Journal articles: 'Renal progenitors'

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Hasegawa, Sho, Tetsuhiro Tanaka, and Masaomi Nangaku. "Recent advances in renal regeneration." F1000Research 8 (February 25, 2019): 216. http://dx.doi.org/10.12688/f1000research.17127.1.

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Regeneration of a functional kidney from pluripotent stem cells (PSCs) is challenging because of its complex structure. Kidneys are derived from embryonic metanephros, which are composed of three progenitor cells: nephron progenitors, ureteric bud, and stromal progenitors. Nephron progenitors and ureteric bud have been induced successfully from PSCs as a result of the understanding of their detailed developmental process through cell-lineage tracing analysis. Moreover, these induced progenitors can be used to reconstruct the three-dimensional (3D) structure of kidneys in vitro, including glomeruli with podocytes, renal tubules, and the branching ureters. Induction of the remaining renal progenitors (that is, stromal progenitors from PSCs and the further maturation of reconstructed kidneys) needs to be studied extensively to regenerate functional and sophisticated kidneys from PSCs. In addition to the proper induction of renal progenitors, new bioengineering methods such as decellularization and 3D bioprinting and the recent advancements in the regeneration of kidneys in other species are promising leads for regenerating the complex spatial arrangement of kidneys, including the vascular network and urinary excretion pathway in humans.

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Al-Marsoummi, Sarmad, Aaron A. Mehus, Swojani Shrestha, Rayna Rice, Brooke Rossow, Seema Somji, Scott H. Garrett, and Donald A. Sens. "Proteasomes Are Critical for Maintenance of CD133+CD24+ Kidney Progenitor Cells." International Journal of Molecular Sciences 24, no. 17 (August 27, 2023): 13303. http://dx.doi.org/10.3390/ijms241713303.

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Kidney progenitor cells, although rare and dispersed, play a key role in the repair of renal tubules after acute kidney damage. However, understanding these cells has been challenging due to the limited access to primary renal tissues and the absence of immortalized cells to model kidney progenitors. Previously, our laboratory utilized the renal proximal tubular epithelial cell line, RPTEC/TERT1, and the flow cytometry technique to sort and establish a kidney progenitor cell model called Human Renal Tubular Precursor TERT (HRTPT) which expresses CD133 and CD24 and exhibits the characteristics of kidney progenitors, such as self-renewal capacity and multi-potential differentiation. In addition, a separate cell line was established, named Human Renal Epithelial Cell 24 TERT (HREC24T), which lacks CD133 expression and shows no progenitor features. To further characterize HRTPT CD133+CD24+ progenitor cells, we performed proteomic profiling which showed high proteasomal expression in HRTPT kidney progenitor cells. RT-qPCR, Western blot, and flow cytometry analysis showed that HRTPT cells possess higher proteasomal expression and activity compared to HREC24T non-progenitor cells. Importantly, inhibition of the proteasomes with bortezomib reduced the expression of progenitor markers and obliterated the potential for self-renewal and differentiation of HRTPT progenitor cells. In conclusion, proteasomes are critical in preserving progenitor markers expression and self-renewal capacity in HRTPT kidney progenitors.

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Holmes, David. "Budding renal progenitors." Nature Reviews Nephrology 10, no. 1 (December 3, 2013): 4. http://dx.doi.org/10.1038/nrneph.2013.245.

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Sequeira-Lopez, Maria Luisa S., Eugene E. Lin, Minghong Li, Yan Hu, Curt D. Sigmund, and R. Ariel Gomez. "The earliest metanephric arteriolar progenitors and their role in kidney vascular development." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 308, no. 2 (January 15, 2015): R138—R149. http://dx.doi.org/10.1152/ajpregu.00428.2014.

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The development of the kidney arterioles is poorly understood. Mature arterioles contain several functionally and morphologically distinct cell types, including smooth muscle, endothelial, and juxtaglomerular cells, and they are surrounded by interconnected pericytes, fibroblasts, and other interstitial cells. We have shown that the embryonic kidney possesses all of the necessary precursors for the development of the renal arterial tree, and those precursors assemble in situ to form the kidney arterioles. However, the identity of those precursors was unclear. Within the embryonic kidney, several putative progenitors marked by the expression of either the winged-forkhead transcription factor 1 (Foxd1+ progenitor), the aspartyl-protease renin (Ren+ progenitor), and/or hemangioblasts (Scl+ progenitor) are likely to differentiate and endow most of the cells of the renal arterial tree. However, the lineage relationships and the role of these distinct progenitors in renal vascular morphogenesis have not been delineated. We, therefore, designed a series of experiments to ascertain the hierarchical lineage relationships between Foxd1+ and Ren+ progenitors and the role of these two precursors in the morphogenesis and patterning of the renal arterial tree. Results show that 1) Foxd1+ cells are the precursors for all the mural cells (renin cells, smooth muscle cells, perivascular fibroblasts, and pericytes) of the renal arterial tree and glomerular mesangium, and 2) Foxd1 per se directs the origin, number, orientation, and cellular composition of the renal vessels.

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Peired, Anna Julie, Maria Elena Melica, Alice Molli, Cosimo Nardi, Paola Romagnani, and Laura Lasagni. "Molecular Mechanisms of Renal Progenitor Regulation: How Many Pieces in the Puzzle?" Cells 10, no. 1 (January 2, 2021): 59. http://dx.doi.org/10.3390/cells10010059.

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Kidneys of mice, rats and humans possess progenitors that maintain daily homeostasis and take part in endogenous regenerative processes following injury, owing to their capacity to proliferate and differentiate. In the glomerular and tubular compartments of the nephron, consistent studies demonstrated that well-characterized, distinct populations of progenitor cells, localized in the parietal epithelium of Bowman capsule and scattered in the proximal and distal tubules, could generate segment-specific cells in physiological conditions and following tissue injury. However, defective or abnormal regenerative responses of these progenitors can contribute to pathologic conditions. The molecular characteristics of renal progenitors have been extensively studied, revealing that numerous classical and evolutionarily conserved pathways, such as Notch or Wnt/β-catenin, play a major role in cell regulation. Others, such as retinoic acid, renin-angiotensin-aldosterone system, TLR2 (Toll-like receptor 2) and leptin, are also important in this process. In this review, we summarize the plethora of molecular mechanisms directing renal progenitor responses during homeostasis and following kidney injury. Finally, we will explore how single-cell RNA sequencing could bring the characterization of renal progenitors to the next level, while knowing their molecular signature is gaining relevance in the clinic.

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Phua, Yu Leng, Kevin Hong Chen, Shelby L. Hemker, April K. Marrone, Andrew J. Bodnar, Xiaoning Liu, Andrew Clugston, Dennis Kostka, Michael B. Butterworth, and Jacqueline Ho. "Loss of miR-17~92 results in dysregulation of Cftr in nephron progenitors." American Journal of Physiology-Renal Physiology 316, no. 5 (May 1, 2019): F993—F1005. http://dx.doi.org/10.1152/ajprenal.00450.2018.

