Graft immaturity and safety concerns in transplanted human kidney organoids.,Experimental & Molecular Medicine

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Graft immaturity and safety concerns in transplanted human kidney organoids.
Experimental & Molecular Medicine ( IF 9.5 ) Pub Date : 2019-11-28 , DOI: 10.1038/s12276-019-0336-x
Sun Ah Nam _{1,

2} , Eunjeong Seo ₁ , Jin Won Kim ₁ , Hyung Wook Kim ₂ , Hong Lim Kim ₃ , Kyuryung Kim _{4,

5} , Tae-Min Kim _{4,

5} , Ji Hyeon Ju ₆ , Ivan G Gomez ₇ , Kohei Uchimura ₈ , Benjamin D Humphreys ₈ , Chul Woo Yang ₂ , Jae Yeon Lee ₉ , Jin Kim ₁ , Dong Woo Cho ₉ , Benjamin S Freedman ₇ , Yong Kyun Kim _{1,

2}

Affiliation

Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Integrative Research Support Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Cancer Research Institute, College of Medicine, The Catholic University of Korea and Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Catholic iPSC Research Center, and Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Division of Nephrology, Kidney Research Institute, and Institute for Stem Cell and Regenerative Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
Division of Nephrology, Department of Medicine, and Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.
Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), Pohang, Kyungbuk, South Korea.

For chronic kidney disease, regeneration of lost nephrons with human kidney organoids derived from induced pluripotent stem (iPS) cells is proposed to be an attractive potential therapeutic option. It remains unclear, however, whether organoids transplanted into kidneys in vivo would be safe or functional. Here, we purified kidney organoids and transplanted them beneath the kidney capsules of immunodeficient mice to test their safety and maturity. Kidney organoid grafts survived for months after transplantation and became vascularized from host mouse endothelial cells. Nephron-like structures in grafts appeared more mature than kidney organoids in vitro, but remained immature compared with the neighboring mouse kidney tissue. Ultrastructural analysis revealed filtration barrier-like structures, capillary lumens, and tubules with brush border in the transplanted kidney organoids, which were more mature than those of the kidney organoids in vitro but not as organized as adult mammalian kidneys. Immaturity was a common feature of three separate differentiation protocols by immunofluorescence analysis and single cell RNA sequencing. Stroma of transplanted kidney organoid grafts were filled with vimentin-positive mesenchymal cells, and chondrogenesis, cystogenesis, and stromal expansion were observed in the long term. Transcription profiles showed that long-term maintenance after kidney organoid transplantation induced transcriptomic reprogramming with prominent suppression of cell-cycle-related genes and upregulation of extracellular matrix organization. Our data suggest that kidney organoids derived from iPS cells may be transplantable but strategies to improve nephron differentiation and purity are required before they can be applied in humans as a therapeutic option.

中文翻译：

移植的人肾类器官中的移植物不成熟和安全问题。

对于慢性肾脏疾病，使用源自诱导多能干 (iPS) 细胞的人类肾脏类器官再生丢失的肾单位被认为是一种有吸引力的潜在治疗选择。然而，目前尚不清楚体内移植到肾脏的类器官是否安全或有效。在这里，我们纯化了肾脏类器官并将它们移植到免疫缺陷小鼠的肾囊下方，以测试它们的安全性和成熟度。肾类器官移植物在移植后存活了几个月，并从宿主小鼠内皮细胞中血管化。移植物中的肾单位样结构在体外似乎比肾类器官更成熟，但与邻近的小鼠肾组织相比仍然不成熟。超微结构分析显示过滤屏障状结构、毛细血管腔、移植的肾类器官中的刷状缘小管比体外的肾类器官更成熟，但不像成年哺乳动物的肾脏那样有组织。通过免疫荧光分析和单细胞 RNA 测序，不成熟是三种不同分化方案的共同特征。移植肾类器官的基质充满波形蛋白阳性间充质细胞，长期观察到软骨形成、囊肿形成和基质扩张。转录谱显示，肾类器官移植后的长期维持诱导转录组重编程，显着抑制细胞周期相关基因和上调细胞外基质组织。

更新日期：2019-11-28

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