Asynchronous mixing of kidney progenitor cells potentiates nephrogenesis in organoids

• Published in: Communications biology 2020-05, Vol.3 (1), p.231-231, Article 231
• Main Authors: Kumar Gupta, Ashwani, Sarkar, Prasenjit, Wertheim, Jason A., Pan, Xinchao, Carroll, Thomas J., Oxburgh, Leif
• Format: Article
• Language: English
• Subjects: 13/1; 13/100; 13/106; 13/107; 14; 14/19; 59; 631/136/2060; 631/443/272; 631/532/1360; 64/60; 692/4022; Biology; Biomedical and Life Sciences; Cell differentiation; Computed tomography; Fetuses; Kidneys; Life Sciences; Organoids; Pluripotency; Progenitor cells; Stem cell transplantation; Stem cells; Stromal cells; Vascularization
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-020-0948-7

A fundamental challenge in emulating kidney tissue formation through directed differentiation of human pluripotent stem cells is that kidney development is iterative, and to reproduce the asynchronous mix of differentiation states found in the fetal kidney we combined cells differentiated at different times in the same organoid. Asynchronous mixing promoted nephrogenesis, and heterochronic organoids were well vascularized when engrafted under the kidney capsule. Micro-CT and injection of a circulating vascular marker demonstrated that engrafted kidney tissue was connected to the systemic circulation by 2 weeks after engraftment. Proximal tubule glucose uptake was confirmed, but despite these promising measures of graft function, overgrowth of stromal cells prevented long-term study. We propose that this is a technical feature of the engraftment procedure rather than a specific shortcoming of the directed differentiation because kidney organoids derived from primary cells and whole embryonic kidneys develop similar stromal overgrowth when engrafted under the kidney capsule. Ashwani Gupta et al. report an improved protocol for kidney organoid differentiation from pluripotent stem cells. The authors simulate the condition of the fetal kidney by mixing cells differentiated at different times from the same organoid, thereby promoting nephrogenesis in vitro and vascularization after engraftment under the kidney capsule in mice.