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Human behavior is a key driver of the biodiversity crisis, and addressing it requires changing individual choices and actions. Yet, the same processes that imperil biodiversity (e.g., urbanization) also alienate people from the experience of nature, eroding care for the natural world. Although averting this extinction of experience is increasingly recognized as a major contemporary conservation challenge, understanding of what constitutes nature experience remains elusive and few empirical studies have explored it directly. Most researchers have used nature interactions as a stand-in for experience, even though experience extends beyond interactions. We aimed to determine what constitutes the experience of nature and to propose a holistic, empirically derived framework that incorporates the multiple dimensions and components of the experience of nature. Using a mixed-method approach across 3 countries (the United States, Switzerland, and Israel), we conducted a multistage, conceptual content, cognitive mapping (3CM) exercise with 106 participants. This methodology included developing a prompt to capture participants' perceptions of nature experiences and subsequently refining and organizing their input into distinct components and underlying dimensions through an iterative engagement process. Beyond multisensory interactions with nature, experience of nature consisted of 2 dimensions: the circumstances in which interactions occur and the internal responses that encompass various cognitive, affective, and restorative benefits associated with nature interactions. These 3 dimensions had 33 components that occurred consistently across participants in the 3 countries. Frequently mentioned components included seeing animals, landscapes, or scenery; lack of human influence; weather conditions; relaxing, recharging; feeling good; and awe for nature. Fear and nature experienced at home were the least mentioned components. Together, our results showed that nature experience is a combination of nature interactions, circumstances, and internal responses. The emphasized components underscore the significance of offering access to extensive, less human-influenced natural spaces. This in turn can foster a profound nature experience, cultivating feelings of connectedness and care for nature.
Un marco de trabajo para entender la experiencia humana de la naturaleza a través del mapeo cognitivo Resumen El comportamiento humano es un factor clave en la crisis de la biodiversidad, por lo que abordarlo requiere cambios en las acciones y elecciones individuales. Aun así, los mismos procesos que ponen en peligro la biodiversidad (p. ej.: la urbanización) también alejan a las personas de experimentar la naturaleza, lo que disminuye el cuidado por la naturaleza. Aunque cada vez se reconoce más que evitar la extinción de las experiencias es un reto importante para la conservación, todavía no está claro qué constituye una experiencia de la naturaleza y pocos estudios empíricos lo han estudiado directamente. La mayoría de los investigadores ha usado las interacciones con la naturaleza como un sustituto para las experiencias, aunque éstas van más allá de las interacciones. Buscamos determinar qué constituye a las experiencias de la naturaleza y proponer un marco holístico y empírico que incorpore las múltiples dimensiones y componentes de la experiencia de la naturaleza. Usamos una estrategia de método mixto en tres países (EUA, Suiza e Israel) para realizar un ejercicio de un mapeo cognitivo de contenido conceptual en varias fases (3CM) con 106 participantes. Esta metodología incluyó el desarrollo de una entrada para capturar la percepción de los participantes con respecto a las experiencias de la naturaleza y con ello refinar y organizar sus contribuciones en diferentes componentes y dimensiones subyacentes por medio de un proceso iterativo de participación. Más allá de las interacciones multisensoriales con la naturaleza, las vivencias de la naturaleza consistieron en dos dimensiones: las circunstancias en las que ocurren las interacciones y las respuestas internas que engloban varios beneficios cognitivos, afectivos y restauradores asociados con las interacciones con la naturaleza. Estas dos dimensiones contaron con 33 componentes que aparecieron constantemente entre los participantes de los tres países. Con frecuencia mencionaron componentes que incluían avistamiento de animales o paisajes; la ausencia de influencia humana; las condiciones del clima; relajarse, recargarse; sentirse bien; y asombro por la naturaleza. El miedo y la naturaleza vivida en casa fueron los componentes menos mencionados. En conjunto, nuestros resultados mostraron que las vivencias de la naturaleza son una combinación de interacciones con la naturaleza, circunstancias y respuestas internas. Los componentes enfatizados resaltan la importancia de ofrecer acceso a los espacios naturales extensos con menos influencia humana. Esto a la vez puede promover una experiencia profunda de la naturaleza, lo que genera sentimientos de conexión y cuidado de la naturaleza.