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We have previously demonstrated that loss of miR-17~92 in nephron progenitors in a mouse model results in renal hypodysplasia and chronic kidney disease. Clinically, decreased congenital nephron endowment because of renal hypodysplasia is associated with an increased risk of hypertension and chronic kidney disease, and this is at least partly dependent on the self-renewal of nephron progenitors. Here, we present evidence for a novel molecular mechanism regulating the self-renewal of nephron progenitors and congenital nephron endowment by the highly conserved miR-17~92 cluster. Whole transcriptome sequencing revealed that nephron progenitors lacking this cluster demonstrated increased Cftr expression. We showed that one member of the cluster, miR-19b, is sufficient to repress Cftr expression in vitro and that perturbation of Cftr activity in nephron progenitors results in impaired proliferation. Together, these data suggest that miR-19b regulates Cftr expression in nephron progenitors, with this interaction playing a role in appropriate nephron progenitor self-renewal during kidney development to generate normal nephron endowment.

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Volovelsky, Oded, Thi Nguyen, Alison E. Jarmas, Alexander N. Combes, Sean B. Wilson, Melissa H. Little, David P. Witte, Eric W. Brunskill, and Raphael Kopan. "Hamartin regulates cessation of mouse nephrogenesis independently of Mtor." Proceedings of the National Academy of Sciences 115, no. 23 (May 21, 2018): 5998–6003. http://dx.doi.org/10.1073/pnas.1712955115.

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Nephrogenesis concludes by the 36th week of gestation in humans and by the third day of postnatal life in mice. Extending the nephrogenic period may reduce the onset of adult renal and cardiovascular disease associated with low nephron numbers. We conditionally deleted either Mtor or Tsc1 (coding for hamartin, an inhibitor of Mtor) in renal progenitor cells. Loss of one Mtor allele caused a reduction in nephron numbers; complete deletion led to severe paucity of glomeruli in the kidney resulting in early death after birth. By contrast, loss of one Tsc1 allele from renal progenitors resulted in a 25% increase in nephron endowment with no adverse effects. Increased progenitor engraftment rates ex vivo relative to controls correlated with prolonged nephrogenesis through the fourth postnatal day. Complete loss of both Tsc1 alleles in renal progenitors led to a lethal tubular lesion. The hamartin phenotypes are not dependent on the inhibitory effect of TSC on the Mtor complex but are dependent on Raptor.

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Peired, Anna Julie, Giulia Antonelli, Maria Lucia Angelotti, Marco Allinovi, Francesco Guzzi, Alessandro Sisti, Roberto Semeraro, et al. "Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells." Science Translational Medicine 12, no. 536 (March 25, 2020): eaaw6003. http://dx.doi.org/10.1126/scitranslmed.aaw6003.

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Acute tissue injury causes DNA damage and repair processes involving increased cell mitosis and polyploidization, leading to cell function alterations that may potentially drive cancer development. Here, we show that acute kidney injury (AKI) increased the risk for papillary renal cell carcinoma (pRCC) development and tumor relapse in humans as confirmed by data collected from several single-center and multicentric studies. Lineage tracing of tubular epithelial cells (TECs) after AKI induction and long-term follow-up in mice showed time-dependent onset of clonal papillary tumors in an adenoma-carcinoma sequence. Among AKI-related pathways, NOTCH1 overexpression in human pRCC associated with worse outcome and was specific for type 2 pRCC. Mice overexpressing NOTCH1 in TECs developed papillary adenomas and type 2 pRCCs, and AKI accelerated this process. Lineage tracing in mice identified single renal progenitors as the cell of origin of papillary tumors. Single-cell RNA sequencing showed that human renal progenitor transcriptome showed similarities to PT1, the putative cell of origin of human pRCC. Furthermore, NOTCH1 overexpression in cultured human renal progenitor cells induced tumor-like 3D growth. Thus, AKI can drive tumorigenesis from local tissue progenitor cells. In particular, we find that AKI promotes the development of pRCC from single progenitors through a classical adenoma-carcinoma sequence.

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Rymer, Christopher, Jose Paredes, Kimmo Halt, Caitlin Schaefer, John Wiersch, Guangfeng Zhang, Douglas Potoka, et al. "Renal blood flow and oxygenation drive nephron progenitor differentiation." American Journal of Physiology-Renal Physiology 307, no. 3 (August 1, 2014): F337—F345. http://dx.doi.org/10.1152/ajprenal.00208.2014.

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During kidney development, the vasculature develops via both angiogenesis (branching from major vessels) and vasculogenesis (de novo vessel formation). The formation and perfusion of renal blood vessels are vastly understudied. In the present study, we investigated the regulatory role of renal blood flow and O2 concentration on nephron progenitor differentiation during ontogeny. To elucidate the presence of blood flow, ultrasound-guided intracardiac microinjection was performed, and FITC-tagged tomato lectin was perfused through the embryo. Kidneys were costained for the vasculature, ureteric epithelium, nephron progenitors, and nephron structures. We also analyzed nephron differentiation in normoxia compared with hypoxia. At embryonic day 13.5 (E13.5), the major vascular branches were perfused; however, smaller-caliber peripheral vessels remained unperfused. By E15.5, peripheral vessels started to be perfused as well as glomeruli. While the interior kidney vessels were perfused, the peripheral vessels (nephrogenic zone) remained unperfused. Directly adjacent and internal to the nephrogenic zone, we found differentiated nephron structures surrounded and infiltrated by perfused vessels. Furthermore, we determined that at low O2 concentration, little nephron progenitor differentiation was observed; at higher O2 concentrations, more differentiation of the nephron progenitors was induced. The formation of the developing renal vessels occurs before the onset of blood flow. Furthermore, renal blood flow and oxygenation are critical for nephron progenitor differentiation.

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Chu, Jessica Y. S., Sunder Sims-Lucas, Daniel S. Bushnell, Andrew J. Bodnar, Jordan A. Kreidberg, and Jacqueline Ho. "Dicer function is required in the metanephric mesenchyme for early kidney development." American Journal of Physiology-Renal Physiology 306, no. 7 (April 1, 2014): F764—F772. http://dx.doi.org/10.1152/ajprenal.00426.2013.

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MicroRNAs (miRNAs) are small, noncoding regulatory RNAs that act as posttranscriptional repressors by binding to the 3′-untranslated region (3′-UTR) of target genes. They require processing by Dicer, an RNase III enzyme, to become mature regulatory RNAs. Previous work from our laboratory revealed critical roles for miRNAs in nephron progenitors at midgestation (Ho J, Pandey P, Schatton T, Sims-Lucas S, Khalid M, Frank MH, Hartwig S, Kreidberg JA. J Am Soc Nephrol 22: 1053–1063, 2011). To interrogate roles for miRNAs in the early metanephric mesenchyme, which gives rise to nephron progenitors as well as the renal stroma during kidney development, we conditionally ablated Dicer function in this lineage. Despite normal ureteric bud outgrowth and condensation of the metanephric mesenchyme to form nephron progenitors, early loss of miRNAs in the metanephric mesenchyme resulted in severe renal dysgenesis. Nephron progenitors are initially correctly specified in the mutant kidneys, with normal expression of several transcription factors known to be critical in progenitors, including Six2, Pax2, Sall1, and Wt1. However, there is premature loss of the nephron progenitor marker Cited1, marked apoptosis, and increased expression of the proapoptotic protein Bim shortly after the initial inductive events in early kidney development. Subsequently, there is a failure in ureteric bud branching and nephron progenitor differentiation. Taken together, our data demonstrate a previously undetermined requirement for miRNAs during early kidney organogenesis and indicate a crucial role for miRNAs in regulating the survival of this lineage.

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Meyer-Schwesinger, Catherine. "The Role of Renal Progenitors in Renal Regeneration." Nephron 132, no. 2 (2016): 101–9. http://dx.doi.org/10.1159/000442180.

