Urine of Preterm Neonates as a Novel Source of Kidney Progenitor Cells

Arcolino, Fanny Oliveira; Zia, Silvia; Held, Katharina; Papadimitriou, Elli; Theunis, Koen; Bussolati, Benedetta; Raaijmakers, Anke; Allegaert, Karel; Voet, Thierry; Deprest, Jan; Vriens, Joris; Toelen, Jaan; Heuvel, Lambertus van den; Levtchenko, Elena

doi:10.1681/asn.2015060664

Cited by 36 publications

(50 citation statements)

References 47 publications

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“…Remarkably, we confirmed the presence of FODX1 + cells in the CM SIX2 + CITED1 + cells (Fig. 5B) . It is important to note that the isolation method for these cells differs from the Smartflare technique used in the current work.…”

Section: Resultssupporting

confidence: 74%

Direct Isolation and Characterization of Human Nephron Progenitors

Sacco

Thornton

Petrosyan

et al. 2016

Stem Cells Translational Medicine

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Mature nephrons originate from a small population of uninduced nephrogenic progenitor cells (NPs) within the cap mesenchyme. These cells are characterized by the coexpression of SIX2 and CITED1. Many studies on mouse models as well as on human pluripotent stem cells have advanced our knowledge of NPs, but very little is known about this population in humans, since it is exhausted before birth and strategies for its direct isolation are still limited. Here we report an efficient protocol for direct isolation of human NPs without genetic manipulation or stepwise induction procedures. With the use of RNA‐labeling probes, we isolated SIX2+CITED1+ cells from human fetal kidney for the first time. We confirmed their nephrogenic state by gene profiling and evaluated their nephrogenic capabilities in giving rise to mature renal cells. We also evaluated the ability to culture these cells without complete loss of SIX2 and CITED1 expression over time. In addition to defining the gene profile of human NPs, this in vitro system facilitates studies of human renal development and provides a novel tool for renal regeneration and bioengineering purposes. Stem Cells Translational Medicine 2017;6:419–433

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Section: Resultssupporting

confidence: 74%

Direct Isolation and Characterization of Human Nephron Progenitors

Sacco

Thornton

Petrosyan

et al. 2016

Stem Cells Translational Medicine

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“…UdRPCs express key renal progenitor-regulatory proteins SIX2, CITED1, WT1 and NPHS1 ( Figure 2A) indicating they originate from the kidney as described from others. 13,56,60 Furthermore, UdRPCs transport Albumin ( Figure 2B) as observed in renal stem cells. 41,61 We have shown that UdRPCs are in fact bon-fide MSCs-i.e.…”

Section: Discussionmentioning

confidence: 66%

“…Here we describe urine as a reliable, robust and cheap source of renal stem cells, in contrast to amniotic fluid or kidney biopsies. 41,56 Urine can be accessed non-invasively, without risk for the patient and repeated samples can be collected from the same donor over prolonged periods. Urine derived stem cells can be expand from a single clone with high proliferation potency.…”

Section: Discussionmentioning

confidence: 99%

“…Typical of MSCs, UdRPCs can be differentiated into osteoblasts, chondrocytes and adipocytes ( Figure 1E). 41,56,62 They also secrete a plethora of cytokines and growth factors-such as EGF, GDF, PDGF and Serpin E1 ( Figure 1F). 63 With regards to nephrogenesis-associated regulatory genes, 17,30 we observed SIX2, CITED1, GDNF, WT1, NPHS1, PAX2 expression in UdRPCs but at variable expression levels between individual cell preparations ( Figure 3A).…”

Section: Discussionmentioning

confidence: 99%

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A Comprehensive Molecular Portrait of Human Urine-derived Renal Progenitor Cells