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Cognición , Conservación de los Recursos Naturales , Humanos , Conservación de los Recursos Naturales/métodos , Estados Unidos , Israel , Naturaleza , Suiza , BiodiversidadRESUMEN
Psychological restoration and place attachment may be related to beliefs about environmental governance, with place attachment a likely mediator. We analyze data from a public survey in the Puget Sound area of Washington state (n = 2323) regarding beliefs about environmental governance, place attachment to the Puget Sound area, and psychological restoration related to this area. On average, individuals felt neutral in their beliefs about environmental governance, had high place attachment, and had high frequency of psychological restoration in natural environments. Structural equation modeling indicated that those who more frequently experienced psychological restoration from natural environments had stronger place attachment and more positive beliefs about environmental governance. Place attachment was significantly associated with governance perceptions, but explained only a small portion of variance (R2 = 0.02), while psychological restoration was significantly associated with place attachment and explained a moderate portion of its variance (R2 = 0.37). Place attachment fully mediated the effects of frequency of psychological restoration on beliefs about governance. Promoting psychological restoration and place attachment without attending to the process factors associated with good governance would not likely be a viable strategy for environmental managers to substantially increase positive beliefs about environmental governance.
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Conservación de los Recursos Naturales , Política Ambiental , Humanos , WashingtónRESUMEN
Research has shown an increasing trend in attempts to integrate social and ecological data that use indicators to improve quality of life. This includes understanding people's beliefs about environmental governance. Understanding patterns in beliefs of environmental governance can be a powerful way to help policy makers take informed actions that meet individuals' needs and expectations. This study examines connections between spatial patterns of beliefs about environmental governance and the health of the environment where people live, measured from both a public health and ecological perspective. Data on people's beliefs about environmental governance were collected in the Puget Sound area of Washington state. Environmental health data include environmental public health disparities including effects and exposures, bird diversity, and tree cover. Results indicate local scale heterogeneity exists within the Puget Sound region. Using AIC model selection, there was strong evidence for effects of canopy cover, environmental effects and exposures, and years of residency, and moderate to strong evidence for the effects on beliefs about environmental governance of race and sex. There was little support for effects of political ideology, income, age, education, or bird diversity. The Akaike Information Criteria (AIC) top model included a negative effect of canopy cover, years of residency, race (i.e., of being non-white), and sex (i.e., of being male), and a positive effect of environmental effects and of environmental exposures. Relating data on environmental health and beliefs about environmental governance generates a more nuanced understanding of determinants of environmental governance success and public support.
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Conservación de los Recursos Naturales , Calidad de Vida , Humanos , Salud Ambiental , Política Ambiental , Ambiente , WashingtónRESUMEN
Prior research demonstrates widespread persistence of beliefs about climate change causes and risks that are arguably misconceptions. They include believing pollution causes climate change, believing ozone depletion causes climate change, the combination of these two "green beliefs," referred to as environmental problems, and believing natural climate variation significantly contributes to current climate trends. Each of these causal beliefs has the potential to weaken or divert support away from effective climate change risk mitigation policies. To assess this potential, we explore the nature and prevalence of these beliefs in the United States with a national sample of interviews (N = 77) and two national surveys (N = 1,013, N = 1,820), and apply regression and mediation analyses to explore whether they explain any of the variation in individuals' concern or support for policy to mitigate climate change. Adherence to these beliefs-which reflect a variety of misconceptions illustrated in the interviews-differs by political ideology but is common, with over a third of interviewees mentioning one or more. Controlling for general knowledge, political ideology, and other factors, misconceptions about environmental problems are still associated directly with support for climate change policies. On average adherence to the belief that environmental problems cause climate change is associated with a 25% higher probability of policy support. In contrast, believing natural climate variability is a major recent cause of climate change is associated with a 7% lower probability of supporting climate policy, even after controlling for political ideology and other knowledge about climate change.
