Growth-promoting Factors Research Articles

Altered tetrapyrrole metabolism and transcriptome during growth-promoting actions in rice plants treated with 5-aminolevulinic acid

As a precursor of chlorophyll, 5-aminolevulinic acid (ALA) acts as a growth-promoting factor in plants, but little is known of molecular basis of plant growth action. The exogenous supply of an optimal concentration of 75 µM ALA without photooxidative risks, as indicated by a negligible change in conductivity, increased dry shoot biomass of rice up to 16 % after 10 days of ALA treatment, compared to the untreated control. Although rice plants treated with ALA gradually increased levels of ALA-synthesizing capacity during 30 h of the treatment, a noticeable increase in chlorophyll content was not observed. Levels of protoporphyrin IX and Mg–porphyrins were not significantly changed 6 h after ALA treatment and then decreased 30 h after the treatment, while transcript levels of most biosynthetic genes in tetrapyrrole pathway almost kept constant or slightly decreased. In microarray analysis of ALA-treated rice plants, categories of significantly up-regulated transcripts highlight particular biological processes involved in cell cycle, transcription factors, posttranscriptional regulation, and metabolisms of macromolecules. Our results demonstrate that the regulation of tetrapyrrole biosynthesis did not contribute significantly to growth enhancement in ALA-treated rice. We propose that the elevated status of ALA in plant cells alters the transcriptional control of genes involved in physiological processes vital for plant growth, thereby contributing to enhancement of plant biomass.

YAP enhances autophagic flux to promote breast cancer cell survival in response to nutrient deprivation.

The Yes-associated protein (YAP), a transcriptional coactivator inactivated by the Hippo tumor suppressor pathway, functions as an oncoprotein in a variety of cancers. However, its contribution to breast cancer remains controversial. This study investigated the role of YAP in breast cancer cells under nutrient deprivation (ND). Here, we show that YAP knockdown sensitized MCF7 breast cancer cells to nutrient deprivation-induced apoptosis. Furthermore, in response to ND, YAP increased the autolysosome degradation, thereby enhancing the cellular autophagic flux in breast cancer cells. Of note, autophagy is crucial for YAP to protect MCF7 cells from apoptosis under ND conditions. In addition, the TEA domain (TEAD) family of growth-promoting transcription factors was indispensable for YAP-mediated regulation of autophagy. Collectively, our data reveal a role for YAP in promoting breast cancer cell survival upon ND stress and uncover an unappreciated function of YAP/TEAD in the regulation of autophagy.

Industrial structure and total factor productivity: the Tunisian manufacturing sector between 1998 and 2004

Using a panel of manufacturing firms operating in 138 delegations across the Tunisian coast and observed over the 1998–2004 period, we study the impact of industrial structure on regional economic growth measured by total factor productivity. The results of an unbalanced panel data-based model indicate that the diversity of the industrial scene seems to be a local growth-promoting factor for high-tech sectors. Specialization often articulates the impact of diversity, while competition positively affects productivity.

Outcomes of topical applications of melatonin in implant dentistry: a systematic review.

Due to its antioxidant properties and its ability to detoxify free radicals, melatonin may interfere in the function of osteoclasts and thereby inhibit bone resorption. This inhibition of bone resorption may be enhanced by a reaction of indolamine in osteoclastogenesis and this may contribute to certain benefits in implantology. This systematic literature review on the use of melatonin in implant dentistry aims to provide guidelines for clinicians. PubMed, Science Direct, ISI Web of Knowledge, and the Cochrane base databases were used to identify articles published between 1999 and 2013 on melatonin use in implant dentistry. Ten articles were selected consisting of 9 animal research studies and 1 review article, involving 60 Beagle dogs, 57 rats, and 30 rabbits and a total of 352 implants. Melatonin, which is released into the saliva, has important implications in the oral cavity. To achieve dental implant stability, osseointegration involves a cascade of protein and cell apposition, vascular invasion, bone formation, and maturation. This process may be accelerated by local delivery of growth-promoting factors, as occurs with the topical application of melatonin over the implant surface. The experimental evidence suggests that topical applications of melatonin may be useful in oral surgery and implant dentistry, increasing bone-to-implant contact values and new bone formation, and so improving the success and long-term survival of implant treatments.