Rahman

Wruck

Spitzhorn

et al. 2019

Preprint

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Human urine is a non-invasive source of stem cells with regeneration potential. Here, we investigated the cellular and molecular identities, and the gene regulation driving self-renewal and differentiation of these cells in vitro. These cells express pluripotency-associated markers enabling easy reprogramming. Based on the expression of renal associated genes, proteins and functionality, we refer to these cells as urine derived renal progenitor cells-UdRPCs. CHIR99021-induced differentiation of UdRPCs activated WNT-related genes-AXIN2, JUN and NKD1. Protein interaction network identified JUN as a putative regulator of differentiation whereas self-renewal is maintained by FGF2-driven TGFβ-SMAD2/3. Our data will enhance understanding of the molecular identities of UdRPCs, and enable the generation of renal disease models in vitro and eventually kidney-associated regenerative therapies.3 Abstract Background Human urine is now recognised as a non-invasive source of stem cells with regeneration potential. These cells are mesenchymal stem cells but their detailed molecular and cellular identities are poorly defined. Furthermore, unlike the mouse, the gene regulatory network driving self-renewal and differentiation into functional renal cells in vitro remain unresolved. MethodsWe isolated urine stem cells from 10 individuals from both genders and distinct ages, characterized them as renal progenitor cells and explored the gene regulatory network sustaining self-renewal. ResultsThese cells express pluripotency-associated proteins-TRA-1-60, TRA-1-81, SSEA4, C-KIT and CD133. Expression of pluripotency-associated proteins enabled rapid reprogramming into iPSCs using episomal-based plasmids without pathway perturbations. Transcriptome analysis revealed expression of a plethora of nephrogenesis-related genes such as SIX2, OSR1, CITED1, NPHS2, NPHS1, PAX2, SALL1, AQP2, EYA1, SLC12A1 and UMOD. As expected, the cells transport Albumin by endocytosis. Based on this, we refer to these cells as urine derived renal progenitor cells-UdRPCs. Associated GO-term analysis of UdRPCs and UdRPC-iPSCs underlined their renal identity and functionality. Upon differentiation by WNT activation using the GSK3β-inhibitor (CHIR99021), 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 regulator of self-renewal and differentiation in UdRPCs. Furthermore, like pluripotent stem cells, self-renewal is maintained by FGF2-driven TGFβ-SMAD2/3 pathway.Conclusion This in vitro model and the data presented should lay the foundation for studying nephrogenesis in man.

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“…Generating renal cells using human stem cells offers a promising approach to study podocytopathies. Amniotic fluid stem cells as well as kidney progenitor cells from neonatal urine have the potential to differentiate towards podocyte-like cells, though these sources are relatively scarce [54]. The recent progress of reprogramming any somatic cell type (e.g., human dermal fibroblasts) into pluripotent stem cells has opened a new dimension to develop, in principal, any desired cell type, including renal tissue.…”

Section: Modeling Ns Using Stem Cellsmentioning

confidence: 99%

Nephrotic syndrome in a dish: recent developments in modeling in vitro

et al. 2019

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Nephrotic syndrome is a heterogeneous disease, and one of the most frequent glomerular disorders among children. Depending on the etiology, it may result in end-stage renal disease and the need for renal replacement therapy. A dysfunctional glomerular filtration barrier, comprising of endothelial cells, the glomerular basement membrane and podocytes, characterizes nephrotic syndrome. Podocytes are often the primary target cells in the pathogenesis, in which not only the podocyte function but also their crosstalk with other glomerular cell types can be disturbed due to a myriad of factors. The pathophysiology of nephrotic syndrome is highly complex and studying molecular mechanisms in vitro requires state-of-the-art cell-based models resembling the in vivo situation and preferably a fully functional glomerular filtration barrier. Current advances in stem cell biology and microfluidic platforms have heralded a new era of three-dimensional (3D) cultures that might have the potential to recapitulate the glomerular filtration barrier in vitro. Here, we highlight the molecular basis of nephrotic syndrome and discuss requirements to accurately study nephrotic syndrome in vitro, including an overview of specific podocyte markers, cutting-edge stem cell organoids, and the implementation of microfluidic platforms. The development of (patho) physiologically relevant glomerular models will accelerate the identification of molecular targets involved in nephrotic syndrome and may be the harbinger of a new era of therapeutic avenues.

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Urine of Preterm Neonates as a Novel Source of Kidney Progenitor Cells

Cited by 36 publications

References 47 publications

Direct Isolation and Characterization of Human Nephron Progenitors

Direct Isolation and Characterization of Human Nephron Progenitors

A Comprehensive Molecular Portrait of Human Urine-derived Renal Progenitor Cells

Nephrotic syndrome in a dish: recent developments in modeling in vitro

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