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Causalidad , Cambio Climático , Conocimiento , Humanos , Políticas , Encuestas y Cuestionarios , Estados UnidosRESUMEN
This paper sought to understand the extent to which, and how individuals use personal or collective language when asked to articulate sense of place from a collective perspective. Understanding a collective sense of place could illuminate place-based connections in natural resource industries, where it is as groups or as institutions that organizations interact with the environment rather than as individuals. While there are well known methods for collecting information about sense of place at the individual level, there is a gap in understanding the best method to collect information at a collective level. We examined the use of key-informant interviews as a method to understand collective sense of place. In Bocas del Toro, Panama, ecotourism and environmentally based organizations are becoming more prolific due to abundant natural resources, making it an interesting case study for understanding sense of place from an organizational perspective. The use of personal and collective language is examined though in-depth semi-structured interviews from 15 environmentally-oriented organizations with a total of 17 interviews. This study specifically examined whether and how key informants, when prompted to speak for their organization, spoke collectively, reflecting a collective perspective versus their own. Methods included both quantitative analysis of personal versus collective language use frequency, and qualitative examinations of how individuals used personal versus collective language. Our results indicated no difference in the frequency with which individuals use personal versus collective language. We found that how individuals situated their perspectives into an organization reflects a complex personal and collective point of view reflecting five themes of personal versus collective language use: 1) sole personal perspective, 2) sole collective perspective, 3) distinction between collective and personal perspective; 4) organization perspective with insertion of "I think"; and 5) personal and collective perspective about organization and greater community. Our research identifies a previously undiscussed potential bias of key informant interviews. These findings have implications for how researchers approach collecting information beyond the individual level.
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Encuestas y CuestionariosRESUMEN
Neurogenic heterotopic ossifications (NHOs) are incapacitating complications of traumatic brain and spinal cord injuries (SCI) that manifest as abnormal bone formation in periarticular muscles. Using a unique model of NHO after SCI in genetically unmodified mice, we have previously established that the innate immune system plays a key driving role in NHO pathogenesis. The role of adaptive immune cells in NHO pathogenesis, however, remains unexplored in this model. Here we established that B lymphocytes were reduced in the spleen and blood after SCI and increased in muscles of mice in which NHO develops, whereas minimal changes in T cell frequencies were noted. Interestingly, Rag1 -/- mice lacking mature T and B lymphocytes, developed NHO, similar to wild-type mice. Finally, mice that underwent splenectomy before SCI and muscle damage also developed NHO to the same extent as non-splenectomized SCI controls. Overall, our findings show that functional T and B lymphocytes have minimal influence or dispensable contributions to NHO development after experimental SCI in mice.
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We show that pro-inflammatory oncostatin M (OSM) is an important regulator of hematopoietic stem cell (HSC) niches in the bone marrow (BM). Treatment of healthy humans and mice with granulocyte colony-stimulating factor (G-CSF) dramatically increases OSM release in blood and BM. Using mice null for the OSM receptor (OSMR) gene, we demonstrate that OSM provides a negative feed-back acting as a brake on HSPC mobilization in response to clinically relevant mobilizing molecules G-CSF and CXCR4 antagonist. Likewise, injection of a recombinant OSM molecular trap made of OSMR complex extracellular domains enhances HSC mobilization in poor mobilizing C57BL/6 and NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice. Mechanistically, OSM attenuates HSC chemotactic response to CXCL12 and increases HSC homing to the BM signaling indirectly via BM endothelial and mesenchymal cells which are the only cells expressing OSMR in the BM. OSM up-regulates E-selectin expression on BM endothelial cells indirectly increasing HSC proliferation. RNA sequencing of HSCs from Osmr-/- and wild-type mice suggest that HSCs have altered cytoskeleton reorganization, energy usage and cycling in the absence of OSM signaling in niches. Therefore OSM is an important regulator of HSC niche function restraining HSC mobilization and anti-OSM therapy combined with current mobilizing regimens may improve HSPC mobilization for transplantation.
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Médula Ósea/fisiología , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Movilización de Célula Madre Hematopoyética/métodos , Células Madre Hematopoyéticas/citología , Oncostatina M/metabolismo , Nicho de Células Madre , Animales , Médula Ósea/efectos de los fármacos , Femenino , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NODRESUMEN
Neurogenic heterotopic ossifications (NHOs) form in periarticular muscles after severe spinal cord (SCI) and traumatic brain injuries. The pathogenesis of NHO is poorly understood with no effective preventive treatment. The only curative treatment remains surgical resection of pathological NHOs. In a mouse model of SCI-induced NHO that involves a transection of the spinal cord combined with a muscle injury, a differential gene expression analysis revealed that genes involved in inflammation such as interleukin-1ß (IL-1ß) were overexpressed in muscles developing NHO. Using mice knocked-out for the gene encoding IL-1 receptor (IL1R1) and neutralizing antibodies for IL-1α and IL-1ß, we show that IL-1 signaling contributes to NHO development after SCI in mice. Interestingly, other proteins involved in inflammation that were also overexpressed in muscles developing NHO, such as colony-stimulating factor-1, tumor necrosis factor, or C-C chemokine ligand-2, did not promote NHO development. Finally, using NHO biopsies from SCI and TBI patients, we show that IL-1ß is expressed by CD68+ macrophages. IL-1α and IL-1ß produced by activated human monocytes promote calcium mineralization and RUNX2 expression in fibro-adipogenic progenitors isolated from muscles surrounding NHOs. Altogether, these data suggest that interleukin-1 promotes NHO development in both humans and mice. © 2021 American Society for Bone and Mineral Research (ASBMR).