IL-6 polymorphism in non-small cell lung cancer: a prognostic value?

Lung cancer was found to be the most commonly diagnosed cancer, as well as the primary cause of cancer-related mortality for males worldwide and the second leading cause of cancer-related deaths for women. Cytokines are fundamental for several biological processes-associated malignant tumors. The IL-6 is a cytokine involved in the regulation of cellular functions including processes associated with cancer, such as proliferation, apoptosis, angiogenesis, and differentiation. Furthermore, IL-6 is a potent pleiotropic inflammatory cytokine that is considered a key growth-promoting and antiapoptotic factor. The polymorphism-174G/C SNP is a G to C transition in the -174 position of the promoter region of the IL-6 gene. The aim of our study was to evaluate the influence of -174G/C polymorphism in clinical outcome of non-small cell cancer (NSCLC) patients. DNA was extracted from peripheral blood of 424 patients diagnosed with cytologically or histologically NSCLC. The characterization of IL-6 -174G/C genotypes was performed by PCR-RFLP (NlaIII). IL-6 polymorphism's genotypes were divided according to functional activity, so the G carriers (CG/GG) is the high-producer IL-6, and CC genotype is the low-producer IL-6. Regarding survival, we verify that patients with genotypes carrying the G allele (CG/GG) had a statistically significant diminished survival when compared with patients with CC genotype (62.79 and 42.31 months, respectively; P = 0.032). In the promoter region of the IL-6 gene, polymorphic variants were located and may be responsible for alterations in transcription that consequently affect serum levels of the cytokine. With our study, we demonstrated that genetic variant (-174G/G and G/C) can be responsible for changes in prognosis of NSCLC patients.

RAFting the rapids of axon regeneration signaling.

The functional regeneration of damaged axons and severed connections in the mature central nervous system (CNS) remains a challenging goal of neurological research. Mature CNS neurons are refractory to axon regeneration for two major reasons, one, because the activity of cell-intrinsic mechanisms that drive axon growth during development is low – and often further suppressed after an injury – and two, because certain molecules that are part of mature extracellular matrix and myelin act as strong inhibitors of axon growth. Genetic removal of growth inhibitory molecules can increase axon sprouting, but is not sufficient to enable long-range axon growth. Since axon growth is robust during early developmental stages, it has long been hypothesized that mature injured neurons may be “reprogrammed” to the earlier growth state by re-activation of the intracellular growth signaling cascades that drive axon elongation in the developing fetus.

Bacterial community shift along with the changes in operational conditions in a membrane-aerated biofilm reactor.

Membrane-aerated biofilm reactor (MABR) is a promising wastewater treatment process. Although bacteria inhabiting the MABR biofilm are important in wastewater treatment, the community composition and its correlation with operating conditions were less clear. A laboratory-scale MABR was designed to investigate the shift of bacterial community through a complete operational process by pyrosequencing the bacterial 16S rRNA genes. From around 19,000 sequences, 175 bacterial genera were retrieved, mainly belonging to Betaproteobacteria, Gammaproteobacteria, Alphaproteobacteria, Bacteroidetes, and Actinobacteria. A large number of unclassified bacterial sequences were also detected in the biofilm, suggesting a wide variety of uncharacterized species in MABR. Redundancy analysis (RDA) revealed that influent chemical oxygen demand (COD), NH4-N, and NaHCO3 concentrations could exert distinct influences on the composition of the bacterial community. The influent COD and NaHCO3 concentrations stimulated proliferation of denitrification-related species such as Dokdonella, Azospira, Hydrogenophaga, Rhodocyclaceae, and Thauera, while inhibiting the growth of Acidovorax and Sinobacteraceae. Some denitrifying Thermomonas spp. tended to survive in NH4-N-rich environments, while Flavobacterium preferred to inhabit NH4-N-poor or COD-rich environments. Conversely, the influent NH4-N and NaHCO3, to some extent, appeared to be the growth-promoting factors for nitrifying bacteria. Furthermore, the presence of potential aerobic denitrifiers such as Comamonas, Enterobacter, and Aeromonas indicated that MABR could have the capability of simultaneous aerobic and anoxic denitrification particularly during treatment of low-ammonia nitrogen sewage.

HARIP2 is a putative growth-promoting factor involved in human colon tumorigenesis.