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Gupta, Ashwani Kumar, David Z. Ivancic, Bilal A. Naved, Jason A. Wertheim, and Leif Oxburgh. "An efficient method to generate kidney organoids at the air-liquid interface." Journal of Biological Methods 8, no. 2 (June 29, 2021): e150. http://dx.doi.org/10.14440/jbm.2021.357.

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The prevalence of kidney dysfunction continues to increase worldwide, driving the need to develop transplantable renal tissues. The kidney develops from four major renal progenitor populations: nephron epithelial, ureteric epithelial, interstitial and endothelial progenitors. Methods have been developed to generate kidney organoids but few or dispersed tubular clusters within the organoids hamper its use in regenerative applications. Here, we describe a detailed protocol of asynchronous mixing of kidney progenitors using organotypic culture conditions to generate kidney organoids tightly packed with tubular clusters and major renal structures including endothelial network and functional proximal tubules. This protocol provides guidance in the culture of human embryonic stem cells from a National Institute of Health-approved line and their directed differentiation into kidney organoids. Our 18-day protocol provides a rapid method to generate kidney organoids that facilitate the study of different nephrological events including in vitro tissue development, disease modeling and chemical screening. However, further studies are required to optimize the protocol to generate additional renal-specific cell types, interconnected nephron segments and physiologically functional renal tissues.

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Bussolati, Benedetta, Aldo Moggio, Federica Collino, Giulia Aghemo, Giuseppe D'Armento, Cristina Grange, and Giovanni Camussi. "Hypoxia modulates the undifferentiated phenotype of human renal inner medullary CD133+ progenitors through Oct4/miR-145 balance." American Journal of Physiology-Renal Physiology 302, no. 1 (January 1, 2012): F116—F128. http://dx.doi.org/10.1152/ajprenal.00184.2011.

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Low-oxygen tension is an important component of the stem cell microenvironment. In rodents, renal resident stem cells have been described in the papilla, a relatively hypoxic region of the kidney. In the present study, we found that CD133+ cells, previously described as renal progenitors in the human cortex, were enriched in the renal inner medulla and localized within the Henle's loop and thin limb segments. Once isolated, the CD133+ cell population expressed renal embryonic and stem-related transcription factors and was able to differentiate into mature renal epithelial cells. When injected subcutaneously in immunodeficient mice within Matrigel, CD133+ cells generated canalized structures positive for renal specific markers of different nephron segments. Oct4A levels and differentiation potential of papillary CD133+ cells were higher than those of CD133+ cells from cortical tubuli. Hypoxia was able to promote the undifferentiated phenotype of CD133+ progenitors from papilla. Hypoxia stimulated clonogenicity, proliferation, vascular endothelial growth factor synthesis, and expression of CD133 that were in turn reduced by epithelial differentiation with parallel HIF-1α downregulation. In addition, hypoxia downregulated microRNA-145 and promoted the synthesis of Oct4A. Epithelial differentiation increased microRNA-145 and reduced Oct4 level, suggesting a balance between Oct4 and microRNA-145. MicroRNA-145 overexpression in CD133+ cells induced downrelation of Oct4A at the protein level, inhibited cell proliferation, and stimulated terminal differentiation. This study underlines the role of the hypoxic microenvironment in controlling the proliferation and maintaining a progenitor phenotype and stem/progenitor properties of CD133+ cells of the nephron. This mechanism may be at the basis of the maintenance of a CD133+ population in the papillary region and may be involved in renal regeneration after injury.

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Tanigawa, Shunsuke, and Alan O. Perantoni. "Modeling renal progenitors – defining the niche." Differentiation 91, no. 4-5 (April 2016): 152–58. http://dx.doi.org/10.1016/j.diff.2016.01.007.

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Schrankl, Julia, Bjoern Neubauer, Michaela Fuchs, Katharina Gerl, Charlotte Wagner, and Armin Kurtz. "Apparently normal kidney development in mice with conditional disruption of ANG II-AT1 receptor genes in FoxD1-positive stroma cell precursors." American Journal of Physiology-Renal Physiology 316, no. 6 (June 1, 2019): F1191—F1200. http://dx.doi.org/10.1152/ajprenal.00305.2018.

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An intact renin-angiotensin system involving ANG II type 1 (AT1) receptors is crucial for normal kidney development. It is still unclear in which cell types AT1 receptor signaling is required for normal kidney development, maturation, and function. Because all kidney cells deriving from stroma progenitor cells express AT1 receptors and because stromal cells fundamentally influence nephrogenesis and tubular maturation, we investigated the relevance of AT1 receptors in stromal progenitors and their descendants for renal development and function. For this aim, we generated and analyzed mice with conditional deletion of AT1A receptor in the FoxD1 cell lineage in combination with global disruption of the AT1B receptor gene. These FoxD1-AT1ko mice developed normally. Their kidneys showed neither structural nor functional abnormalities compared with wild-type mice, whereas in isolated perfused FoxD1-AT1ko kidneys, the vasoconstrictor and renin inhibitory effects of ANG II were absent. In vivo, however, plasma renin concentration and renal renin expression were normal in FoxD1-AT1ko mice, as were blood pressure and glomerular filtration rate. These findings suggest that a strong reduction of AT1 receptors in renal stromal progenitors and their descendants does not disturb normal kidney development.

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Rossbach, Bella, Krithika Hariharan, Nancy Mah, Su-Jun Oh, Hans-Dieter Volk, Petra Reinke, and Andreas Kurtz. "Human iPSC-Derived Renal Cells Change Their Immunogenic Properties during Maturation: Implications for Regenerative Therapies." Cells 11, no. 8 (April 13, 2022): 1328. http://dx.doi.org/10.3390/cells11081328.

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The success of human induced pluripotent stem cell (hiPSC)-based therapy critically depends on understanding and controlling the immunological effects of the hiPSC-derived transplant. While hiPSC-derived cells used for cell therapy are often immature with post-grafting maturation, immunological properties may change, with adverse effects on graft tolerance and control. In the present study, the allogeneic and autologous cellular immunity of hiPSC-derived progenitor and terminally differentiated cells were investigated in vitro. In contrast to allogeneic primary cells, hiPSC-derived early renal progenitors and mature renal epithelial cells are both tolerated not only by autologous but also by allogeneic T cells. These immune-privileged properties result from active immunomodulation and low immune visibility, which decrease during the process of cell maturation. However, autologous and allogeneic natural killer (NK) cell responses are not suppressed by hiPSC-derived renal cells and effectively change NK cell activation status. These findings clearly show a dynamic stage-specific dependency of autologous and allogeneic T and NK cell responses, with consequences for effective cell therapies. The study suggests that hiPSC-derived early progenitors may provide advantageous immune-suppressive properties when applied in cell therapy. The data furthermore indicate a need to suppress NK cell activation in allogeneic as well as autologous settings.

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Takahashi, Takamune, Keiko Takahashi, Sebastian Gerety, Hai Wang, David J. Anderson, and Thomas O. Daniel. "Temporally Compartmentalized Expression of Ephrin-B2 during Renal Glomerular Development." Journal of the American Society of Nephrology 12, no. 12 (December 2001): 2673–82. http://dx.doi.org/10.1681/asn.v12122673.

