Up-Regulation of Fetal Rat Lung Parathyroid Hormone-Related Protein Gene Regulatory Network Down-Regulates the Sonic Hedgehog/Wnt/βcatenin Gene Regulatory Network

Torday, John S.; Rehan, Virender K.

doi:10.1203/01.pdr.0000238326.42590.03

Cited by 38 publications

(42 citation statements)

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“…It should not be surprising that RGZ stimulation of lipofibroblast differentiation would be cytoprotective against oxidant injury, since lipofibroblasts have intrinsic antioxidant properties, and they produce specific growth and differentiation factors that have both direct and indirect effects on alveolar differentiation and homeostasis (27,29,35). The uptake of neutral lipids by lipofibroblasts, which protects them against oxidant injury, is specifically dependent on PPAR-␥ induction of adipocyte differentiation-related protein, which determines the uptake and storage of neutral lipid (9,22).…”

Section: Discussionmentioning

confidence: 99%

Antenatally administered PPAR-γ agonist rosiglitazone prevents hyperoxia-induced neonatal rat lung injury

Rehan

Sakurai

Corral

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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The physiological development and homeostasis of the lung alveolus is determined by the expression of peroxisome proliferator-activated receptor-␥ (PPAR-␥) by the interstitial lipofibroblast. We have recently shown (Dasgupta C et al., Am J Physiol Lung Cell Mol Physiol 296: L1031-L1041, 2009.) that PPAR-␥ agonists administered postnatally accelerate lung maturation and prevent hyperoxia-induced lung injury. However, whether the same occurs antenatally is not known. The objective of this study was to test the hypothesis that the potent PPAR-␥ agonist rosiglitazone (RGZ), administered antenatally, enhances fetal lung maturation and protects against hyperoxia-induced neonatal lung injury. Sprague-Dawley rat dams were administered either diluent or RGZ (3 mg/kg), at late gestation, to determine its effect on lung maturation and on hyperoxia (95% O 2 exposure for 24 h)-induced neonatal lung injury. The lungs were examined for the expression of specific markers of alveolar development (surfactant proteins A and B, cholinephosphate cytidylyltransferase-␣, leptin receptor, triglyceride uptake, and [ 3 H]choline incorporation into saturated phosphatidylcholine) and injury/repair, in particular, the markers of transforming growth factor-␤ signaling (activin receptor-like kinase-5, SMAD3, lymphoid enhancer factor-1, fibronectin, and calponin). Overall, antenatal RGZ accelerated lung maturation and blocked the inhibition of alveolar sacculation and septal wall thinning by hyperoxia. RGZ specifically stimulated the development of the alveolar epithelial type II cell, the lipofibroblast, and the vasculature. The increased expression of the transforming growth factor-␤ intermediates, such as SMAD3 and lymphoid enhancer factor-1, implicated in hyperoxic lung injury, was also blocked by antenatal RGZ treatment. In conclusion, PPAR-␥ agonists can enhance fetal lung maturation and can effectively prevent hyperoxia-induced neonatal lung injury. lung development; peroxisome proliferator-activated receptor-␥; surfactant; lipofibroblast; hyperoxia SEVERAL LINES OF EVIDENCE suggest that lipids are cytoprotective against oxygen free radical lung injury in vitro and in vivo (5,23,37). Investigators have suggested that the greater oxygen tolerance of newborn rats and mice, compared with their adult counterparts, relates, in part, to the greater amount of triglyceride in the lipid fraction of the newborn compared with the adult lung (14,24,25,37). Feeding pregnant rats a high triglyceride diet results in increased triglyceride content in the lungs of their offspring, increased survival, and improved pathological status after prolonged hyperoxic exposure (25). In contrast, newborn offspring of rats fed low-polyunsaturated fatty acid diets are more susceptible to pulmonary oxygen toxicity and early lethality in hyperoxia (24). Furthermore, Kehrer and Autor (14) demonstrated that increasing the saturated fatty acid composition of lung triglycerides in adult rats by dietary manipulation produced increased susceptibility to oxygen toxicity.Ou...

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Section: Discussionmentioning

confidence: 99%

Antenatally administered PPAR-γ agonist rosiglitazone prevents hyperoxia-induced neonatal rat lung injury

Rehan

Sakurai

Corral

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Primer sequences are shown in supplementary material Table S2. Primers for other mRNAs were as reported previously: Wnt (Mohamed et al, 2004b), Fzds (Chen et al, 2004;Torday and Rehan, 2006), Ror2 (Mikels and Nusse, 2006) and LRP5/6 (Stump et al, 2003). PCR was performed using the program: 95°C for 3 minutes followed by 25-30 cycles of 95°C for 30 seconds, 51.1-61.5°C for 30 seconds, 72°C for 30 seconds with a final extension at 72°C for 5 minutes.…”

Section: Rna Isolation and Rt-pcr Analysismentioning

confidence: 99%

Wnt5a is a cell-extrinsic factor that supports self-renewal of mouse spermatogonial stem cells

