan, David L.
中科院分区：
文献类型：
--
作者：
Subramanian, Balajikarthick;Ko, Wei-Che;Yadav, Vikas;DesRochers, Teresa M.;Perrone, Ronald D.;Zhou, Jing;Kaplan, David L.
常染色体显性遗传性多囊肾病（ADPKD）仍然是一个主要的卫生保健问题，影响着全球数百万患者，并且没有具体的治疗方法。本研究采用三维组织工程类疾病系统模拟体外囊性结构，并分析其中细胞外基质（extracellular matrix，ECM）的相互作用。在该系统中，蚕丝支架提供缓慢的降解、生物相容性，并维持3D系统的结构和运输，而ECM分子保留生物信号。使用这种三维组织系统，我们提供了自分泌信号环的证据，涉及异常基质沉积（IV型胶原和层粘连蛋白）及其整合素受体亚基蛋白（整合素-β1）在Pkd 1沉默的mIMCD细胞。此外，我们报告说，异常的囊周ECM之间的相互作用基质分子和整合素亚基蛋白调节疾病系统中的囊肿发生率。分子信号显示Pkd 1敲低后细胞周期蛋白和细胞周期进程异常。重要的是，在Pkd 1沉默细胞中通过整合素-β1的额外敲低（双重沉默）破坏异常基质相互作用逆转了异常并降低了囊肿发生率。总之，这些发现表明，在ADPKD中观察到的异常基质沉积和改变的整合素谱分布在囊肿形成中至关重要，应被视为开发治疗药物的靶点。
Autosomal Dominant Polycystic Kidney Disease (ADPKD) remains a major health care concern affecting several million patients worldwide and for which there is no specific treatment. We have employed a 3D tissue engineered disease-like system to emulate cystic structures in vitro and analyzed the extracellular matrix (ECM) interactions in it. The tissue system was developed by culturing normal or polycystin-1 silenced mouse Inner Medullary Collecting Duct (mIMCD) cells in ECM infused into 3D porous silk protein biomaterial scaffolds. In this system, the silk scaffolds provide slow degradation, biocompatibility, and maintain structure and transport for the 3D system, while the ECM molecules retain biological signaling. Using this 3D tissue system we provide evidence for an autocrine signaling loop involving abnormal matrix deposition (collagen type IV and laminin) and its integrin receptor subunit protein (Integrin-β1) in Pkd1 silenced mIMCD cells. In addition, we report that abnormal pericystic ECM interactions between matrix molecules and integrin subunit proteins regulate the rate of cystogenesis in the disease system. Molecular signaling showed abnormalities in cyclin proteins and cell-cycle progression upon Pkd1 knockdown. Importantly, disruption of the abnormal matrix interactions by an additional knockdown (double-silencing) of integrin-β1 in Pkd1 silenced cells reversed the abnormalities and reduced the rate of cystogenesis. Together, these findings indicate that abnormal matrix deposition and altered integrin profile distribution as observed in ADPKD and are critical in cystogenesis and should be considered a target for the development of therapeutics.
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