Patients with kidney failure can generally only be treated with kidney replacement therapies, such as transplantation or dialysis. Now, Benjamin Dekel and colleagues report that, in mice, 3D-cultured kidney human cell grafts might encourage tissue regeneration.
“Our previous work suggested that the adult kidney constantly renews itself via lineage-restricted clonal cell proliferation,” notes Dekel. “We showed that 3D cultures of adult human kidney cells have tissue-regenerative capacity and might be used for kidney regeneration and cellular therapy.”
The researchers established 3D spheres (nephrospheres; nSPHs) derived from 2D cultures of human adult kidney epithelial cells obtained from either healthy or diseased kidneys. Transcriptomic analysis revealed that, whereas cells from the initial 2D culture were enriched for genes associated with epithelial–mesenchymal transition and cell cycle, nSPH cells initially expressed genes involved in early kidney development, followed by a mesenchymal–epithelial transition gene profile as they began to differentiate into kidney epithelial cells.
The researchers then transplanted nSPHs into immunodeficient mice. “Human nSPHs restored self-organogenetic properties that were lost in 2D cultures; long-term engraftment depended on the ability of nSPHs to establish tubular structures and renal parenchyma, which enabled prolonged donor–host interactions,” explains Dekel. In mouse models of chronic kidney disease, nSPH grafts led to improved creatinine clearance compared with controls.
When co-cultured, nSPHs derived from diseased kidneys inhibited collagen production by human fibroblasts in the absence of cell contact. “nSPH cell therapy may be unique in targeting fibroblasts in a paracrine fashion,” adds Dekel. “nSPH grafts also induced transcriptional signatures of proliferation and release from quiescence in recipient mouse kidney cells; further studies should clarify how these mechanisms might contribute to a therapeutic benefit.”
Harari-Steinberg, O. et al. Ex vivo expanded 3D human kidney spheres engraft long term and repair chronic renal injury in mice. Cell Rep. https://doi.org/10.1016/j.celrep.2019.12.047 (2020)
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Wang, M. Kidney sphere grafts for tissue regeneration. Nat Rev Nephrol 16, 188 (2020). https://doi.org/10.1038/s41581-020-0258-9