Activin is a multifunctional growth and differentiation factor of the growth factor-beta (TGF-β) superfamily, which inhibits the proliferation of colon cancer cells. It induces phosphorylation of intracellular signaling molecules (Smads) by interacting with its type I and type II receptors. Previous studies showed that human activin receptor-interacting protein 2 (hARIP2) can reduce activin signaling by interacting with activin type II receptors; however, the activity of hARIP2 in colon cancer has yet to be detailed. In vitro, overexpression of hARIP2 reduced activin-induced transcriptional activity and enhanced cell proliferation and colony formation in human colon cancer HCT8 cells and SW620 cells. Also, hARIP2 promoted colon cancer cell apoptosis, suggesting that a vital role in the initial stage of colon carcinogenesis. In vivo, immunohistochemistry revealed that hARIP2 was expressed more frequently and much more intensely in malignant colon tissues than in controls. These results indicate that hARIP2 is involved in human colon tumorigenesis and could be a predictive maker for colon carcinoma aggressiveness.

A novel Bcr-Abl-mTOR-eIF4A axis regulates IRES-mediated translation of LEF-1.

Internal ribosome entry sites (IRESs) in cellular mRNAs direct expression of growth-promoting factors through an alternative translation mechanism that has yet to be fully defined. Lymphoid enhancer factor-1 (LEF-1), a Wnt-mediating transcription factor important for cell survival and metastasis in cancer, is produced via IRES-directed translation, and its mRNA is frequently upregulated in malignancies, including chronic myeloid leukaemia (CML). In this study, we determined that LEF1 expression is regulated by Bcr-Abl, the oncogenic protein that drives haematopoietic cell transformation to CML. We have previously shown that the LEF1 5′ untranslated region recruits a complex of proteins to its IRES, including the translation initiation factor eIF4A. In this report, we use two small molecule inhibitors, PP242 (dual mTOR (mammalian target of rapamycin) kinase inhibitor) and hippuristanol (eIF4A inhibitor), to define IRES regulation via a Bcr-Abl–mTOR–eIF4A axis in CML cell lines and primary patient leukaemias. We found that LEF1 and other IRESs are uniquely sensitive to the activities of Bcr-Abl/mTOR. Most notably, we discovered that eIF4A, an RNA helicase, elicits potent non-canonical effects on the LEF1 IRES. Hippuristanol inhibition of eIF4A stalls translation of IRES mRNA and triggers dissociation from polyribosomes. We propose that a combination drug strategy which targets mTOR and IRES-driven translation disrupts key factors that contribute to growth and proliferation in CML.

Initial Culture Conditions for Primary Cell Populations Derived from Radula Tissue in Abalone Haliotis discus hannai

Abstract Abalone immortal cell lines can be used to study the physiological properties and disease mechanisms of abalone at the cellular and molecular level. As a first step for the final goal to establish abalone immortal cell lines, we examined various initial culture conditions for primary cell populations derived from Haliotis discus hannai radula tissue. The survival rate after cell isolation pro -cedures using the enzymatic method was as low as 9.95 ± 2.37%. Based on three different experimental conditions for H. discus hannai radula-derived cell culture, we found that the salinity of the media and the presence of growth-promoting factors were im-portant to support radula-derived primary cell populations during the initial culture. The growth factor-containing media adjusted to 35 psu salinity could induce 100% (8 out of 8 trials) initial cell attachment, and the rate of cell attachment reached 50–70%. The data obtained from this study will provide useful information for developing immortal cell lines from abalone species.

Conversion of yellow wine lees into high-protein yeast culture by solid-state fermentation

This study is focussed on the possibility of producing a yeast culture with yellow wine lees as a substrate by solid-state fermentation (SSF). Results showed that a yeast count of 1.58 × 109 CFU/g was achieved by signal factor and orthogonal experiments. After fermentation, the starch content in the yeast culture reduced from 32.2% ± 0.5% to 7.5% ± 0.2%, and the contents of crude protein and peptide increased from 36.1% ± 0.8% to 48.0% ± 1.0% and 3.9% ± 0.2% to 7.2% ± 0.4%, respectively. Additionally, large amounts of short peptides and free amino acids were detected by fast protein liquid chromatography (FPLC). These results suggest that yellow wine lees are a suitable substrate for the production of yeast cultures. It can serve as a growth-promoting factor and help reduce the shortage of protein feed in the animal industry. This research provides a potential way for the utilization of agro-industrial residues.

