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“Mini-kidneys” Grown from Adult Kidney Stem Cells?

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Review of “Single Adult Kidney Stem/Progenitor Cells Reconstitute 3-Dimensional Nephron Structures in Vitro” from Stem Cells by Stuart P. Atkinson

Due to its complex structure and multiple functions, the regeneration of the kidney in vitro is a very difficult task. Even so, research groups have attempted to generate kidney-like structures from adult tissues/cells with differing success rates [1-3], while many recent strategies involve the directed differentiation of pluripotent stem cells [4] which carries some risk of latent tumorigenesis. The research group of Shinji Kitamura (Okayama University Graduate School of Medicine, Japan) had previously identified putative adult kidney stem (KS) cells with excellent regenerative capacity [5, 6], and they now report on their successful studies into the differentiation of these KS cells into kidney-like structures [7].

KS cells established from adult rat kidneys [5] expressed several adult stem cell markers (Sca‐1, c‐Kit, Nestin and Mushashi‐1), renal lineage marker (Pax‐2 and WT‐1) as well as multiple putative kidney stem cells markers (Six2, CD133, and Vimentin). In 2D culture conditions, cells grew and differentiated as a cobble stone-like monolayer, but transfer to a 3D growth system mediated the development of mini kidney‐like structures at high efficiency. 3D growth of these cells entailed using the hanging drop culture technique to create cell clusters that were then implanted into extracellular matrix (ECM) gels and cultured in the presence of an optimised combination of specific growth factors (GDNF, ‐FGF, HGF, EGF and BMP‐7). However, kidney-like structures did not develop when the researchers substituted KS cells for embryonic kidney derived uretic bud cell or metanephric mesenchyme cells, two related cell types.

Encouragingly, kidney‐like structure contained at least 3 distinct segments, which were morphologically similar to the kidney glomerulus, proximal tubules and distal tubules. Kidney differentiation was further corroborated by the expression of site specific gene expression consistent with a kidney in the process of differentiation/maturation. Glomerulus‐like structures expressed Nephrin and Thy‐1 protein, similar to embryonic day 17 kidney glomeruli, while in the proximal tubule‐like structures, there was evidence of proximal cell (Aquaporin-1), loop of Henle cell (Na‐K‐Cl cotransporter 2), and distal‐collecting duct cell (Tamm‐Horsfall glycoprotein) markers, although this was more similar to adult kidney (See Figure). Lastly, the group were also able to produce cell clusters from single cells which went on to produce kidney‐like structures, suggesting that indeed these cells represented adult kidney stem cells.

While further work is required to show appropriate kidney functionality and integration into the vascular system, according to the evidence gathered within this report, there is excellent potential for these kidney-like structures to be useful in the future for kidney regeneration. The identification of a human counterpart also lies in the future, but the work done in identifying potential markers and growth conditions should aid this important endeavour.

References

  1. Yokoo T, Ohashi T, Shen JS, et al. Human mesenchymal stem cells in rodent whole-embryo culture are reprogrammed to contribute to kidney tissues. Proceedings of the National Academy of Sciences of the United States of America 2005;102:3296-3300.
  2. Song JJ, Guyette JP, Gilpin SE, et al. Regeneration and experimental orthotopic transplantation of a bioengineered kidney. Nature medicine 2013;19:646-651.
  3. Rosines E, Sampogna RV, Johkura K, et al. Staged in vitro reconstitution and implantation of engineered rat kidney tissue. Proceedings of the National Academy of Sciences of the United States of America 2007;104:20938-20943.
  4. Mae S, Shono A, Shiota F, et al. Monitoring and robust induction of nephrogenic intermediate mesoderm from human pluripotent stem cells. Nature communications 2013;4:1367.
  5. Kitamura S, Yamasaki Y, Kinomura M, et al. Establishment and characterization of renal progenitor like cells from S3 segment of nephron in rat adult kidney. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2005;19:1789-1797.
  6. Kinomura M, Kitamura S, Tanabe K, et al. Amelioration of cisplatin-induced acute renal injury by renal progenitor-like cells derived from the adult rat kidney. Cell transplantation 2008;17:143-158.
  7. Kitamura S, Sakurai H, and Makino H Single adult kidney stem/progenitor cells reconstitute three-dimensional nephron structures in vitro. Stem Cells 2015;33:774-784.