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Biology subjects

Baker, A.

Publications and source records attributed to Baker, A..

At least 19 recordsLinked to original sources

Widespread occurrence of bovine-like and new viruses in wild deer across the United States

Over the past several decades, deer populations in North America have grown considerably, resulting in frequent contact with humans and livestock, and increased potential for pathogen spillover. Despite the importance of pathogen spillover among humans, wildlife, and livestock, the diversity of viruses present in deer remains largely unknown. Using a metagenomic high-throughput sequencing approach, we characterized viral communities in the upper respiratory tracts of live mule deer (Odocoileus hemionus) and white-tailed deer (Odocoileus virginianus) captured at fourteen study sites in nine states across the United States. We identified vertebrate-infecting viruses in both deer species at all but two of the study sites, located in Illinois and Utah. Viral richness did not vary among species or study sites. However, viral community composition was different across study sites but not among deer species. Amongst the detected viral sequences, several originate from or were closely related to viruses previously described in humans (e.g., severe acute respiratory syndrome coronavirus 2) and livestock (e.g., bovine-like coronavirus). We also documented viruses recently discovered in deer, such as CHeRI orbivirus 1. Finally, we identified several new putative viruses in the Picornaviridae, Rhabdoviridae and Tobaniviridae families, including a novel Aphthovirus related to bovine rhinitis A virus in both deer species, across seven states and nine study sites. Our findings expand the understanding of viral diversity in two deer species across the United States, providing important insights for managing pathogens at the wildlife, livestock, and human interface.

microbiology↗

Iron-deficiency in the tumor microenvironment reprograms tumor-immune interactions in a sex biased manner

BackgroundGlioblastoma (GBM) is a sex-biased disease characterized by higher incidence and poorer survival in males. These sex differences are primarily driven by metabolic and immune signatures, with iron metabolism playing a major role. While iron is essential for tumor cell proliferation, it is also critical for T cell recruitment and function within the tumor microenvironment (TME). Clinical data indicates that iron deficiency impacts GBM survival in a sex-biased manner; however, the underlying mechanisms remain unexplored. MethodsWe employed a FTH1 heterozygous knockdown mouse model to induce tumor iron deficiency in GBM-bearing mice. TME dynamics were interrogated using flow cytometry and spatial transcriptomics (10X Xenium) to analyze immune infiltration, localization, and ligand-receptor signaling between GBM and immune cells. ResultsFTH1 knockdown resulted in iron deficiency in the GBM TME. Iron deficiency altered the TME dynamics in a sex biased manner. FTH1 knockdown in females caused an anti-inflammatory, cytokine deficient TME which failed to recruit CD4 and CD8 T cells. In males, FTH1 knockdown caused a proinflammatory environment by activating the innate immune response. Additionally, FTH1 knockdown increased the density of TAMs in the immediate surrounding of GBM cells in a sex biased manner. ConclusionThese results demonstrate that tumor iron plays a sex-biased role in immune infiltration and anti-tumor immunity.

cancer biology↗

Dynamic Stiffening to Improve Vasculogenesis of hiPSC-Derived Endothelial Progenitors

Multiple groups have reported on the impact of hydrogel stiffness on vascular network formation in vitro, with overall findings indicating that less stiff hydrogels better support vasculogenesis. However, the majority of this research utilized hydrogels with static stiffness, even though vasculogenesis occurs in tandem with changes in extracellular matrix material properties. To that end, we hypothesize that dynamic modulation of hydrogel stiffness during the process of vasculogenesis, recapitulating changes observed during embryonic development, would improve vascular network formation. Using our Collagen I/Norbornene-modified hyaluronic acid hydrogel system, we swelled in additional crosslinker and photoinitiator and exposed the hydrogel to UV light, enabling hydrogel stiffening at user-defined time points with no significant effect on cell viability. We observed that in situ stiffening at early time points, prior to the onset of significant cell migration, resulted in more robust vascular network formation relative to unstiffened controls, while stiffening at later time points disrupted existing vascular networks. These trends continued in in vivo experiments in nude mice, with cell-laden hydrogels stiffened at early time points resulting in improved blood flow, while those stiffened at later time points had the opposite effect. We hypothesized that this was due to differential impacts of focal adhesion kinase (FAK) activation following in situ stiffening, as supplementation with a Rho kinase inhibitor, downstream of FAK, partially reversed the effects of in situ stiffening. Taken together, this research demonstrates the benefits of incorporating dynamic cues into hydrogel design to create more physiologically relevant vasculature.

