Generation of mitochondria-rich kidney organoids from expandable intermediate mesoderm progenitors reprogrammed from human urine cells under defined medium.
Generation of mitochondria-rich kidney organoids from expandable intermediate mesoderm progenitors reprogrammed from human urine cells under defined medium.
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在特定培养基下从人尿细胞重编程的可扩展中间中胚层祖细胞生成富含线粒体的肾类器官
DOI：
10.1186/s13578-022-00909-0
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发表时间：
2022-10-15
影响因子：
7.5
通讯作者：
Hou, Fan Fan
中科院分区：
文献类型：
--
作者：
Yuan, Yapei;Chen, Huan;Ou, Sihua;Cai, Baomei;Zhang, Ruifang;Qin, Yue;Pan, Mengjie;Cao, Shangtao;Pei, Duanqing;Hou, Fan Fan
关键词：
肾脏需要大量的线粒体提供充足的能量来重吸收营养物质，调节电解质、液体和血压的稳态。缺乏的人类模型阻碍了调查线粒体稳态相关的肾脏生理和diseases.ResultsHere，我们报告了通过部分重编程的人尿细胞（hUCs）下的定义medium的生成富含维生素A的肾脏类器官。首先，我们将富含胡萝卜素的hUC重编程为可扩展的中间中胚层祖细胞样细胞（U-iIMPLC），其进而在2D和3D培养物中产生肾单位祖细胞并形成肾类器官。通过RNA和蛋白质水平上的标记物表达以及染色质可及性动态沿着，在每个阶段确认细胞命运转变。单细胞RNA-seq显示hUC诱导的肾类器官（U-iKO）由足细胞、小管和间充质细胞组成，其中2D以间充质为主，3D以小管为主，并富集特异性线粒体功能相关基因。具体的细胞类型，如足细胞和近端小管，亨利环，和远端小管，很容易确定。与这些细胞类型一致，3D类器官表现出肾脏的功能和结构特征，如葡聚糖摄取和透射电子显微镜所示。这些类器官可以在鸡胚绒毛尿囊膜中进一步成熟。最后，顺铂，庆大霉素，和毛喉素治疗导致典型的肾损伤和改变线粒体homeostasis.ConclusionsOur研究表明，U-iKO概括的结构和功能特点的肾脏，提供了一个有前途的模型来研究肾脏相关的生理和疾病的个性化方式。
BackgroundThe kidneys require vast amounts of mitochondria to provide ample energy to reabsorb nutrients and regulate electrolyte, fluid, and blood pressure homeostasis. The lack of the human model hinders the investigation of mitochondria homeostasis related to kidney physiology and disease.ResultsHere, we report the generation of mitochondria-rich kidney organoids via partial reprogramming of human urine cells (hUCs) under the defined medium. First, we reprogrammed mitochondria-rich hUCs into expandable intermediate mesoderm progenitor like cells (U-iIMPLCs), which in turn generated nephron progenitors and formed kidney organoids in both 2D and 3D cultures. Cell fate transitions were confirmed at each stage by marker expressions at the RNA and protein levels, along with chromatin accessibility dynamics. Single cell RNA-seq revealed hUCs-induced kidney organoids (U-iKOs) consist of podocytes, tubules, and mesenchyme cells with 2D dominated with mesenchyme and 3D with tubule and enriched specific mitochondria function associated genes. Specific cell types, such as podocytes and proximal tubules, loop of Henle, and distal tubules, were readily identified. Consistent with these cell types, 3D organoids exhibited the functional and structural features of the kidney, as indicated by dextran uptake and transmission electron microscopy. These organoids can be further matured in the chick chorioallantoic membrane. Finally, cisplatin, gentamicin, and forskolin treatment led to anatomical abnormalities typical of kidney injury and altered mitochondria homeostasis respectively.ConclusionsOur study demonstrates that U-iKOs recapitulate the structural and functional characteristics of the kidneys, providing a promising model to study mitochondria-related kidney physiology and disease in a personalized manner.
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