Glucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease.
Glucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease.
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DOI：
10.1038/s41467-022-35537-2
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发表时间：
2022-12-23
影响因子：
16.6
通讯作者：
Freedman, Benjamin S.
中科院分区：
文献类型：
--
作者：
Li, Sienna R.;Gulieva, Ramila E.;Helms, Louisa;Cruz, Nelly M.;Vincent, Thomas;Fu, Hongxia;Himmelfarb, Jonathan;Freedman, Benjamin S.
在多囊肾病(PKD)中，充满液体的囊肿是由肾脏和其他器官的小管形成的。人类肾脏器官类物质可以以一种基因特异性的方式重建PKD的成囊，但成囊的机制仍不清楚。在这里，我们表明，在芯片上的PKD微生理系统中，使有机物质受到流体剪应力通过吸收途径而不是分泌途径促进囊扩张。扩散的静态条件部分取代了流体流动，意味着体积和溶质浓度是这一效应的关键中介。令人惊讶的是，有机物质中的囊壁上皮细胞向外极化，与分泌机制相抵触。相反，囊肿的形成是由葡萄糖向外上皮细胞腔内的葡萄糖运输驱动的，而后者可以被药物阻断。在PKD小鼠中，葡萄糖通过包囊进入肾间质，肾间质脱离小管以允许扩张。因此，吸收可以调节人体器官中PKD包囊的生长，对疾病机制和治疗开发具有潜在的意义。在多囊肾病(PKD)中，充满液体的囊由肾小管形成。在这里，作者表明，在芯片上PKD微生理系统中，使有机物质受到流体剪应力通过吸收途径促进囊泡扩张。
In polycystic kidney disease (PKD), fluid-filled cysts arise from tubules in kidneys and other organs. Human kidney organoids can reconstitute PKD cystogenesis in a genetically specific way, but the mechanisms underlying cystogenesis remain elusive. Here we show that subjecting organoids to fluid shear stress in a PKD-on-a-chip microphysiological system promotes cyst expansion via an absorptive rather than a secretory pathway. A diffusive static condition partially substitutes for fluid flow, implicating volume and solute concentration as key mediators of this effect. Surprisingly, cyst-lining epithelia in organoids polarize outwards towards the media, arguing against a secretory mechanism. Rather, cyst formation is driven by glucose transport into lumens of outwards-facing epithelia, which can be blocked pharmacologically. In PKD mice, glucose is imported through cysts into the renal interstitium, which detaches from tubules to license expansion. Thus, absorption can mediate PKD cyst growth in human organoids, with implications for disease mechanism and potential for therapy development. In polycystic kidney disease (PKD), fluid-filled cysts arise from tubules. Here the authors show that subjecting organoids to fluid shear stress in a PKD-on-a-chip microphysiological system promotes cyst expansion via an absorptive pathway.
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影响因子：
3.7
作者：
Kapoor S;Rodriguez D;Riwanto M;Edenhofer I;Segerer S;Mitchell K;Wüthrich RP
通讯作者：
Wüthrich RP
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
23.9
作者：
Czerniecki SM;Cruz NM;Harder JL;Menon R;Annis J;Otto EA;Gulieva RE;Islas LV;Kim YK;Tran LM;Martins TJ;Pippin JW;Fu H;Kretzler M;Shankland SJ;Himmelfarb J;Moon RT;Paragas N;Freedman BS
通讯作者：
Freedman BS
DOI：
10.1073/pnas.0804954105
发表时间：
2008-08-12
影响因子：
11.1
作者：
Duan, Yi;Gotoh, Nanami;Weinbaum, Sheldon
通讯作者：
Weinbaum, Sheldon
影响因子：
15.9
作者：
Hopp, Katharina;Ward, Christopher J.;Harris, Peter C.
通讯作者：
Harris, Peter C.