bioengineering↗

Developing an approach to list bryophytes of conservation interests for England's Local Nature Recovery Strategies

Biodiversity is globally declining, and the United Kingdom (UK) recognised as one of the most nature-depleted countries. With an aim to restore ecosystems, the UK has initiated a policy of Local Nature Recovery Strategies (LNRS), to be published for 48 areas across England. We devised and applied a workflow using open access data to produce preliminary lists of bryophytes of conservation interest for each LNRS area. Our objectives include: (i) to ascertain which LNRS area match the current recording scheme based on Watsonian vice-counties; (ii) to produce data-driven draft lists for each LNRS area, (iii) to compare this list in the Tees Valley area with a species list derived from expert knowledge. Using an inclusion threshold at 90% of surface area, we found that 20 out of the 48 LNRS areas are compatible with the vice-county-based scheme. We determine that LNRS areas included on average 9.3 (+/- 6.9) species threatened by extinction, a supplementary 3.6 (+/- 3.4) species near threatened and, adding nationally rare or scarce species, a total of 66.3 (+/- 35.1) species. A case study based on the Tees Valley revealed an overall good match between data and expert driven species lists, despite discrepancies relating to geographical attributions near boundaries and additional species solely selected by expert opinion. It is anticipated that the preliminary lists produced could save valuable time to local experts when working towards LNRS bryophyte lists, and that the approach developed will be relevant to other organism groups, supporting effectively LNRSs across England.

ecology↗

Glucocorticoids unleash immune-dependent melanoma control through inhibition of the GARP/TGF-β axis

Half of advanced melanoma patients fail to benefit from immune checkpoint blockade and novel treatments are urgently required. Testing topical medications used in other skin diseases for anti-cancer activity in an immunotherapy-resistant murine melanoma model, we counterintuitively found that glucocorticoids elicit rapid cytotoxic T lymphocyte (CTL)-dependent tumor control. Genetic ablation of the glucocorticoid receptor in different cellular compartments revealed glucocorticoids acted not on immune cells but directly on tumor cells to downregulate expression of GARP (glycoprotein A repetitions predominant). This inhibited TGF-{beta} signaling and unleashed CTL killing. In agreement, glucocorticoids stimulated tumor control in multiple cancer models, but only if the tumors also responded to pharmacological inhibition of TGF-{beta} signaling. Furthermore, melanoma patients with high glucocorticoid receptor expression or signaling showed improved prognosis and lower TGF-{beta} signaling in tumor-infiltrating CTLs. Additionally, elevated GARP expression correlated with reduced survival, including in immunotherapy-treated patients. Thus, the GARP/TGF-{beta} axis emerges as a glucocorticoid-sensitive cancer cell-intrinsic immune evasive mechanism. SignificanceScreening widely used topical treatments in a melanoma model, this study uncovers a surprising role for glucocorticoids in triggering CD8+ T cell-dependent tumor control through downregulation of GARP and thus TGF-{beta} signaling. Melanoma patient sample analysis supported these findings suggesting GARP/TGF-{beta} activity functions as a tumor cell-intrinsic immune evasive mechanism, and GARP expression may serve as both a biomarker of poor antitumor immunity and a therapeutic target to improve the response to immunotherapy.

cancer biology↗

A human pluripotent stem cell tri-culture platform to elucidate microglial regulation of retinal ganglion cells in neuroinflammation

Optic neuropathies, including glaucoma, are characterized by the progressive degeneration of retinal ganglion cells (RGCs), ultimately leading to irreversible vision loss. Increasing evidence implicates microglia, the resident immune cells of the central nervous system, as key modulators of RGC health and disease progression. However, the precise mechanisms by which microglia influence RGCs remain poorly understood, particularly in the human context. In this study, we established human pluripotent stem cell (hPSC)-derived co-culture systems incorporating microglia, astrocytes, and RGCs to explore how microglia shape RGC growth and maturation under physiological conditions. We first examined the impact of homeostatic microglia on RGCs in both co-culture and tri-culture systems, revealing distinct influences of cell types in co-culture compared to when they were grown individually. We then modeled inflammatory states by activating microglia with lipopolysaccharide (LPS) and evaluated their effects on RGCs both directly and in the context of astrocyte co-culture. This stepwise, reductionist approach enabled us to dissect the cellular interactions driving RGC vulnerability in inflammatory conditions relevant to optic neuropathies. Our findings provide new insight into the complex neuroimmune landscape that underlies RGC degeneration and identify key pathways that may serve as therapeutic targets across a range of optic nerve diseases.

neuroscience↗

Exploring influenza A virus receptor distribution in the lactating mammary gland of domesticated livestock and in human breast tissue.