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ABSTRACT. Glomerular development proceeds through the spatially ordered and sequential recruitment, proliferation, assembly, and differentiation of endothelial, mesangial, and epithelial progenitors. The molecular determinants of cell-cell recognition and targeting in this process have yet to be defined. The Eph/ephrin family of membrane receptors and counter-receptors are critical participants of developmental vascular assembly in extrarenal sites. Renal expression patterns of ephrin-B2 and EphB4 were investigated using mice expressing β-galactosidase under control of ephrin-B2 or EphB4 promoters. The earliest glomerular expression of ephrin-B2 was identified in a subset of differentiating comma-stage glomerular epithelial cells (podocyte progenitors) adjacent to the vascular cleft where endothelial progenitors are subsequently recruited. Epithelial ephrin-B2 expression was accompanied by expression in endothelial and mesangial cells as capillary assembly progressed. At or near completion of glomerular maturation, epithelial ephrin-B2 expression was extinguished, with persistence in glomerular endothelial cells. Throughout development, one of several ephrin-B2 receptors, EphB4, was persistently and exclusively expressed in endothelial cells of venous structures. The findings show sequential ephrin-B2 expression across glomerular lineages, first in a distinct subset of podocyte progenitors and subsequently in endothelial cells of the developing glomerulus. Given targeting functions for Eph/ephrin family proteins, the findings suggest that ephrin-B2 expression marks podocyte progenitors at the site of vascular cleft formation, where expression may establish an “address” to which endothelial and mesangial progenitors are recruited. Thus, the present results suggest that ephrin-B2 and EphB interactions play an important role in glomerular microvascular assembly.

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Lazzeri, Elena, Clara Crescioli, Elisa Ronconi, Benedetta Mazzinghi, Costanza Sagrinati, Giuseppe Stefano Netti, Maria Lucia Angelotti, et al. "Regenerative Potential of Embryonic Renal Multipotent Progenitors in Acute Renal Failure." Journal of the American Society of Nephrology 18, no. 12 (October 31, 2007): 3128–38. http://dx.doi.org/10.1681/asn.2007020210.

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Bussolati, Benedetta, Alessia Brossa, and Giovanni Camussi. "Resident Stem Cells and Renal Carcinoma." International Journal of Nephrology 2011 (2011): 1–6. http://dx.doi.org/10.4061/2011/286985.

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According to the cancer stem cell hypothesis tumors are maintained by a cancer stem cell population which is able to initiate and maintain tumors. Tumor-initiating stem cells display stem or progenitor cell properties such as self-renewal and capacity to re-establish tumors that recapitulate the tumor of origin. In this paper, we discuss data relative to the presence of cancer stem cells in human renal carcinoma and their possible origin from normal resident stem cells. The cancer stem cells identified in human renal carcinomas are not derived from the normal CD133+progenitors of the kidney, but rather from a more undifferentiated population that retains a mesenchymal phenotype. This population is able to self-renewal, clonogenicity, and in vivo tumor initiation. Moreover, they retain pluripotent differentiation capability, as they can generate not only the epithelial component of the tumor, but also tumor endothelial cells. This suggests that renal cancer stem cells may contribute to the intratumor vasculogenesis.

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Tan, Zenglai, Aleksandra Rak-Raszewska, Ilya Skovorodkin, and Seppo J. Vainio. "Mouse Embryonic Stem Cell-Derived Ureteric Bud Progenitors Induce Nephrogenesis." Cells 9, no. 2 (January 31, 2020): 329. http://dx.doi.org/10.3390/cells9020329.

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Generation of kidney organoids from pluripotent stem cells (PSCs) is regarded as a potentially powerful way to study kidney development, disease, and regeneration. Direct differentiation of PSCs towards renal lineages is well studied; however, most of the studies relate to generation of nephron progenitor population from PSCs. Until now, differentiation of PSCs into ureteric bud (UB) progenitor cells has had limited success. Here, we describe a simple, efficient, and reproducible protocol to direct differentiation of mouse embryonic stem cells (mESCs) into UB progenitor cells. The mESC-derived UB cells were able to induce nephrogenesis when co-cultured with primary metanephric mesenchyme (pMM). In generated kidney organoids, the embryonic pMM developed nephron structures, and the mESC-derived UB cells formed numerous collecting ducts connected with the nephron tubules. Altogether, our study established an uncomplicated and reproducible platform to generate ureteric bud progenitors from mouse embryonic stem cells.

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Lindström, Nils O., Jinjin Guo, Albert D. Kim, Tracy Tran, Qiuyu Guo, Guilherme De Sena Brandine, Andrew Ransick, et al. "Conserved and Divergent Features of Mesenchymal Progenitor Cell Types within the Cortical Nephrogenic Niche of the Human and Mouse Kidney." Journal of the American Society of Nephrology 29, no. 3 (February 15, 2018): 806–24. http://dx.doi.org/10.1681/asn.2017080890.

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Cellular interactions among nephron, interstitial, and collecting duct progenitors drive mammalian kidney development. In mice, Six2+ nephron progenitor cells (NPCs) and Foxd1+ interstitial progenitor cells (IPCs) form largely distinct lineage compartments at the onset of metanephric kidney development. Here, we used the method for analyzing RNA following intracellular sorting (MARIS) approach, single-cell transcriptional profiling, in situ hybridization, and immunolabeling to characterize the presumptive NPC and IPC compartments of the developing human kidney. As in mice, each progenitor population adopts a stereotypical arrangement in the human nephron-forming niche: NPCs capped outgrowing ureteric branch tips, whereas IPCs were sandwiched between the NPCs and the renal capsule. Unlike mouse NPCs, human NPCs displayed a transcriptional profile that overlapped substantially with the IPC transcriptional profile, and key IPC determinants, including FOXD1, were readily detected within SIX2+ NPCs. Comparative gene expression profiling in human and mouse Six2/SIX2+ NPCs showed broad agreement between the species but also identified species-biased expression of some genes. Notably, some human NPC-enriched genes, including DAPL1 and COL9A2, are linked to human renal disease. We further explored the cellular diversity of mesenchymal cell types in the human nephrogenic niche through single-cell transcriptional profiling. Data analysis stratified NPCs into two main subpopulations and identified a third group of differentiating cells. These findings were confirmed by section in situ hybridization with novel human NPC markers predicted through the single-cell studies. This study provides a benchmark for the mesenchymal progenitors in the human nephrogenic niche and highlights species-variability in kidney developmental programs.

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Dessypris, E., SE Graber, SB Krantz, and WJ Stone. "Effects of recombinant erythropoietin on the concentration and cycling status of human marrow hematopoietic progenitor cells in vivo." Blood 72, no. 6 (December 1, 1988): 2060–62. http://dx.doi.org/10.1182/blood.v72.6.2060.2060.

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Abstract The concentration of human marrow progenitors CFU-E, BFU-E, CFU-GM, and CFU-Mk and the percentage of these progenitor cells in DNA synthesis were studied in nine patients with transfusion-dependent anemia of end- stage renal failure before and 2 weeks after treatment with human recombinant erythropoietin (Epo) at a dose of 150 to 300 U/kg intravenously three times per week. The concentration of CFU-E in the posttreatment marrow increased by a mean of 4.15-fold, BFU-E by 3.37- fold, CFU-GM by 1.86-fold, and CFU-Mk by 1.96-fold as compared with their respective concentrations in the pretreatment marrows. This increase in the concentrations of marrow progenitors was accompanied by almost a doubling of the percentage of these cells in DNA synthesis as assessed by the 3H-thymidine suicide technique. These observations demonstrate that at the progenitor cell level the human marrow responds to therapeutic doses of Epo as an organ rather than by a selective expansion of the erythroid cell line.