Photobody Localization of Phytochrome B Is Tightly Correlated with Prolonged and Light-Dependent Inhibition of Hypocotyl Elongation in the Dark.

Photobody localization of Arabidopsis (Arabidopsis thaliana) phytochrome B (phyB) fused to green fluorescent protein (PBG) correlates closely with the photoinhibition of hypocotyl elongation. However, the amino-terminal half of phyB fused to green fluorescent protein (NGB) is hypersensitive to light despite its inability to localize to photobodies. Therefore, the significance of photobodies in regulating hypocotyl growth remains debatable. Accumulating evidence indicates that under diurnal conditions, photoactivated phyB persists into darkness to inhibit hypocotyl elongation. Here, we examine whether photobodies are involved in inhibiting hypocotyl growth in darkness by comparing the PBG and NGB lines after the red light-to-dark transition. Surprisingly, after the transition from 10 μmol m-2 s-1 red light to darkness, PBG inhibits hypocotyl elongation three times longer than NGB. The disassembly of photobodies in PBG hypocotyl nuclei correlates tightly with the accumulation of the growth-promoting transcription factor PHYTOCHROME-INTERACTING FACTOR3 (PIF3). Destabilizing photobodies by either decreasing the light intensity or adding monochromatic far-red light treatment before the light-to-dark transition leads to faster PIF3 accumulation and a dramatic reduction in the capacity for hypocotyl growth inhibition in PBG. In contrast, NGB is defective in PIF3 degradation, and its hypocotyl growth in the dark is nearly unresponsive to changes in light conditions. Together, our results support the model that photobodies are required for the prolonged, light-dependent inhibition of hypocotyl elongation in the dark by repressing PIF3 accumulation and by stabilizing the far-red light-absorbing form of phyB. Our study suggests that photobody localization patterns of phyB could serve as instructive cues that control light-dependent photomorphogenetic responses in the dark.

Tumor microenvironment revisited

A number of authoritative reviews devoted to the role of the tumor microenvironment have been published in recent years [1], [2]. It is evident that the tumor stroma can modulate many tumor characteristics including the response to therapy. We need to keep this in mind, especially now that there is an increasing tendency to base intervention strategies on the driver mutations present in the tumor cells. This diagnostic mutation analysis receives attention for a good reason: it allows stratification of patients on the basis of molecular parameters with predictive power. Furthermore, the complexity of tumor cell populations is already challenging enough given the presence of a multitude of different cell types and their genetic heterogeneity. The contribution of stromal cells to a tumor tissue, including deposited matrices [3], can greatly vary, sometimes making up more than 90% of the tumor mass, for example as …

Perspectives in the use of tannins as alternative to antimicrobial growth promoter factors in poultry.

Antibiotics have been included in the formulation of feed for livestock production for more than 40 years as a strategy to improve feed conversion rates and to reduce costs. The use of antimicrobials as growth-promoting factors (AGP) in sub-therapeutic doses for long periods is particularly favorable for the selection of antimicrobial resistant microorganisms. In the last years, global concern about development of antimicrobial resistance and transference of resistance genes from animal to human strains has been rising. Removal of AGP from animal diets involves tremendous pressure on the livestock and poultry farmers, one of the main consequences being a substantial increase in the incidence of infectious diseases with the associated increase in the use of antibiotics for therapy, and concomitantly, economic cost. Therefore, alternatives to AGP are urgently needed. The challenge is to implement new alternatives without affecting the production performances of livestock and avoiding the increase of antimicrobial resistant microorganisms. Plant extracts and purified derived substances are showing promising results for animal nutrition, either from their efficacy as well as from an economical point of view. Tannins are plant derived compounds that are being successfully used as additives in poultry feed to control diseases and to improve animal performance. Successful use of any of these extracts as feed additives must ensure a product of consistent quality in enough quantity to fulfill the actual requirements of the poultry industry. Chestnut (hydrolysable) and Quebracho (condensed) tannins are probably the most readily available commercial products that are covering those needs. The present report intends to analyze the available data supporting their use.

Perturbation of copper homeostasis is instrumental in early developmental arrest of intraerythrocytic Plasmodium falciparum.

