Engineering of new organs (i.e. artificial organogenesis) from pluripotent stem cells represents the holy grail of modern medicine. The number of organ donors and available transplantable tissue is unmatched by the increased global organ demand. Moreover, novel drugs that are being developed are tested first on animals, while obviously any results yielded from such animal experimentation do not reflect on the possible effects in human subjects. Therefore, many efforts are being invested in growing ex-vivo miniature 3-dimentional organ-like structures of various tissues. The human kidney represent such a complex organ, composed of more than 20 cell types, and is responsible for the versatile mechanisms of pH regulation, as well as fluid and electrolyte balance. Engineering of an artificial kidney in the lab necessitate the control of cellular differentiation pathways into different kidney cells, and their composition into a complex microanatomy. As noted above, this process is increasingly challenging in the kidney, since it contains many cell types (the formation of whom is triggered by several specific signaling proteins), and that are formed in different chronologic phases.
Recently, researchers from the University of Queensland, Australia, and from Leiden University Medical Center, positioned in The Netherlands, were able to overcome some of these obstacles and develop in-vitro small kidney-like structures from induced pleuripotent stem (iPS) cells. The iPS-driven renogenic cells were differentiated into metanephrogenic mesenchyme and ureteric epithelium. Consequently, the engineered orgainoids were found to be composed of nephrons (glumeruli, distal and proximal tubules, early loops of Henle), and collecting duct network, which were surrounded by renal interstitium and endothelial cells (see figure; adopted from doi: 10.1038/nature15695). These kidney orgaonoids were reported to resemble those found in the first trimester during human kidney development. The possible immediate applications are in-vitro study of human kidney diseases, and drug screening for nephrotoxicity (which is expected to be superior to any animal experimentation). Further advancement and up scaling of this robust technology may be translated some day into in-vitro engineering of organs and curing patients with various organ-specific diseases. Minoru Takasato PhD, a senior author of the article, was available to answer some of our questions:
Udi Nussinovitch, Medgadget: How far do you think are we from growing a full scale organs in-vitro, and which challenges are found ahead?
Minoru Takasato: Here we generated kidney organoids with 5-6 mm in size and equivalent to only human foetal kidney. To make kidney organoids capable of transplantation, they will need to grow bigger with enough number of nephron, develop the capillary loop in glomeruli and have the ureter as a way out of urine. As our kidney organoids comprise all anticipated kidney cell type, next challenge is how to grow them up with developing above features. Especially, sufficient nutrients supply to kidney tissues through blood vessels will be one of key factors to grow kidney organoids to human size.
Medgadget: In your opinion, what are the chances for an immune rejection occurring in iPS-driven engineered kidney?
Takasato: The advantage of using induced pluripotent stem cells (iPSCs) for transplantation is no immune rejection because iPSCs are generated from patient’s own skin/blood cells. Indeed, in a previous study of transplanting mouse iPSCs-derived differentiated tissues into mice, immune rejections have not been observed (doi:10.1038/nature11807). Also, recent world first clinical trial of transplanting iPSCs-derived retina cells into an age-related macular degeneration patient has not been reporting any immune rejection happened till now (doi:10.1038/513287a). Based on these previous studies of transplanting iPSCs-derived tissues into mouse or human, the chances of immune rejection of iPS-derived kidney is also expected to be low.
Medgadget: Do you believe that your research system could be used for routine drug-testing?
Takasato: In the study, we tested a nephrotoxicity assay in kidney organoids using cisplatin, an anti-cancer drug, which induces damage to kidney tubules. The result showed tubules in the organoids are susceptible to cislatin induced kidney injury, suggesting that they will be of great use for drug toxicity studies.