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Dessypris, E., SE Graber, SB Krantz, and WJ Stone. "Effects of recombinant erythropoietin on the concentration and cycling status of human marrow hematopoietic progenitor cells in vivo." Blood 72, no. 6 (December 1, 1988): 2060–62. http://dx.doi.org/10.1182/blood.v72.6.2060.bloodjournal7262060.

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The concentration of human marrow progenitors CFU-E, BFU-E, CFU-GM, and CFU-Mk and the percentage of these progenitor cells in DNA synthesis were studied in nine patients with transfusion-dependent anemia of end- stage renal failure before and 2 weeks after treatment with human recombinant erythropoietin (Epo) at a dose of 150 to 300 U/kg intravenously three times per week. The concentration of CFU-E in the posttreatment marrow increased by a mean of 4.15-fold, BFU-E by 3.37- fold, CFU-GM by 1.86-fold, and CFU-Mk by 1.96-fold as compared with their respective concentrations in the pretreatment marrows. This increase in the concentrations of marrow progenitors was accompanied by almost a doubling of the percentage of these cells in DNA synthesis as assessed by the 3H-thymidine suicide technique. These observations demonstrate that at the progenitor cell level the human marrow responds to therapeutic doses of Epo as an organ rather than by a selective expansion of the erythroid cell line.

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Chambers, Brooke E., and Rebecca A. Wingert. "Renal progenitors: Roles in kidney disease and regeneration." World Journal of Stem Cells 8, no. 11 (2016): 367. http://dx.doi.org/10.4252/wjsc.v8.i11.367.

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Ronconi, Elisa, Costanza Sagrinati, Maria Lucia Angelotti, Elena Lazzeri, Benedetta Mazzinghi, Lara Ballerini, Eliana Parente, et al. "Regeneration of Glomerular Podocytes by Human Renal Progenitors." Journal of the American Society of Nephrology 20, no. 2 (December 17, 2008): 322–32. http://dx.doi.org/10.1681/asn.2008070709.

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Romagnani, Paola, and Giuseppe Remuzzi. "Renal progenitors in non-diabetic and diabetic nephropathies." Trends in Endocrinology & Metabolism 24, no. 1 (January 2013): 13–20. http://dx.doi.org/10.1016/j.tem.2012.09.002.

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Becherucci, Francesca, Elena Lazzeri, Laura Lasagni, and Paola Romagnani. "Renal progenitors and childhood: from development to disorders." Pediatric Nephrology 29, no. 4 (January 4, 2014): 711–19. http://dx.doi.org/10.1007/s00467-013-2686-2.

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Sheybani-Deloui, Sepideh, Lijun Chi, Marian V. Staite, Jason E. Cain, Brian J. Nieman, R. Mark Henkelman, Brandon J. Wainwright, et al. "Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction." Journal of the American Society of Nephrology 29, no. 2 (November 6, 2017): 532–44. http://dx.doi.org/10.1681/asn.2017050482.

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Intrinsic ureteropelvic junction obstruction is the most common cause of congenital hydronephrosis, yet the underlying pathogenesis is undefined. Hedgehog proteins control morphogenesis by promoting GLI-dependent transcriptional activation and inhibiting the formation of the GLI3 transcriptional repressor. Hedgehog regulates differentiation and proliferation of ureteric smooth muscle progenitor cells during murine kidney-ureter development. Histopathologic findings of smooth muscle cell hypertrophy and stroma-like cells, consistently observed in obstructing tissue at the time of surgical correction, suggest that Hedgehog signaling is abnormally regulated during the genesis of congenital intrinsic ureteropelvic junction obstruction. Here, we demonstrate that constitutively active Hedgehog signaling in murine intermediate mesoderm–derived renal progenitors results in hydronephrosis and failure to develop a patent pelvic-ureteric junction. Tissue obstructing the ureteropelvic junction was marked as early as E13.5 by an ectopic population of cells expressing Ptch2, a Hedgehog signaling target. Constitutive expression of GLI3 repressor in Ptch1-deficient mice rescued ectopic Ptch2 expression and obstructive hydronephrosis. Whole transcriptome analysis of isolated Ptch2+ cells revealed coexpression of genes characteristic of stromal progenitor cells. Genetic lineage tracing indicated that stromal cells blocking the ureteropelvic junction were derived from intermediate mesoderm–derived renal progenitors and were distinct from the smooth muscle or epithelial lineages. Analysis of obstructive ureteric tissue resected from children with congenital intrinsic ureteropelvic junction obstruction revealed a molecular signature similar to that observed in Ptch1-deficient mice. Together, these results demonstrate a Hedgehog-dependent mechanism underlying mammalian intrinsic ureteropelvic junction obstruction.

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Dionne, Lai Kuan, Kyuhwan Shim, Masato Hoshi, Tao Cheng, Jinzhi Wang, Veronique Marthiens, Amanda Knoten, Renata Basto, Sanjay Jain, and Moe R. Mahjoub. "Centrosome amplification disrupts renal development and causes cystogenesis." Journal of Cell Biology 217, no. 7 (June 12, 2018): 2485–501. http://dx.doi.org/10.1083/jcb.201710019.

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Centrosome number is tightly controlled to ensure proper ciliogenesis, mitotic spindle assembly, and cellular homeostasis. Centrosome amplification (the formation of excess centrosomes) has been noted in renal cells of patients and animal models of various types of cystic kidney disease. Whether this defect plays a causal role in cystogenesis remains unknown. Here, we investigate the consequences of centrosome amplification during kidney development, homeostasis, and after injury. Increasing centrosome number in vivo perturbed proliferation and differentiation of renal progenitors, resulting in defective branching morphogenesis and renal hypoplasia. Centrosome amplification disrupted mitotic spindle morphology, ciliary assembly, and signaling pathways essential for the function of renal progenitors, highlighting the mechanisms underlying the developmental defects. Importantly, centrosome amplification was sufficient to induce rapid cystogenesis shortly after birth. Finally, we discovered that centrosome amplification sensitized kidneys in adult mice, causing cystogenesis after ischemic renal injury. Our study defines a new mechanism underlying the pathogenesis of renal cystogenesis, and identifies a potentially new cellular target for therapy.

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Vinsonneau, C., A. Girshovich, M. Ben M'rad, J. Perez, L. Mesnard, S. Vandermersch, S. Placier, E. Letavernier, L. Baud, and J. P. Haymann. "Intrarenal urothelium proliferation: an unexpected early event following ischemic injury." American Journal of Physiology-Renal Physiology 299, no. 3 (September 2010): F479—F486. http://dx.doi.org/10.1152/ajprenal.00585.2009.

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Identification of renal cell progenitors and recognition of the events contributing to cell regeneration following ischemia-reperfusion injury (IRI) are a major challenge. In a mouse model of unilateral renal IRI, we demonstrated that the first cells to proliferate within injured kidneys were urothelial cells expressing the progenitor cell marker cytokeratin 14. A systematic cutting of the injured kidney revealed that these urothelial cells were located in the deep cortex at the corticomedullary junction in the vicinity of lobar vessels. Contrary to multilayered bladder urothelium, these intrarenal urothelial cells located in the upper part of the medulla constitute a monolayered barrier and express among uroplakins only uroplakin III. However, like bladder progenitors, intrarenal urothelial cells proliferated through a FGF receptor-2 (FGFR2)-mediated process. They strongly expressed FGFR2 and proliferated in vivo after recombinant FGF7 administration to control mice. In addition, IRI led to FGFR phosphorylation together with the selective upregulation of FGF7 and FGF2. Conversely, by day 2 following IRI, renal urothelial cell proliferation was significantly inhibited by FGFR2 antisense oligonucleotide administration into an intrarenal urinary space. Of notice, no significant migration of these early dividing urothelial cells was detected in the cortex within 7 days following IRI. Thus our data show that following IRI, proliferation of urothelial cells is mediated by the FGFR2 pathway and precedes tubular cell proliferation, indicating a particular sensitivity of this structure to changes caused by the ischemic process.

