Graft immaturity and safety concerns in transplanted human kidney organoids

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. The safety and effectiveness of treating kidney disease by transplanting cultured clumps of kidney structures grown from stem cells and known as organoids need further investigation. Sun Ah Nam at The Catholic University of Korea in Seoul, with colleagues elsewhere in South Korea and the USA investigated the potential of the procedure by transplanting organoids made from human stem cells into mice. The animals were immunodeficient, thus avoiding rejection problems. The grafts generated resembled the blood-filtering structures of the kidney called nephrons, but remained insufficiently developed. Analyzing gene activity also suggested that the organoids were not adequately differentiating into the cells needed to treat disease effectively. The researchers conclude that methods to improve development and maturity of the organoids are required before organoid transplantation becomes a safe and viable treatment option in humans.