Endothelial Progenitors Exist within the Kidney and Lung Mesenchyme

The renal endothelium has been debated as arising from resident hemangioblast precursors that transdifferentiate from the nephrogenic mesenchyme (vasculogenesis) and/or from invading vessels (angiogenesis). While the Foxd1-positive renal cortical stroma has been shown to differentiate into cells that support the vasculature in the kidney (including vascular smooth muscle and pericytes) it has not been considered as a source of endothelial cell progenitors. In addition, it is unclear if Foxd1-positive mesenchymal cells in other organs such as the lung have the potential to form endothelium. This study examines the potential for Foxd1-positive cells of the kidney and lung to give rise to endothelial progenitors. We utilized immunofluorescence (IF) and fluorescence-activated cell sorting (FACS) to co-label Foxd1-expressing cells (including permanently lineage-tagged cells) with endothelial markers in embryonic and postnatal mice. We also cultured FACsorted Foxd1-positive cells, performed in vitro endothelial cell tubulogenesis assays and examined for endocytosis of acetylated low-density lipoprotein (Ac-LDL), a functional assay for endothelial cells. Immunofluorescence and FACS revealed that a subset of Foxd1-positive cells from kidney and lung co-expressed endothelial cell markers throughout embryogenesis. In vitro, cultured embryonic Foxd1-positive cells were able to differentiate into tubular networks that expressed endothelial cell markers and were able to endocytose Ac-LDL. IF and FACS in both the kidney and lung revealed that lineage-tagged Foxd1-positive cells gave rise to a significant portion of the endothelium in postnatal mice. In the kidney, the stromal-derived cells gave rise to a portion of the peritubular capillary endothelium, but not of the glomerular or large vessel endothelium. These findings reveal the heterogeneity of endothelial cell lineages; moreover, Foxd1-positive mesenchymal cells of the developing kidney and lung are a source of endothelial progenitors that are likely critical to patterning the vasculature. © 2013 Sims-Lucas et al

Ablation of the renal stroma defines its critical role in nephron progenitor and vasculature patterning

The renal stroma is an embryonic cell population located in the cortex that provides a structural framework as well as a source of endothelial progenitors for the developing kidney. The exact role of the renal stroma in normal kidney development hasn't been clearly defined. However, previous studies have shown that the genetic deletion of Foxd1, a renal stroma specific gene, leads to severe kidney malformations confirming the importance of stroma in normal kidney development. This study further investigates the role of renal stroma by ablating Foxd1-derived stroma cells themselves and observing the response of the remaining cell populations. A Foxd1cre (renal stroma specific) mouse was crossed with a diphtheria toxin mouse (DTA) to specifically induce apoptosis in stromal cells. Histological examination of kidneys at embryonic day 13.5-18.5 showed a lack of stromal tissue, mispatterning of renal structures, and dysplastic and/or fused horseshoe kidneys. Immunofluorescence staining of nephron progenitors, vasculature, ureteric epithelium, differentiated nephron progenitors, and vascular supportive cells revealed that mutants had thickened nephron progenitor caps, cortical regions devoid of nephron progenitors, aberrant vessel patterning and thickening, ureteric branching defects and migration of differentiated nephron structures into the medulla. The similarities between the renal deformities caused by Foxd1 genetic knockout and Foxd1DTA mouse models reveal the importance of Foxd1 in mediating and maintaining the functional integrity of the renal stroma. © 2014 Hum et al

Deletion of Fibroblast Growth Factor Receptor 2 from the Peri-Wolffian Duct Stroma Leads to Ureteric Induction Abnormalities and Vesicoureteral Reflux

Purpose: Pax3cre-mediated deletion of fibroblast growth factor receptor 2 (Fgfr2) broadly in renal and urinary tract mesenchyme led to ureteric bud (UB) induction defects and vesicoureteral reflux (VUR), although the mechanisms were unclear. Here, we investigated whether Fgfr2 acts specifically in peri-Wolffian duct stroma (ST) to regulate UB induction and development of VUR and the mechanisms of Fgfr2 activity. Methods: We conditionally deleted Fgfr2 in ST (Fgfr2 ST-/- ) using Tbx18cre mice. To look for ureteric bud induction defects in young embryos, we assessed length and apoptosis of common nephric ducts (CNDs). We performed 3D reconstructions and histological analyses of urinary tracts of embryos and postnatal mice and cystograms in postnatal mice to test for VUR. We performed in situ hybridization and real-time PCR in young embryos to determine mechanisms underlying UB induction defects. Results: We confirmed that Fgfr2 is expressed in ST and that Fgfr2 was efficiently deleted in this tissue in Fgfr2 ST-/- mice at embryonic day (E) 10.5. E11.5 Fgfr2 ST-/- mice had randomized UB induction sites with approximately 1/3 arising too high and 1/3 too low from the Wolffian duct; however, apoptosis was unaltered in E12.5 mutant CNDs. While ureters were histologically normal, E15.5 Fgfr2 ST-/- mice exhibit improper ureteral insertion sites into the bladder, consistent with the ureteric induction defects. While ureter and bladder histology appeared normal, postnatal day (P) 1 mutants had high rates of VUR versus controls (75% versus 3%, p = 0.001) and occasionally other defects including renal hypoplasia and duplex systems. P1 mutant mice also had improper ureteral bladder insertion sites and shortened intravesicular tunnel lengths that correlated with VUR. E10.5 Fgfr2 ST-/- mice had decreases in Bmp4 mRNA in stromal tissues, suggesting a mechanism underlying the ureteric induction and VUR phenotypes. Conclusion: Mutations in FGFR2 could possibly cause VUR in humans. © 2013 Walker et al

