Abstract
Human urine is a non-invasive source of renal stem cells with regeneration potential. Urine-derived renal progenitor cells were isolated from 10 individuals of both genders and distinct ages. These renal progenitors express pluripotency-associated proteins- TRA-1-60, TRA-1-81, SSEA4, C-KIT and CD133, as well as the renal stem cell markers -SIX2, CITED1, WT1, CD24 and CD106. The transcriptomes of all SIX2+ renal progenitors clustered together, and distinct from the human kidney biopsy-derived epithelial proximal cells (hREPCs). Stimulation of the urine-derived renal progenitor cells (UdRPCs) with the GSK3β-inhibitor (CHIR99021) induced differentiation. Transcriptome and KEGG pathway analysis revealed upregulation of WNT-associated genes- AXIN2, JUN and NKD1. Protein interaction network identified JUN- a downstream target of the WNT pathway in association with STAT3, ATF2 and MAPK1 as a putative negative regulator of self-renewal. Furthermore, like pluripotent stem cells, self-renewal is maintained by FGF2-driven TGFβ-SMAD2/3 pathway. The urine-derived renal progenitor cells and the data presented should lay the foundation for studying nephrogenesis in human.
Highlights
According to the International Society of Nephrology, more than 850 million people worldwide are afflicted with kidney diseases[1], which raises the quest for alternative therapies to overcome the limitations associated with current treatments including transplantation and dialysis
We propose that using native renal stem cells isolated directly from urine will circumvent most of the shortfalls and deficiencies associated with human pluripotent stem cell-based models
Urine samples were collected from 10 healthy adult donors (4 males-UM and 6 females-UF) with ages ranging from 21 to 61 years, and of mixed ethnicity (3 Africans and 7 Caucasians) (Supplemental Table S1)
Summary
According to the International Society of Nephrology, more than 850 million people worldwide are afflicted with kidney diseases[1], which raises the quest for alternative therapies to overcome the limitations associated with current treatments including transplantation and dialysis. A subpopulation of these urine-derived cells are renal stem/progenitor cells which express master renal markers such as Sine Oculis Homeobox Homolog 2 (SIX2), Cbp/P300 Interacting Transactivator With Glu/Asp Rich Carboxy-Terminal Domain 1 (CITED1) and Wilms’ Tumor 1 (WT1)[13,14,15] and CD24 and CD10616 These cells exhibit stem cell properties, i.e. expression of pluripotency-associated markers such as TRA-1-60, TRA-1-81, C-KIT (CD117), CD133 and SSEA4 and possess high proliferation capacity as they show telomerase activity. Studies in mice have shown that Odd-skipped related 1 (Osr1), Six[2], Wnt, Cited[1] and Wt1 are required to maintain renal progenitor cells during kidney organogenesis[19,20,21,22,23,24,25] Signalling pathways such as Fgf, Tgfβ and Notch play major roles in renal stem cell maintenance and differentiation[26,27,28,29]. These are all further evidence in support of the need of a reliable and robust human renal cell culture model
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