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iPSC-Derived Renal Progenitors Successfully Treat Kidney Injury

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Review of “Cell Therapy Using hiPSC-Derived Renal Progenitors Ameliorates Acute Kidney Injury in Mice” from Stem Cells Translational Medicine by Stuart P. Atkinson.

Acute kidney injury (AKI) represents a serious condition with a high mortality rate [1], and unfortunately currently lacks successful treatment strategies [2]. The application of human fetal nephron progenitor cells has shown some success [3], and this led researchers from the laboratory of Kenji Osafune (Center for iPS Cell Research and Application, Kyoto, Japan) to assess if nephron progenitor cells differentiated from induced pluripotent stem cells (iPSCs) may be a potentially effective therapeutic option. Their new study, in Stem Cells Translational Medicine, describes a protocol for renal progenitor derivation and demonstrates their ability to form renal tubule-like structures in vitro and to ameliorate AKI in vivo [4].

The study employed iPSC fluorescent reporter lines to monitor OSR1+ and SIX2+ renal progenitor cells differentiation from hiPSCs following treatment with different combinations of growth factors and small molecules during embryoid body-based intermediate mesoderm culture. These assessments found that a combination of an -RAR agonist (TTNPB), a BMP antagonist (DMH1), and TGF-1 maximized the differentiation of OSR1+SIX2+ cells by day 28. At this stage, OSR1+SIX2+ cells expressed multiple nephron progenitor marker genes and a nephric duct marker but did not express marker genes for other non-renal mesoderm, endoderm, or ectoderm tissues.

These iPSC-derived renal progenitors formed tubule-like structures when co-aggregated with mouse spinal cord, NIH3T3 fibroblasts expressing Wnt4, or dissociated E11.5 mouse metanephric cells in organ culture. This demonstrates that, while they are not as competent as nephron progenitors in embryos, they did have some developmental potential to generate kidney-like structures (See Figure).

The final part of this exciting study assessed whether these iPSC-derived renal progenitors could be used to treat renal injury in a mouse model of AKI. While transplantation of OSR1+SIX2+ cells into the kidney parenchyma of injured mice led to some cellular integration, the authors found no beneficial effects on renal function. However, OSR1+SIX2+ aggregate transplantation into the renal sub-capsule to promote paracrine effects led to an improvement in renal functional parameter values and a reduction in renal parenchymal areas with tubular necrosis, urinary casts, and tubular dilatation. These improvements all correlated to the secretion of reno-protective factors (ANG-1, VEGF-A, and HGF) [5] from the OSR1+SIX2+ cells, overall suggesting that paracrine support from iPSC-derived renal progenitors may represent a viable therapeutic option for kidney repair.

The development of an effective protocol for the derivation of renal progenitors from patient-specific iPSC cells and the demonstration of their therapeutic value should propel this research towards pre-clinical animal trials. However, the authors do note that further protocol optimization could further enhance developmental and/or therapeutic abilities, and additional manipulation to enhance their paracrine action may also add value to this therapeutic option. Furthermore, extending the ability of these progenitors to generate glomerular podocytes or distal tubular cells in addition to proximal tubular cells could also allow us to study mechanisms behind renal development.

References

  1. Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 2005;294:813-818.
  2. Prowle JR Acute kidney injury: an intensivist's perspective. Pediatr Nephrol 2014;29:13-21.
  3. Harari-Steinberg O, Metsuyanim S, Omer D, et al. Identification of human nephron progenitors capable of generation of kidney structures and functional repair of chronic renal disease. EMBO Mol Med 2013;5:1556-1568.
  4. Toyohara T, Mae S, Sueta S, et al. Cell Therapy Using Human Induced Pluripotent Stem Cell-Derived Renal Progenitors Ameliorates Acute Kidney Injury in Mice. Stem Cells Transl Med 2015;4:980-992.
  5. Cantaluppi V, Biancone L, Quercia A, et al. Rationale of mesenchymal stem cell therapy in kidney injury. Am J Kidney Dis 2013;61:300-309.