2011

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SummaryThe maintenance of spermatogonial stem cells (SSCs) provides the foundation for life-long spermatogenesis. Although glial-cell-linederived neurotrophic factor and fibroblast growth factor 2 are crucial for self-renewal of SSCs, recent studies have suggested that other growth factors have important roles in controlling SSC fate. Because -catenin-dependent Wnt signaling promotes self-renewal of various stem cell types, we hypothesized that this pathway contributes to SSC maintenance. Using transgenic reporter mice for -catenin-dependent signaling, we found that this signaling was not active in SSCs in vitro and in most spermatogonia in vivo. Nonetheless, a pan-Wnt antagonist significantly reduced SSC activity in vitro, suggesting that some Wnt molecules exist in our serumfree culture system and contribute to SSC maintenance. Here, we report that Wnt5a promotes SSC activity. We found that Wnt5a-expressing fibroblasts supported SSC activity better than those not expressing Wnt5a in culture, and that recombinant Wnt5a stimulated SSC maintenance. Furthermore, Wnt5a promoted SSC survival in the absence of feeder cells, and this effect was abolished by inhibiting the Jun N-terminal kinase cascade. In addition, Wnt5a blocked -catenin-dependent signaling. We detected the expression of Wnt5a and potential Wnt5a receptors in Sertoli cells and stem/progenitor spermatogonia, respectively. These results indicate that Wnt5a is a cell-extrinsic factor that supports SSC self-renewal through -catenin-independent mechanisms.

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“…We have shown that during alveolarization, the formation of lung fluid upregulates the PTHrP signaling pathway in the endoderm, causing the downregulation of the Wnt/␤-catenin pathway (49), leading to the differentiation of the lipofibroblast. These cells dominate the alveolar acinus during fetal lung development but are highly apoptotic in the postnatal lung (3), giving rise to the alveolar septa (1).…”

Section: Myofibroblast Transdifferentiation As Evolution In Reversementioning

confidence: 99%

The evolutionary continuum from lung development to homeostasis and repair

Torday¹,

Rehan²

2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Torday JS, Rehan VK. The evolutionary continuum from lung development to homeostasis and repair. Am J Physiol Lung Cell Mol Physiol 292: L608-L611, 2007. First published November 3, 2006; doi:10.1152/ajplung.00379.2006.-A functional, developmental, and comparative biological approach is probably the most effective way for arranging gene regulatory networks (GRNs) in their biological contexts. Evolutionary developmental biology allows comparison of GRNs during development across phyla. For lung evolution, the parathyroid hormone-related protein (PTHrP) GRN exemplifies a continuum from ontogeny to phylogeny, homeostasis, and repair. PTHrP signaling between the lung endoderm and mesoderm stimulates lipofibroblast differentiation by downregulating the myofibroblast Wnt signaling pathway and upregulating the protein kinase A-dependent cAMP signaling pathway, inducing the lipofibroblast phenotype. Leptin secreted by the lipofibroblast, in turn, binds to its receptor on the alveolar type II cell, stimulating surfactant synthesis to ensure alveolar homeostasis. Failure of the PTHrP/PTHrP receptor signaling mechanism causes transdifferentiation of lipofibroblasts to myofibroblasts, which are the hallmark for lung fibrosis. We have shown that by targeting peroxisome proliferator-activated receptor ␥, the downstream target for lipofibroblast PTHrP signaling, we can prevent lung fibrosis. We speculate that the recapitulation of the myofibroblast phenotype during transdifferentiation is consistent with lung injury as lung evolution in reverse. Repair recapitulates ontogeny because it is programmed to express the cross talk between epithelium and mesoderm through evolution. This model demonstrates how epithelial-mesenchymal cross talk, when seen as a recapitulation of ontogeny and phylogeny (in both a forward and reverse direction), predicts novel, effective diagnostic and therapeutic targets.Evo-Devo; alveoli; parathyroid hormone-related protein; peroxisome proliferator-activated receptor ␥; Wnt PUBLICATION OF THE HUMAN GENOME has ushered in the "Golden Age" of biomedical research. But we lack an effective algorithm for arranging gene regulatory networks in a biological context (35), one which, like the periodic table of the elements, would predict the functions of genes, unlike interactomes that merely annotate gene and protein associations. Contemporary biology mirrors what happened in physics at the turn of the 20th century. We now have the genetic "elements" of the periodic table, and the Cambrian Burst is analogous to the Big Bang, so we should now consider the "initial conditions" for lung evolution and the "continuing strategy" for surviving the Permian extinction rather than continuing to reason backwards from phenotypes to genes (42). But we don't have the biological analog of quantum mechanics. Statistical analysis of complex genomic databases, i.e., Systems Biology, will not achieve that goal because evolution did not occur by chance. Therefore, a functional genomic approach would seem like the most effective wa...

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Up-Regulation of Fetal Rat Lung Parathyroid Hormone-Related Protein Gene Regulatory Network Down-Regulates the Sonic Hedgehog/Wnt/βcatenin Gene Regulatory Network

Cited by 38 publications

References 38 publications

Antenatally administered PPAR-γ agonist rosiglitazone prevents hyperoxia-induced neonatal rat lung injury

Antenatally administered PPAR-γ agonist rosiglitazone prevents hyperoxia-induced neonatal rat lung injury

Wnt5a is a cell-extrinsic factor that supports self-renewal of mouse spermatogonial stem cells

The evolutionary continuum from lung development to homeostasis and repair

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