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Nag, Sparshita, and Ashleigh S. Boyd. "Decellularization of Mouse Kidneys to Generate an Extracellular Matrix Gel for Human Induced Pluripotent Stem Cell Derived Renal Organoids." Organoids 2, no. 1 (March 22, 2023): 66–78. http://dx.doi.org/10.3390/organoids2010005.

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Chronic Kidney Disease (CKD) is a major cause of morbidity and mortality characterized by progressive renal fibrosis, and in extreme cases, renal failure. Human CKD models that replicate the biological complexity of the kidney and CKD are lacking and will be invaluable in identifying drugs to revert and/or prevent fibrosis. To address this unmet need, we developed 3D renal organoids where human induced pluripotent stem cells (hiPSCs) were differentiated to renal progenitors within a renal extracellular matrix (rECM) gel, based on the premise that an rECM could recreate the renal niche to facilitate hiPSC-derived renal progenitor generation. We used mouse kidneys as a source of rECM and identified that superior detergent-mediated decellularization of mouse kidneys was achieved with a combination of 0.5% w/v Sodium Dodecyl Sulphate and 1% v/v Triton-X and mechanical agitation for 60 h. HiPSCs that underwent specification to become metanephric mesenchyme (MM) were subsequently cultured within the rECM gel and, notably, mesenchymal to epithelial transition (MET) was observed, as judged by expression of nephron markers K-cadherin, Nephrin and WT1. These data demonstrate a role for rECM gel in developing human renal organoids from hiPSCs, which will aid the further development of a human disease model for renal fibrosis.

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Drummond, Bridgette E., Brooke E. Chambers, Hannah M. Wesselman, Shannon Gibson, Liana Arceri, Marisa N. Ulrich, Gary F. Gerlach, et al. "osr1 Maintains Renal Progenitors and Regulates Podocyte Development by Promoting wnt2ba via the Antagonism of hand2." Biomedicines 10, no. 11 (November 9, 2022): 2868. http://dx.doi.org/10.3390/biomedicines10112868.

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Knowledge about the genetic pathways that control nephron development is essential for better understanding the basis of congenital malformations of the kidney. The transcription factors Osr1 and Hand2 are known to exert antagonistic influences to balance kidney specification. Here, we performed a forward genetic screen to identify nephrogenesis regulators, where whole genome sequencing identified an osr1 lesion in the novel oceanside (ocn) mutant. The characterization of the mutant revealed that osr1 is needed to specify not renal progenitors but rather their maintenance. Additionally, osr1 promotes the expression of wnt2ba in the intermediate mesoderm (IM) and later the podocyte lineage. wnt2ba deficiency reduced podocytes, where overexpression of wnt2ba was sufficient to rescue podocytes and osr1 deficiency. Antagonism between osr1 and hand2 mediates podocyte development specifically by controlling wnt2ba expression. These studies reveal new insights about the roles of Osr1 in promoting renal progenitor survival and lineage choice.

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Urbach, A., A. Yermalovich, J. Zhang, C. S. Spina, H. Zhu, A. R. Perez-Atayde, R. Shukrun, et al. "Lin28 sustains early renal progenitors and induces Wilms tumor." Genes & Development 28, no. 9 (April 14, 2014): 971–82. http://dx.doi.org/10.1101/gad.237149.113.

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Romagnani, Paola, Laura Lasagni, and Giuseppe Remuzzi. "Renal progenitors: an evolutionary conserved strategy for kidney regeneration." Nature Reviews Nephrology 9, no. 3 (January 22, 2013): 137–46. http://dx.doi.org/10.1038/nrneph.2012.290.

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Barasch, J., J. Yang, and K. Mori. "INDUCTION OF NEPHRONS FROM RENAL PROGENITORS BY MULTIPLE SIGNALS." ASAIO Journal 49, no. 2 (March 2003): 198. http://dx.doi.org/10.1097/00002480-200303000-00230.

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Barak, Y., L. Sinai-Treiman, Y. Karov, A. Abrahamov, and A. Drukker. "Hematopoietic Progenitors in Children with End-Stage Renal Disease." Pediatric Hematology and Oncology 11, no. 6 (January 1994): 633–39. http://dx.doi.org/10.3109/08880019409141810.

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Wang, Honghe, Yili Yang, Nirmala Sharma, Nadya I. Tarasova, Olga A. Timofeeva, Robin T. Winkler-Pickett, Shunsuke Tanigawa, and Alan O. Perantoni. "STAT1 activation regulates proliferation and differentiation of renal progenitors." Cellular Signalling 22, no. 11 (November 2010): 1717–26. http://dx.doi.org/10.1016/j.cellsig.2010.06.012.

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Osafune, Kenji. "iPSC technology-based regenerative medicine for kidney diseases." Clinical and Experimental Nephrology 25, no. 6 (March 3, 2021): 574–84. http://dx.doi.org/10.1007/s10157-021-02030-x.

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AbstractWith few curative treatments for kidney diseases, increasing attention has been paid to regenerative medicine as a new therapeutic option. Recent progress in kidney regeneration using human-induced pluripotent stem cells (hiPSCs) is noteworthy. Based on the knowledge of kidney development, the directed differentiation of hiPSCs into two embryonic kidney progenitors, nephron progenitor cells (NPCs) and ureteric bud (UB), has been established, enabling the generation of nephron and collecting duct organoids. Furthermore, human kidney tissues can be generated from these hiPSC-derived progenitors, in which NPC-derived glomeruli and renal tubules and UB-derived collecting ducts are interconnected. The induced kidney tissues are further vascularized when transplanted into immunodeficient mice. In addition to the kidney reconstruction for use in transplantation, it has been demonstrated that cell therapy using hiPSC-derived NPCs ameliorates acute kidney injury (AKI) in mice. Disease modeling and drug discovery research using disease-specific hiPSCs has also been vigorously conducted for intractable kidney disorders, such as autosomal dominant polycystic kidney disease (ADPKD). In an attempt to address the complications associated with kidney diseases, hiPSC-derived erythropoietin (EPO)-producing cells were successfully generated to discover drugs and develop cell therapy for renal anemia. This review summarizes the current status and future perspectives of developmental biology of kidney and iPSC technology-based regenerative medicine for kidney diseases.

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Jackson, Ashley R., Monica L. Hoff, Birong Li, Christina B. Ching, Kirk M. McHugh, and Brian Becknell. "Krt5+ urothelial cells are developmental and tissue repair progenitors in the kidney." American Journal of Physiology-Renal Physiology 317, no. 3 (September 1, 2019): F757—F766. http://dx.doi.org/10.1152/ajprenal.00171.2019.