BackgroundMalaria continues to be a devastating disease. The elucidation of factors inducing asexual growth versus arrest of Plasmodium falciparum can provide information about the development of the parasite, and may help in the search for novel malaria medication. Based on information from genome-wide transcriptome profiling of different developmental stages of P. falciparum, we investigated the critical importance of copper homeostasis in the developmental succession of P. falciparum with regard to three aspects of copper function. These were:1) inhibition of copper-binding proteins, 2) copper-ion chelation, and 3) down-regulated expression of genes encoding copper-binding proteins associated with a specific growth-promoting factor.ResultsInhibition of copper-binding proteins with tetrathiomolybdate (TTM) caused cessation of growth of the parasite. TTM arrested the parasite irreversibly during the trophozoite to schizont stage progression. Target molecules for TTM may be present in P. falciparum. The involvement of copper ions in developmental arrest was also investigated by copper-ion chelating methods, which indicated a critical function of reduced copper ions (Cu1+) in the parasite during the early developmental stage. Copper ions, not only in the parasite but also in host cells, were targets of the chelators. Chelation of Cu1+caused blockage of trophozoite progression from the ring stage. Profound growth arrest was detected in parasites cultured in a chemically defined medium containing hexadecanoic acid alone as a growth-promoting factor. This developmental arrest was associated with down-regulated expression of genes encoding copper-binding proteins. Cis-9-octadecenoic acid completely prevented the down-regulation of gene expression and developmental arrest that were observed with the use of hexadecanoic acid.ConclusionsThe critical importance of copper homeostasis in early developmental stages of P. falciparum was confirmed. Perturbation of copper homeostasis induced profound and early developmental arrest of P. falciparum. These findings should help to elucidate the mechanisms behind the development of P. falciparum, and may be applied in the development of effective antimalarial strategies.

Expression of CD11b and CD18 on polymorphonuclear neutrophils stimulated with interleukin-2.

BackgroundInterleukin-2 (IL-2) is a lymphocyte-activating and growth-promoting factor, and has been widely studied on T-cells and NK-cells. However, the interaction of polymorphonuclear neutrophils (PMNs) with IL-2 is poorly studied and thus, this study aimed at defining IL-2 participation in the expression of CD11b and CD18 on PMNs.Material and methodsPMNs were isolated from heparinized whole blood of healthy donors. Purified cells were incubated with IL-2 (10 ng/ml) for 24 hours at 37°C in a humidified incubator with 5% CO2. After 24 hours’ incubation, surface molecules (CD11b and CD18) were measured by flow cytometry.ResultsInterestingly, the antibodies of IL-2Rβ chain (CD122-FITC) were found in all observed cells. The induction of CD11b mean fluorescence intensity (MFI) in highly purified PMNs stimulated with IL-2 was clearly increased recording 43% in comparison to the freshly isolated PMNs and the un-stimulated PMNs which were found to be 23% and 28% of CD11b, respectively. Furthermore, flow cytometry analysis demonstrated that the highly purified PMNs exposed to IL-2 showed an increase in CD18 MFI, recording 47% with respect to that of the freshly isolated PMNs and PMNs cultured with the medium alone which showed a small amount of 38% and 27%, respectively.ConclusionsResults demonstrated that CD11b and CD18 had been acquired on the surface of the IL-2-in vitro-activated PMNs. These findings indicated that IL-2 may play a crucial role in PMNs migration.

Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration

Event Abstract Back to Event Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration Paolo E. Porporato1, Christophe J. De Saedeleer1, Tamara Copetti1, Jhudit Pérez-Escuredo1, Valéry L. Payen1, Lucie Brisson1, Olivier Feron1 and Pierre Sonveaux1* 1 Université catholique de Louvain (UCL), Institut de Recherche Expérimentale et Clinique (IREC), Belgium Background and aim. The glycolytic end-product lactate is a pleiotropic tumor growth-promoting factor. Its activities primarily depend on its uptake, a process facilitated by the lactate-proton symporter monocarboxylate transporter 1 (MCT1). Therefore, targeting the transporter or its chaperon protein CD147/basigin, itself involved in the aggressive malignant phenotype, is an attractive therapeutic option for cancer, but basic information is still lacking regarding the regulation of the expression, interaction and activities of both proteins in tumors. Methods. Oxidative human cervix cancer SiHa and HeLa cells that express both MCT1 and CD147 were chosen as main cellular models. MCT1 and CD147 mRNA and protein levels were measured after different treatments ranging from glucose deprivation to mitochondrial oxygen consumption impairment. Protein interaction was tested using proximity ligation. Cell migration was assayed in transwells with different chemoattractants, also using tumor cells overexpressing MCT1 or CD147, or infected with specific shRNAs. Results. We found that glucose withdrawal dose-dependently upregulates MCT1 and CD147 protein expression and their interaction in oxidative tumor cells. While this transcription-independent induction could be recapitulated using glycolysis inhibition, hypoxia, the mitochondrial complex I inhibitor rotenone or hydrogen peroxide, it was blocked with alternative oxidative substrates and specific antioxidants, pointing out at a mitochondrial control. Indeed, we found that the stabilization of MCT1 and CD147 proteins upon glucose removal depends on mitochondrial impairment and the associated generation of reactive oxygen species. When glucose was a limited resource (a situation occurring naturally or during the treatment of many tumors), MCT1-CD147 heterocomplexes formed preferentially in cell protrusions. It endowed oxidative tumor cells with increased migratory capacities towards glucose. Migration was inhibited by providing an alternative oxidative fuel to glucose-starved cells or by targeting MCT1 using RNA interference or pharmacological inhibition. Conclusion. While our study identifies the mitochondrion as a glucose sensor promoting tumor cell migration, MCT1 is also revealed as a transducer of this response, providing a new rationale for the use of MCT1 inhibitors in cancer. Acknowledgements This work was supported by ERC Starting Grant 243188 TUMETABO to Pierre Sonveaux. Keywords: mct1, Basigin/CD147, Cancer, tumor metabolism, cell migration, Mitochondria, Reactive Oxygen Species Conference: 4th Annual Meeting of the International Society of Proton Dynamics in Cancer, Garching, Germany, 10 Oct - 12 Oct, 2013. Presentation Type: Abstract Topic: 3. pH, cell signalling and growth Citation: Porporato PE, De Saedeleer CJ, Copetti T, Pérez-Escuredo J, Payen VL, Brisson L, Feron O and Sonveaux P (2014). Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration. Front. Pharmacol. Conference Abstract: 4th Annual Meeting of the International Society of Proton Dynamics in Cancer. doi: 10.3389/conf.fphar.2014.61.00039 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 16 Dec 2013; Published Online: 07 Feb 2014. * Correspondence: Prof. Pierre Sonveaux, Université catholique de Louvain (UCL), Institut de Recherche Expérimentale et Clinique (IREC), Brussels, 1200, Belgium, pierre.sonveaux@uclouvain.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Paolo E Porporato Christophe J De Saedeleer Tamara Copetti Jhudit Pérez-Escuredo Valéry L Payen Lucie Brisson Olivier Feron Pierre Sonveaux Google Paolo E Porporato Christophe J De Saedeleer Tamara Copetti Jhudit Pérez-Escuredo Valéry L Payen Lucie Brisson Olivier Feron Pierre Sonveaux Google Scholar Paolo E Porporato Christophe J De Saedeleer Tamara Copetti Jhudit Pérez-Escuredo Valéry L Payen Lucie Brisson Olivier Feron Pierre Sonveaux PubMed Paolo E Porporato Christophe J De Saedeleer Tamara Copetti Jhudit Pérez-Escuredo Valéry L Payen Lucie Brisson Olivier Feron Pierre Sonveaux Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Modification of heparanase gene expression in response to conditioning and LPS treatment: strong correlation to rs4693608 SNP

