Noncoding dsRNA induces retinoic acid synthesis to stimulate hair follicle regeneration via TLR3
Dong-Won KimRuosi ChenMary SheuNoori KimSooah KimNasif IslamEric M. WierGaofeng WangAng LiAngela ParkWooyang SonBenjamin EvansVictoria YuVicky P. PrizmicEugene OhZixiao WangJianshi YuWeiliang HuangNathan K. ArcherZhiqi HuNashay ClemetsonAmanda M. NelsonAnna L. ChienGinette A. OkoyeLloyd MillerGabriel GhiaurSewon KangJace W. JonesMaureen A. KaneLuis A. Garza
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How developmental programs reactivate in regeneration is a fundamental question in biology. We addressed this question through the study of Wound Induced Hair follicle Neogenesis (WIHN), an adult organogenesis model where stem cells regenerate de novo hair follicles following deep wounding. The exact mechanism is uncertain. Here we show that self-noncoding dsRNA activates the anti-viral receptor toll like receptor 3 (TLR3) to induce intrinsic retinoic acid (RA) synthesis in a pattern that predicts new hair follicle formation after wounding in mice. Additionally, in humans, rejuvenation lasers induce gene expression signatures for dsRNA and RA, with measurable increases in intrinsic RA synthesis. These results demonstrate a potent stimulus for RA synthesis by non-coding dsRNA, relevant to their broad functions in development and immunity.Keywords:
TLR3
Hepatoma cell lines have characteristics derived from both their hepatic lineage and their transformation. We examined the potential of retinoic acid to enhance the function of a hepatoma cell line, HepG2, under conditions of reduced serum as are desired for bioreactor cultivation. We found that retinoic acid drastically slows the growth of HepG2 cells and induces a more spread morphology. Retinoic acid also augments the differentiated function of the cells, as measured by albumin and urea secretion rates. Expression levels of a panel of liver-enriched transcription factor were increased from retinoic acid exposure. Overall, we demonstrate that retinoic acid has significant effects on HepG2 growth and differentiated function. These results have implications for the use of retinoic acid both as a chemotherapeutic agent and as a medium component for cells of hepatic origin.
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Retinoic acid has both early or immediate (within hours) and late (after days) effects on gene expression. We studied the early effects of retinoic acid on the surfactant protein (SP) genes. Exposure of fetal rat lung explants to all trans-retinoic acid for 4 h resulted in a significant dose-dependent increase in SP-A, -B, and -C mRNA with markedly different dose-response characteristics. The maximal (2.5x) increase in SP-A mRNA was observed with 10(-10) M retinoic acid, whereas treatment with 10(-5) M resulted in a tendency to decreased levels. In contrast, maximal stimulation of SP-C (6x) was noted at 10(-5) M retinoic acid and that of SP-B (2x) at 10(-7) to 10(-5) M retinoic acid. Similar differences in the dose-response characteristics of SP-A and SP-C were observed with 9-cis-retinoic acid. A retinoic acid response element consensus sequence was identified in the rat SP-A gene; we hypothesize that retinoic acid-receptor complexes act directly on the SP-A gene via this response element.
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The role of retinoids (vitamin A derivatives) in limb and tail regeneration is the focus of this review. The dramatic effects of excess retinoids on regeneration are considered, which consist of the respecification of each of the cardinal axes of the limb and the transformation of tail regenerates into limbs. The evidence that retinoids are endogenous components of the regeneration blastema and are required for normal regeneration is then addressed. This evidence consists of the fact that various techniques can detect endogenous retinoic acid in the blastema and that retinoic acid receptors are present, and an individual function in regeneration has been established for each of three receptors. Finally, experiments are described in which retinoic synthesis has been inhibited, and this results in the inhibition of both limb development and limb and tail regeneration.
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Effect of retinoic acid (RA) on morphogenesis and proliferation of regenerating extremity and lens cells was studied using 3H-thymidine autoradiography and morphometry. The 3H-thymidine incorporation into the inner layer of dorsal and ventral iris was 1.5-3 times reduced by the 8th day following the RA administration. The applied RA dose (0.25 mg per animal) exerted no significant effect on the morphogenesis of regenerating lens with the exception of the case of forming an additional lens from dorsal iris. The RA effect on the regeneration of extremity corresponds to available data of literature and manifests itself in the decelerated regeneration and the appearance of additional structures along the proximodistal axis.
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Hepatoma cell lines have characteristics derived from both their hepatic lineage and their transformation. We examined the potential of retinoic acid to enhance the function of a hepatoma cell line, HepG2, under conditions of reduced serum as are desired for bioreactor cultivation. We found that retinoic acid drastically slows the growth of HepG2 cells and induces a more spread morphology. Retinoic acid also augments the differentiated function of the cells, as measured by albumin and urea secretion rates. Expression levels of a panel of liver-enriched transcription factor were increased from retinoic acid exposure. Overall, we demonstrate that retinoic acid has significant effects on HepG2 growth and differentiated function. These results have implications for the use of retinoic acid both as a chemotherapeutic agent and as a medium component for cells of hepatic origin.
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Retinoic acid, an active metabolite of vitamin A, plays essential signaling roles in mammalian embryogenesis. Nevertheless, it has long been recognized that overexposure to vitamin A or retinoic acid causes widespread teratogenesis in rodents as well as humans. Although it has a short half-life, exposure to high levels of retinoic acid can disrupt development of yet-to-be formed organs, including the metanephros, the embryonic organ which normally differentiates into the mature kidney. Paradoxically, it is known that either an excess or a deficiency of retinoic acid results in similar malformations in some organs, including the mammalian kidney. Accordingly, we hypothesized that excess retinoic acid is teratogenic by inducing a longer lasting, local retinoic acid deficiency. This idea was tested in an established in vivo mouse model in which exposure to excess retinoic acid well before metanephric rudiments exist leads to failure of kidney formation several days later. Results showed that teratogen exposure was followed by decreased levels of Raldh transcripts encoding retinoic acid-synthesizing enzymes and increased levels of Cyp26a1 and Cyp26b1 mRNAs encoding enzymes that catabolize retinoic acid. Concomitantly, there was significant reduction in retinoic acid levels in whole embryos and kidney rudiments. Restoration of retinoic acid levels by maternal supplementation with low doses of retinoic acid following the teratogenic insult rescued metanephric kidney development and abrogated several extrarenal developmental defects. This previously undescribed and unsuspected mechanism provides insight into the molecular pathway of retinoic acid-induced teratogenesis.
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Retinoic acid signaling is essential for many aspects of early development in vertebrates. To control the levels of signaling, several retinoic acid target genes have been identified that act to suppress retinoic acid signaling in a negative feedback loop. The nuclear protein Ski has been extensively studied for its ability to suppress transforming growth factor-beta (TGF-β) signaling but has also been implicated in the repression of retinoic acid signaling.We demonstrate that ski expression is up-regulated in response to retinoic acid in both early Xenopus embryos and in human cell lines. Blocking retinoic acid signaling using a retinoic acid antagonist results in a corresponding decrease in the levels of ski mRNA. Finally, overexpression of SKI in human cells results in reduced levels of CYP26A1 mRNA, a known target of retinoic acid signaling.Our results, coupled with the known ability of Ski to repress retinoic acid signaling, demonstrate that Ski expression is a novel negative feedback mechanism acting on retinoic acid signaling.
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