You are hereDecember 31, 2017 | ESCs/iPSCs
Podocyte Comparison Highlights the Potential of Pluripotent Stem Cell-derived Kidney Organoids
Review of “Gene-Edited Human Kidney Organoids Reveal Mechanisms of Disease in Podocyte Development” from STEM CELLS by Stuart P. Atkinson
Human pluripotent stem cell (hPSC)-derived kidney organoids containing segments of distal tubules, proximal tubules, and podocytes may soon find use in therapeutic approaches for the treatment of renal disease. The formation and study of podocytes, specialized epithelial cells employed in blood filtration/urine production, is of particular interest due to the difficulty of their in vitro study and in vivo regeneration [1-3].
Researchers from the laboratories of Kelly M. McNagny (University of British Columbia, Canada) and Benjamin S. Freedman (University of Washington School of Medicine, USA) have recently undertaken the first detailed comparisons between in vitro hPSC-derived podocytes and in vivo developing podocytes. Kim et al. now report on the findings of these comparisons in a new STEM CELLS study and additionally reveal a stage-specific role for podocalyxin-induced cellular projections known as microvilli .
The authors employed a previously published adherent culture protocol to differentiate hPSCs into kidney organoids over a two to three week period . Subsequent comparisons of marker expression (e.g., nephrin, podocin, and podocalyxin), marker localization, and cytoskeletal architecture suggested that the hPSC-podocytes within the organoids most closely resembled capillary loop stage (CLS) podocytes in vivo.
The authors also observed the migration of tight junctions from the apical to the basement membrane during the maturation of hPSC-podocytes in vitro, thereby permitting self-organization at later stages of differentiation, and the presence of microvillus-rich apical membranes. However, loss of podocalyxin via CRISPR/Cas9 gene editing of hPSCs led to defects in the assembly of microvilli and lateral spaces between developing podocytes, which inhibited junctional migration. Interestingly, the CLS glomeruli of podocalyxin-deficient mice also display similar defects, suggesting that hPSC-podocytes can recapitulate disease phenotypes and that podocalyxin has a conserved and essential role in mammalian podocyte maturation.
This exciting new comparative study defines hPSC-podocyte maturity and in doing so, will aid the future investigations of human kidney disease and regeneration. However, the authors note that hPSC-podocytes do not develop to form bona fide foot processes with tertiary interdigitating, suggesting the requirement for additional factors to enhance maturity.
To hear more on podocyte maturation, hPSC-derived kidney therapies, and more, stay tuned to the Stem Cells Portal.
- Ronconi, E., et al., Regeneration of glomerular podocytes by human renal progenitors. J Am Soc Nephrol 2009;20:322-32.
- Kim, Y.G., et al., The cyclin kinase inhibitor p21CIP1/WAF1 limits glomerular epithelial cell proliferation in experimental glomerulonephritis. Kidney Int 1999;55:2349-61.
- Saleem, M.A., et al., A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression. J Am Soc Nephrol 2002;13:630-8.
- Kim, Y.K., et al., Gene-Edited Human Kidney Organoids Reveal Mechanisms of Disease in Podocyte Development. STEM CELLS 2017;35:2366-2378.
- Freedman, B.S., et al., Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids. Nature Communications 2015;6:8715.