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Interleucina-1beta/metabolismo , Osificación Heterotópica , Traumatismos de la Médula Espinal , Animales , Humanos , Inflamación/complicaciones , Interleucina-1 , Ratones , Músculos/patología , Osificación Heterotópica/patología , Médula Espinal/metabolismo , Médula Espinal/patología , Traumatismos de la Médula Espinal/complicacionesRESUMEN
The cells of origin of neurogenic heterotopic ossifications (NHOs), which develop frequently in the periarticular muscles following spinal cord injuries (SCIs) and traumatic brain injuries, remain unclear because skeletal muscle harbors two progenitor cell populations: satellite cells (SCs), which are myogenic, and fibroadipogenic progenitors (FAPs), which are mesenchymal. Lineage-tracing experiments using the Cre recombinase/LoxP system were performed in two mouse strains with the fluorescent protein ZsGreen specifically expressed in either SCs or FAPs in skeletal muscles under the control of the Pax7 or Prrx1 gene promoter, respectively. These experiments demonstrate that following muscle injury, SCI causes the upregulation of PDGFRα expression on FAPs but not SCs and the failure of SCs to regenerate myofibers in the injured muscle, with reduced apoptosis and continued proliferation of muscle resident FAPs enabling their osteogenic differentiation into NHOs. No cells expressing ZsGreen under the Prrx1 promoter were detected in the blood after injury, suggesting that the cells of origin of NHOs are locally derived from the injured muscle. We validated these findings using human NHO biopsies. PDGFRα+ mesenchymal cells isolated from the muscle surrounding NHO biopsies could develop ectopic human bones when transplanted into immunocompromised mice, whereas CD56+ myogenic cells had a much lower potential. Therefore, NHO is a pathology of the injured muscle in which SCI reprograms FAPs to undergo uncontrolled proliferation and differentiation into osteoblasts.
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Anemia of inflammation (AI) is the second most prevalent anemia after iron deficiency anemia and results in persistent low blood erythrocytes and hemoglobin, fatigue, weakness, and early death. Anemia of inflammation is common in people with chronic inflammation, chronic infections, or sepsis. Although several studies have reported the effect of inflammation on stress erythropoiesis and iron homeostasis, the mechanisms by which inflammation suppresses erythropoiesis in the bone marrow (BM), where differentiation and maturation of erythroid cells from hematopoietic stem cells (HSCs) occurs, have not been extensively studied. Here we show that in a mouse model of acute sepsis, bacterial lipopolysaccharides (LPS) suppress medullary erythroblastic islands (EBIs) and erythropoiesis in a TLR-4- and MyD88-dependent manner with concomitant mobilization of HSCs. LPS suppressive effect on erythropoiesis is indirect as erythroid progenitors and erythroblasts do not express TLR-4 whereas EBI macrophages do. Using cytokine receptor gene knock-out mice LPS-induced mobilization of HSCs is G-CSF-dependent whereas LPS-induced suppression of medullary erythropoiesis does not require G- CSF-, IL- 1-, or TNF-mediated signaling. Therefore suppression of medullary erythropoiesis and mobilization of HSCs in response to LPS are mechanistically distinct. Our findings also suggest that EBI macrophages in the BM may sense innate immune stimuli in response to acute inflammation or infections to rapidly convert to a pro-inflammatory function at the expense of their erythropoietic function.