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Congenital urinary tract obstruction (UTO) is the leading cause of chronic kidney disease in children; however, current management strategies do not safeguard against progression to end-stage renal disease, highlighting the need for interventions to limit or reverse obstructive nephropathy. Experimental UTO triggers renal urothelial remodeling that culminates in the redistribution of basal keratin 5-positive (Krt5+) renal urothelial cells (RUCs) and the generation of uroplakin-positive (Upk)+ RUCs that synthesize a protective apical urothelial plaque. The cellular source of Upk+ RUCs is currently unknown, limiting the development of strategies to promote renal urothelial remodeling as a therapeutic approach. In the present study, we traced the origins of adult Upk+ RUCs during normal development and in response to UTO. Fate mapping analysis demonstrated that adult Upk+ RUCs derive from embryonic and neonatal Krt5+ RUCs, whereas Krt5+ RUCs lose this progenitor capacity and become lineage restricted by postnatal day 14. However, in response to UTO, postnatal day 14-labeled adult Krt5+ RUCs break their lineage restriction and robustly differentiate into Upk+ RUCs. Thus, Krt5+ RUCs drive renal urothelial formation during normal ontogeny and after UTO by differentiating into Upk+ RUCs in a temporally restricted manner.

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De Filippo, Roger E., Ilenia Zanusso, Stefano Da Sacco, Scott Leslie, Astgik Petrosyan, Kevin V. Lemley, and Laura Perin. "Amniotic fluid renal progenitors and renal extracellular matrix: a new approach for kidney regeneration." Journal of the American College of Surgeons 219, no. 4 (October 2014): e55. http://dx.doi.org/10.1016/j.jamcollsurg.2014.07.531.

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Yosypiv, Ihor V., Maria Luisa S. Sequeira-Lopez, Renfang Song, and Alexandre De Goes Martini. "Stromal prorenin receptor is critical for normal kidney development." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 316, no. 5 (May 1, 2019): R640—R650. http://dx.doi.org/10.1152/ajpregu.00320.2018.

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Formation of the metanephric kidney requires coordinated interaction among the stroma, ureteric bud, and cap mesenchyme. The transcription factor Foxd1, a specific marker of renal stromal cells, is critical for normal kidney development. The prorenin receptor (PRR), a receptor for renin and prorenin, is also an accessory subunit of the vacuolar proton pump V-ATPase. Global loss of PRR is embryonically lethal in mice, indicating an essential role of the PRR in embryonic development. Here, we report that conditional deletion of the PRR in Foxd1+ stromal progenitors in mice ( cKO) results in neonatal mortality. The kidneys of surviving mice show reduced expression of stromal markers Foxd1 and Meis1 and a marked decrease in arterial and arteriolar development with the subsequent decreased number of glomeruli, expansion of Six2+ nephron progenitors, and delay in nephron differentiation. Intrarenal arteries and arterioles in cKO mice were fewer and thinner and showed a marked decrease in the expression of renin, suggesting a central role for the PRR in the development of renin-expressing cells, which in turn are essential for the proper formation of the renal arterial tree. We conclude that stromal PRR is crucial for the appropriate differentiation of the renal arterial tree, which in turn may restrict excessive expansion of nephron progenitors to promote a coordinated and proper morphogenesis of the nephrovascular structures of the mammalian kidney.

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Atala, Anthony. "Re: Lin28 Sustains Early Renal Progenitors and Induces Wilms Tumor." Journal of Urology 193, no. 2 (February 2015): 730–31. http://dx.doi.org/10.1016/j.juro.2014.11.021.

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Franzin, Rossana, Alessandra Stasi, Giuseppe De Palma, Angela Picerno, Claudia Curci, Serena Sebastiano, Monica Campioni, et al. "Human Adult Renal Progenitor Cells Prevent Cisplatin-Nephrotoxicity by Inducing CYP1B1 Overexpression and miR-27b-3p Down-Regulation through Extracellular Vesicles." Cells 12, no. 12 (June 17, 2023): 1655. http://dx.doi.org/10.3390/cells12121655.

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Cisplatin is one of the most effective chemotherapeutic agents strongly associated with nephrotoxicity. Tubular adult renal progenitor cells (tARPC) can regenerate functional tubules and participate in the repair processes after cisplatin exposition. This study investigated the molecular mechanisms underlying the protective effect of tARPC on renal epithelium during cisplatin nephrotoxicity. By performing a whole-genome transcriptomic analysis, we found that tARPC, in presence of cisplatin, can strongly influence the gene expression of renal proximal tubular cell [RPTEC] by inducing overexpression of CYP1B1, a member of the cytochrome P450 superfamily capable of metabolizing cisplatin and of hypoxia/cancer-related lncRNAs as MIR210HG and LINC00511. Particularly, tARPC exerted renoprotection and regeneration effects via extracellular vesicles (EV) enriched with CYP1B1 and miR-27b-3p, a well-known CYP1B1 regulatory miRNA. The expression of CYP1B1 by tARPC was confirmed by analyzing biopsies of cisplatin-treated renal carcinoma patients that showed the colocalization of CYP1B1 with the tARPC marker CD133. CYP1B1 was also overexpressed in urinary EV purified from oncologic patients that presented nephrotoxicity episodes after cisplatin treatment. Interestingly CYP1B1 expression significantly correlated with creatinine and eGFR levels. Taken together, our results show that tARPC are able to counteract cisplatin-induced nephrotoxicity via CYP1B1 release through EV. These findings provide a promising therapeutic strategy for nephrotoxicity risk assessment that could be related to abundance of renal progenitors.

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Chan, Charles, Ching-Cheng Chen, Daniel L. Kraft, Cynthia Luppen, Jae-Beom Kim, Anthony DeBoer, Kevin Wei Wei, and Irving L. Weissman. "Identification and Isolation of the Hematopoietic Stem Cell Niche Initiating Cell Population." Blood 112, no. 11 (November 16, 2008): 3574. http://dx.doi.org/10.1182/blood.v112.11.3574.3574.

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Abstract Introduction: Identification and understanding of the cells and processes that can generate, sustain and influence the HSC niche and hematopoiesis are critical for the development of a more comprehensive knowledge of normal hematopoiesis, stem cell homing, trafficking, differentiation and hematopoietic pathology. Growth and renewal in many tissues are initiated by stem cells, supported by the microenvironment (niche) in which they reside. While recent work has begun to describe functional interactions between stem cells and their niches, little is known about the formation of stem cell niches. Methods & Results: We established a functional, in vivo assay (via implantation of cells under the renal capsule) to isolate the determinants of hematopoietic stem cell (HSC) niche formation and activity. Using this novel assay, we show that a population of progenitor cells (CD45−Tie2-aV+CD105+Thy1.1−; CD105+Thy1−) sorted from 15.5 dpc fetal limbs and transplanted under the adult mouse renal capsule recruit host-derived vasculatures in a VEGF dependent manner, produce donor-derived ectopic bones through endochondral ossification, and generate a marrow cavity populated by host-derived long term reconstituting HSC (LT-HSC). In contrast, CD45−Tie2-aV+CD105+Thy1a+ (CD105+Thy1+) progenitors form bone that does not contain a marrow cavity. While analyzing these and other sorted populations, we did not observe any instances where niche was present without bone, suggesting that skeletal progenitors are necessary for initiating an HSC niche but osteoblasts alone cannot initiate and support niche activity. Suppression of factors important for HSC maintenance, such as steel factor (SLF), in progenitor populations prior to transplant did not alter their ability to initiate and support an HSC niche. On the other hand, suppression of factors involved in endochondral ossification, such as osterix and VEGF, inhibited niche generation. Furthermore, CD105+Thy1− progenitor populations derived from regions of the fetal mandible or calvaria that do not undergo endochondral ossification form only bone without marrow in our assay. Conclusions: In addition to identifying the limb-derived skeletal progenitor capable of endochondral ossification involved and the basic mechanisms of HSC niche initiation, our study provides a functional framework by which future studies on HSC-niche interactions at the cellular level can be carried out.