The Optimal Control of Heteroscedastic Macroeconomic Models

This paper analyses the implications of heteroscedasticity for optimal macroeconomic policy and welfare. We find that changes in the variance structure driven by exogenous processes like generalized autoregressive conditional heteroscedasticity (GARCH) affect welfare but not the optimal feedback rule. However, changes in the variance structure driven by state-dependent processes affect both. We also derive certainty-equivalent transformations of state-dependent volatility models that allow standard quadratic dynamic programming algorithms to be employed to study optimal policy. These results are illustrated numerically using a reduced-form model of the US economy in which changes in volatility are driven by a GARCH process and the rate of inflation. Copyright © 2015 John Wiley & Sons, Ltd

Virtual player design using self-learning via competitive coevolutionary algorithms

The Google Artificial Intelligence (AI) Challenge is an international contest the objective of which is to program the AI in a two-player real time strategy (RTS) game. This AI is an autonomous computer program that governs the actions that one of the two players executes during the game according to the state of play. The entries are evaluated via a competition mechanism consisting of two-player rounds where each entry is tested against others. This paper describes the use of competitive coevolutionary (CC) algorithms for the automatic generation of winning game strategies in Planet Wars, the RTS game associated with the 2010 contest. Three different versions of a prime algorithm have been tested. Their common nexus is not only the use of a Hall-of-Fame (HoF) to keep note of the winners of past coevolutions but also the employment of an archive of experienced players, termed the hall-of-celebrities (HoC), that puts pressure on the optimization process and guides the search to increase the strength of the solutions; their differences come from the periodical updating of the HoF on the basis of quality and diversity metrics. The goal is to optimize the AI by means of a self-learning process guided by coevolutionary search and competitive evaluation. An empirical study on the performance of a number of variants of the proposed algorithms is described and a statistical analysis of the results is conducted. In addition to the attainment of competitive bots we also conclude that the incorporation of the HoC inside the primary algorithm helps to reduce the effects of cycling caused by the use of HoF in CC algorithms.This work is partially supported by Spanish MICINN under Project ANYSELF (TIN2011-28627-C04-01),3 by Junta de Andalucía under Project P10-TIC-6083 (DNEMESIS) and by Universidad de Málaga, Campus de Excelencia Internacional Andalucía Tech

Betaglycan Is Required for the Establishment of Nephron Endowment in the Mouse

Betaglycan is an accessory receptor for the transforming growth factor-β (TGFβ) superfamily, many members of which play key roles in kidney development. The purpose of this study was to define the role of this co-receptor on fetal murine kidney development. Stereological examination of embryonic and adult betaglycan heterozygous kidneys revealed augmented nephron number relative to littermate controls. Fetal heterozygous kidneys exhibited accelerated ureteric branching, which correlated with augmented nephron development at embryonic day (e) 15.5. In contrast, betaglycan null kidneys exhibited renal hypoplasia from e13.5 and reduced nephron number at e15.5. Quantitative real-time PCR analysis of e11.5–e14.5 kidneys demonstrated that heterozygous kidneys exhibited a transient decrease in Bmp4 expression at e11.5 and a subsequent cascade of changes in the gene regulatory network that governs metanephric development, including significant increases in Pax2, Eya1, Gdnf, Ret, Wnt4, and Wt1 expression. Conversely, gene expression in null kidneys was normal until e13.5, when significant reductions were detected in the expression of Bmp4 as well as other key metanephric regulatory genes. Tgfb1 and Tgfb2 mRNA expression was down-regulated in both nulls and heterozygotes at e13.5 and e14.5. The opposing morphological and molecular phenotypes in betaglycan heterozygote and null mutants demonstrate that the levels of betaglycan must be tightly regulated for optimal kidney development