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Anemia/inmunología , Médula Ósea/inmunología , Eritropoyesis/inmunología , Macrófagos/inmunología , Sepsis/complicaciones , Animales , Factor Estimulante de Colonias de Granulocitos , Interleucina-1 , Lipopolisacáridos/inmunología , Ratones , Ratones Endogámicos C57BL , Sepsis/inmunología , Factor de Necrosis Tumoral alfaRESUMEN
Neurogenic heterotopic ossifications (NHOs) are incapacitating heterotopic bones in periarticular muscles that frequently develop following traumatic brain or spinal cord injuries (SCI). Using our unique model of SCI-induced NHO, we have previously established that mononucleated phagocytes infiltrating injured muscles are required to trigger NHO via the persistent release of the pro-inflammatory cytokine oncostatin M (OSM). Because neutrophils are also a major source of OSM, we investigated whether neutrophils also play a role in NHO development after SCI. We now show that surgery transiently increased granulocyte colony-stimulating factor (G-CSF) levels in blood of operated mice, and that G-CSF receptor mRNA is expressed in the hamstrings of mice developing NHO. However, mice defective for the G-CSF receptor gene Csf3r, which are neutropenic, have unaltered NHO development after SCI compared to C57BL/6 control mice. Because the administration of recombinant human G-CSF (rhG-CSF) has been trialed after SCI to increase neuroprotection and neuronal regeneration and has been shown to suppress osteoblast function at the endosteum of skeletal bones in human and mice, we investigated the impact of a 7-day rhG-CSF treatment on NHO development. rhG-CSF treatment significantly increased neutrophils in the blood, bone marrow, and injured muscles. However, there was no change in NHO development compared to saline-treated controls. Overall, our results establish that unlike monocytes/macrophages, neutrophils are dispensable for NHO development following SCI, and rhG-CSF treatment post-SCI does not impact NHO development. Therefore, G-CSF treatment to promote neuroregeneration is unlikely to adversely promote or affect NHO development in SCI patients. © 2020 American Society for Bone and Mineral Research.
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Neutrófilos , Osificación Heterotópica , Animales , Médula Ósea , Factor Estimulante de Colonias de Granulocitos , Humanos , Ratones , Ratones Endogámicos C57BL , Proteínas RecombinantesRESUMEN
We examined whether an early-life event - ethanol exposure in the initial stages of pregnancy - affected offspring brain structure, energy metabolism, and body composition in later life. Consumption of 10% (v/v) ethanol by inbred C57BL/6J female mice from 0.5 to 8.5 days post coitum was used to model alcohol exposure during the first 3-4 weeks of gestation in humans, when pregnancy is not typically recognized. At adolescence (postnatal day [P] 28) and adulthood (P64), the brains of male offspring were scanned ex vivo using ultra-high field (16.4 T) magnetic resonance imaging and diffusion tensor imaging. Energy metabolism and body composition were measured in adulthood by indirect calorimetry and dual-energy X-ray absorptiometry (DXA), respectively. Ethanol exposure had no substantial impact on white matter organization in the anterior commissure, corpus callosum, hippocampal commissure, internal capsule, optic tract, or thalamus. Whole brain volume and the volumes of the neocortex, cerebellum, and caudate putamen were also unaffected. Subtle, but non-significant, effects were observed on the hippocampus and the hypothalamus in adult ethanol-exposed male offspring. Ethanol exposure was additionally associated with a trend toward decreased oxygen consumption, carbon dioxide production, and reduced daily energy expenditure, as well as significantly increased adiposity, albeit with normal body weight and food intake, in adult male offspring. In summary, ethanol exposure restricted to early gestation had subtle long-term effects on the structure of specific brain regions in male offspring. The sensitivity of the hippocampus to ethanol-induced damage is reminiscent of that reported by other studies - despite differences in the level, timing, and duration of exposure - and likely contributes to the cognitive impairment that characteristically results from prenatal ethanol exposure. The hypothalamus plays an important role in regulating metabolism and energy homeostasis. Our finding of altered daily energy expenditure and adiposity in adult ethanol-exposed males is consistent with the idea that central nervous system abnormalities also underpin some of the metabolic phenotypes associated with ethanol exposure in pregnancy.