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Mukherjee, Elina, Katherine Maringer, Emily Papke, Daniel Bushnell, Caitlin Schaefer, Rafael Kramann, Jacqueline Ho, Benjamin D. Humphreys, Carlton Bates, and Sunder Sims-Lucas. "Endothelial marker-expressing stromal cells are critical for kidney formation." American Journal of Physiology-Renal Physiology 313, no. 3 (September 1, 2017): F611—F620. http://dx.doi.org/10.1152/ajprenal.00136.2017.

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Kidneys are highly vascularized and contain many distinct vascular beds. However, the origins of renal endothelial cells and roles of the developing endothelia in the formation of the kidney are unclear. We have shown that the Foxd1-positive renal stroma gives rise to endothelial marker-expressing progenitors that are incorporated within a subset of peritubular capillaries; however, the significance of these cells is unclear. The purpose of this study was to determine whether deletion of Flk1 in the Foxd1 stroma was important for renal development. To that end, we conditionally deleted Flk1 (critical for endothelial cell development) in the renal stroma by breeding-floxed Flk1 mice ( Flk1fl/fl) with Foxd1cre mice to generate Foxd1cre; Flk1fl/fl ( Flk1ST−/−) mice. We then performed FACsorting, histological, morphometric, and metabolic analyses of Flk1ST−/− vs. control mice. We confirmed decreased expression of endothelial markers in the renal stroma of Flk1ST−/− kidneys via flow sorting and immunostaining, and upon interrogation of embryonic and postnatal Flk1ST−/− mice, we found they had dilated peritubular capillaries. Three-dimensional reconstructions showed reduced ureteric branching and fewer nephrons in developing Flk1ST−/− kidneys vs. controls. Juvenile Flk1ST−/− kidneys displayed renal papillary hypoplasia and a paucity of collecting ducts. Twenty-four-hour urine collections revealed that postnatal Flk1ST−/− mice had urinary-concentrating defects. Thus, while lineage-tracing revealed that the renal cortical stroma gave rise to a small subset of endothelial progenitors, these Flk1-expressing stromal cells are critical for patterning the peritubular capillaries. Also, loss of Flk1 in the renal stroma leads to nonautonomous-patterning defects in ureteric lineages.

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Bombelli, Silvia, Chiara Meregalli, Chiara Grasselli, Maddalena M. Bolognesi, Antonino Bruno, Stefano Eriani, Barbara Torsello, et al. "PKHhigh/CD133+/CD24− Renal Stem-Like Cells Isolated from Human Nephrospheres Exhibit In Vitro Multipotency." Cells 9, no. 8 (July 29, 2020): 1805. http://dx.doi.org/10.3390/cells9081805.

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The mechanism upon which human kidneys undergo regeneration is debated, though different lineage-tracing mouse models have tried to explain the cellular types and the mechanisms involved. Different sources of human renal progenitors have been proposed, but it is difficult to argue whether these populations have the same capacities that have been described in mice. Using the nephrosphere (NS) model, we isolated the quiescent population of adult human renal stem-like PKHhigh/CD133+/CD24− cells (RSC). The aim of this study was to deepen the RSC in vitro multipotency capacity. RSC, not expressing endothelial markers, generated secondary nephrospheres containing CD31+/vWf+ cells and cytokeratin positive cells, indicating the coexistence of endothelial and epithelial commitment. RSC cultured on decellularized human renal scaffolds generated endothelial structures together with the proximal and distal tubular structures. CD31+ endothelial committed progenitors sorted from nephrospheres generated spheroids with endothelial-like sprouts in Matrigel. We also demonstrated the double commitment toward endothelial and epithelial lineages of single RSC. The ability of the plastic RSC population to recapitulate the development of tubular epithelial and endothelial renal lineages makes these cells a good tool for the creation of organoids with translational relevance for studying the parenchymal and endothelial cell interactions and developing new therapeutic strategies.

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Namdarian, Benjamin, Kevin V. S. Tan, Matthew J. Fankhauser, Thanh T. Nguyen, Niall M. Corcoran, Anthony J. Costello, and Christopher M. Hovens. "Circulating endothelial cells and progenitors: potential biomarkers of renal cell carcinoma." BJU International 106, no. 7 (September 14, 2010): 1081–87. http://dx.doi.org/10.1111/j.1464-410x.2010.09245.x.

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Dolt, Karamjit Singh, David Edgar, Simon Kenny, and Patricia Murray. "14-P007 Differentiation of human embryonic stem cells towards renal progenitors." Mechanisms of Development 126 (August 2009): S241. http://dx.doi.org/10.1016/j.mod.2009.06.626.

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Becherucci, Francesca, Benedetta Mazzinghi, Marco Allinovi, Maria Lucia Angelotti, and Paola Romagnani. "Regenerating the kidney using human pluripotent stem cells and renal progenitors." Expert Opinion on Biological Therapy 18, no. 7 (July 3, 2018): 795–806. http://dx.doi.org/10.1080/14712598.2018.1492546.

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Zhang, Jiong, Jeffrey W. Pippin, Ronald D. Krofft, Shokichi Naito, Zhi-Hong Liu, and Stuart J. Shankland. "Podocyte repopulation by renal progenitor cells following glucocorticoids treatment in experimental FSGS." American Journal of Physiology-Renal Physiology 304, no. 11 (June 1, 2013): F1375—F1389. http://dx.doi.org/10.1152/ajprenal.00020.2013.

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Prednisone is a mainstay of treatment for patients with focal segmental glomerulosclerosis (FSGS), a disease characterized by reduced podocyte number and glomerulosclerosis. Although the systemic immune-modulatory effects of prednisone are well-known, direct tissue effects on glomerular cells are poorly understood. Experimental FSGS was induced in mice with a cytotoxic anti-podocyte antibody, resulting in an abrupt decrease in podocyte number by day 3, proteinuria, and the development of glomerulosclerosis. Administering daily prednisone to mice with FSGS, beginning at day 3, significantly increased podocyte number at weeks 2 and 4. Podocyte number did not increase in control mice with FSGS given DMSO. The increase in podocyte number in prednisone-treated mice correlated significantly with reduced glomerulosclerosis. Prednisone reduced podocyte apoptosis measured by synaptopodin+/caspase-3+ double staining. Additionally, the number of podocyte progenitors, defined as cells expressing both a parietal epithelial cell protein and a podocyte protein, was significantly increased in prednisone-treated mice with FSGS at weeks 2 and 4. This was associated with increased phospho-ERK staining in both parietal epithelial cells (PAX2+/p-ERK+) and in podocyte progenitors (WT-1+/p-ERK+ lining Bowman's capsule). These data show that in this model of experimental FSGS, prednisone augments glomerular repair by increasing podocyte number through direct effects on both glomerular epithelial cells. Prednisone limits podocyte loss by reducing apoptosis, and it increases regeneration by augmenting the number of podocyte progenitors. The data support a direct glomerular cell action for prednisone in improving outcomes in FSGS.

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Journal articles on the topic 'Renal progenitors'

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