Heparanase is an endo-β-glucuronidase that specifically cleaves the saccharide chains of HSPGs, important structural and functional components of the ECM. Cleavage of HS leads to loss of the structural integrity of the ECM and release of HS-bound cytokines, chemokines, and bioactive angiogenic- and growth-promoting factors. Our previous study revealed a highly significant correlation of HPSE gene SNPs rs4693608 and rs4364254 and their combination with the risk of developing GVHD. We now demonstrate that HPSE is up-regulated in response to pretransplantation conditioning, followed by a gradual decrease thereafter. Expression of heparanase correlated with the rs4693608 HPSE SNP before and after conditioning. Moreover, a positive correlation was found between recipient and donor rs4693608 SNP discrepancy and the time of neutrophil and platelet recovery. Similarly, the discrepancy in rs4693608 HPSE SNP between recipients and donors was found to be a more significant factor for the risk of aGVHD than patient genotype. The rs4693608 SNP also affected HPSE gene expression in LPS-treated MNCs from PB and CB. Possessors of the AA genotype exhibited up-regulation of heparanase with a high ratio in the LPS-treated MNCs, whereas individuals with genotype GG showed down-regulation or no effect on HPSE gene expression. HPSE up-regulation was mediated by TLR4. The study emphasizes the importance of rs4693608 SNP for HPSE gene expression in activated MNCs, indicating a role in allogeneic stem cell transplantation, including postconditioning, engraftment, and GVHD.

Cotransplantation of Glial Restricted Precursor Cells and Schwann Cells Promotes Functional Recovery after Spinal Cord Injury

Oligodendrocyte (OL) replacement can be a promising strategy for spinal cord injury (SCI) repair. However, the poor posttransplantation survival and inhibitory properties to axonal regeneration are two major challenges that limit their use as donor cells for repair of CNS injuries. Therefore, strategies aimed at enhancing the survival of grafted oligodendrocytes as well as reducing their inhibitory properties, such as the use of more permissive oligodendrocyte progenitor cells (OPCs), also called glial restricted precursor cells (GRPs), should be highly prioritized. Schwann cell (SC) transplantation is a promising translational strategy to promote axonal regeneration after CNS injuries, partly due to their expression and secretion of multiple growth-promoting factors. Whether grafted SCs have any effect on the biological properties of grafted GRPs remains unclear. Here we report that either SCs or SC-conditioned medium (SCM) promoted the survival, proliferation, and migration of GRPs in vitro. When GRPs and SCs were cografted into the normal or injured spinal cord, robust survival, proliferation, and migration of grafted GRPs were observed. Importantly, grafted GRPs differentiated into mature oligodendrocytes and formed new myelin on axons caudal to the injury. Finally, cografts of GRPs and SCs promoted recovery of function following SCI. We conclude that cotransplantation of GRPs and SCs, the only two kinds of myelin-forming cells in the nervous system, act complementarily and synergistically to promote greater anatomical and functional recovery after SCI than when either cell type is used alone.

Hypoxia shifts activity of neuropeptide Y in Ewing sarcoma from growth-inhibitory to growth-promoting effects

Ewing sarcoma (ES) is an aggressive malignancy driven by an oncogenic fusion protein, EWS-FLI1. Neuropeptide Y (NPY), and two of its receptors, Y1R and Y5R are up-regulated by EWS-FLI1 and abundantly expressed in ES cells. Paradoxically, NPY acting via Y1R and Y5R stimulates ES cell death. Here, we demonstrate that these growth-inhibitory actions of NPY are counteracted by hypoxia, which converts the peptide to a growth-promoting factor. In ES cells, hypoxia induces another NPY receptor, Y2R, and increases expression of dipeptidyl peptidase IV (DPPIV), an enzyme that cleaves NPY to a shorter form, NPY3-36. This truncated peptide no longer binds to Y1R and, therefore, does not stimulate ES cell death. Instead, NPY3-36 acts as a selective Y2R/Y5R agonist. The hypoxia-induced increase in DPPIV activity is most evident in a population of ES cells with high aldehyde dehydrogenase (ALDH) activity, rich in cancer stem cells (CSCs). Consequently, NPY, acting via Y2R/Y5Rs, preferentially stimulates proliferation and migration of hypoxic ALDHhigh cells. Hypoxia also enhances the angiogenic potential of ES by inducing Y2Rs in endothelial cells and increasing the release of its ligand, NPY3-36, from ES cells. In summary, hypoxia acts as a molecular switch shifting NPY activity away from Y1R/Y5R-mediated cell death and activating the Y2R/Y5R/DPPIV/NPY3-36 axis, which stimulates ES CSCs and promotes angiogenesis. Hypoxia-driven actions of the peptide such as these may contribute to ES progression. Due to the receptor-specific and multifaceted nature of NPY actions, these findings may inform novel therapeutic approaches to ES.