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Adiposidad/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Metabolismo Energético/efectos de los fármacos , Etanol/toxicidad , Efectos Tardíos de la Exposición Prenatal/metabolismo , Adiposidad/fisiología , Factores de Edad , Animales , Encéfalo/diagnóstico por imagen , Metabolismo Energético/fisiología , Etanol/administración & dosificación , Femenino , Trastornos del Espectro Alcohólico Fetal/diagnóstico por imagen , Trastornos del Espectro Alcohólico Fetal/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/diagnóstico por imagenRESUMEN
Neurogenic heterotopic ossifications (NHO) are very incapacitating complications of traumatic brain and spinal cord injuries (SCI) which manifest as abnormal formation of bone tissue in periarticular muscles. NHO are debilitating as they cause pain, partial or total joint ankylosis and vascular and nerve compression. NHO pathogenesis is unknown and the only effective treatment remains surgical resection, however once resected, NHO can re-occur. To further understand NHO pathogenesis, we developed the first animal model of NHO following SCI in genetically unmodified mice, which mimics most clinical features of NHO in patients. We have previously shown that the combination of (1) a central nervous system lesion (SCI) and (2) muscular damage (via an intramuscular injection of cardiotoxin) is required for NHO development. Furthermore, macrophages within the injured muscle play a critical role in driving NHO pathogenesis. More recently we demonstrated that macrophage-derived oncostatin M (OSM) is a key mediator of both human and mouse NHO. We now report that inflammatory monocytes infiltrate the injured muscles of SCI mice developing NHO at significantly higher levels compared to mice without SCI. Muscle infiltrating monocytes and neutrophils expressed OSM whereas mouse muscle satellite and interstitial cell expressed the OSM receptor (OSMR). In vitro recombinant mouse OSM induced tyrosine phosphorylation of the transcription factor STAT3, a downstream target of OSMR:gp130 signaling in muscle progenitor cells. As STAT3 is tyrosine phosphorylated by JAK1/2 tyrosine kinases downstream of OSMR:gp130, we demonstrated that the JAK1/2 tyrosine kinase inhibitor ruxolitinib blocked OSM driven STAT3 tyrosine phosphorylation in mouse muscle progenitor cells. We further demonstrated in vivo that STAT3 tyrosine phosphorylation was not only significantly higher but persisted for a longer duration in injured muscles of SCI mice developing NHO compared to mice with muscle injury without SCI. Finally, administration of ruxolitinib for 7 days post-surgery significantly reduced STAT3 phosphorylation in injured muscles in vivo as well as NHO volume at all analyzed time-points up to 3 weeks post-surgery. Our results identify the JAK/STAT3 signaling pathway as a potential therapeutic target to reduce NHO development following SCI.
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Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Inhibidores de las Cinasas Janus/farmacología , Osificación Heterotópica/metabolismo , Osificación Heterotópica/patología , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Inmunohistoquímica , Janus Quinasa 1/metabolismo , Janus Quinasa 2/metabolismo , Ratones , Monocitos/efectos de los fármacos , Monocitos/inmunología , Monocitos/metabolismo , Células Musculares , Osificación Heterotópica/tratamiento farmacológico , Fosforilación , Factor de Transcripción STAT3/metabolismo , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/etiología , Microtomografía por Rayos XRESUMEN
In normoxia, hypoxia-inducible transcription factors (HIFs) are rapidly degraded within the cytoplasm as a consequence of their prolyl hydroxylation by oxygen-dependent prolyl hydroxylase domain (PHD) enzymes. We have previously shown that hematopoietic stem and progenitor cells (HSPCs) require HIF-1 for effective mobilization in response to granulocyte colony-stimulating factor (G-CSF) and CXCR4 antagonist AMD3100/plerixafor. Conversely, HIF PHD inhibitors that stabilize HIF-1 protein in vivo enhance HSPC mobilization in response to G-CSF or AMD3100 in a cell-intrinsic manner. We now show that extrinsic mechanisms involving vascular endothelial growth factor receptor-2 (VEGFR2), via bone marrow (BM) endothelial cells, are also at play. PTK787/vatalanib, a tyrosine kinase inhibitor selective for VEGFR1 and VEGFR2, and neutralizing anti-VEGFR2 monoclonal antibody DC101 blocked enhancement of HSPC mobilization by FG-4497. VEGFR2 was absent on mesenchymal and hematopoietic cells and was detected only in Sca1+ endothelial cells in the BM. We propose that HIF PHD inhibitor FG-4497 enhances HSPC mobilization by stabilizing HIF-1α in HSPCs as previously demonstrated, as well as by activating VEGFR2 signaling in BM endothelial cells, which facilitates HSPC egress from the BM into the circulation.