The spread of the highly pathogenic avian influenza (HPAI) H5N1 virus among dairy cattle illustrates the adaptability of influenza A viruses (IAV) to infect non-traditional species. While IAV-specific sialic acid (SA) receptors have been identified in the mammary glands of dairy cattle, their presence in pigs, sheep, goats, and alpacas has not been studied until now. The zoonotic transmission of HPAI H5N1 to dairy and poultry farm workers during outbreaks raises public health concerns. This study employed lectin histochemistry to examine the mammary glands of livestock and humans. We found that these tissues were rich in SA 2,6-Gal receptors, followed by SA 2,3-Gal receptors, essential for IAV binding. Notably, the A(H5N1) clade 2.3.4.4b virus could bind to mammary tissue from both cattle and pigs. These findings highlight the potential for HPAI H5N1 to infect and spread within the mammary glands of production animals and humans.

immunology↗

Fractionated radiation alters the extracellular matrix produced by muscle-invasive bladder cancer cells

Muscle-invasive bladder cancer (MIBC) is a prevalent disease that can be treated with radiotherapy, but has a poor prognosis. Radiation-induced extracellular matrix (ECM) remodelling and fibrosis can induce tumour resistance and recurrence, but has not been studied in MIBC. Here we aimed to characterise the impact of radiation on the ECM composition of MIBC. Materials and MethodsThree MIBC cell lines (T24, UMUC3, J82) were treated with fractionated radiation. We used proteomics to analyse the ECM composition produced by surviving cancer cells and immunofluorescence to investigate changes in the morphology and number of ECM fibres. We evaluated the RNA expression of identified ECM proteins (FN1, COL5A1, COL1A1, TNF6AIP6, FLG) in one cystectomy (TCGA-BLCA, n=397) and two radiotherapy (BC2001, n=313; BCON, n=151) cohorts. ResultsThere were 613 proteins affected by radiation (padj<0.05, fold change >2 or <-2), 68 of which were ECM-associated proteins. There was a general increase in proteases and protease regulators but heterogeneity across cell lines. Enrichment analysis showed ECM organisation was the primary pathway affected. Immunofluorescence confirmed radiation affected ECM structure, generally, reducing the number, length and width of fibres. High FN1, COL5A1, COL1A1, TNF6AIP6 and FLG mRNA levels were adverse prognostic markers in clinical cohorts. ConclusionRadiation alters the composition and structure of the ECM produced by MIBC. As a proof-of-concept, we showed the expression of radiation-affected ECM genes are prognostic markers in MIBC. Future studies should validate these radiation-induced ECM changes in clinical samples.

cancer biology↗

Hypoxia-induced extracellular matrix changes are conserved in cancer and directly impact radiotherapy benefit

Our overarching aim was to determine how hypoxia affects the extracellular matrix (ECM). Transcriptomic analysis (21,941 patients; 10 cancer types) identified ECM remodelling as the predominant pathway affected by hypoxia. Multi-omics confirmed that hypoxia impacts ECM organisation and collagen degradation; 53 ECM genes were affected, of which 74% were HIF1/HIF2-regulated. Spatial transcriptomics highlighted different hypoxia remodelling processes in tumour and stroma. Five ECM genes commonly affected in tumour and in vitro constituted a signature. This signature was independently prognostic and independently predictive of radiotherapy benefit in multiple malignancies. Patients within either high or low hypoxic-ECM score tertiles benefited from radiotherapy versus surgery. Hypoxic ECMs generated in vitro increased adhesion and decreased migration of cancer cells, an effect enhanced by irradiation. Immunofluorescence demonstrated that hypoxia decreased collagen fibre number, and irradiation decreased cell-ECM interactions. Taken together, these findings demonstrate hypoxia induces pan-cancer ECM changes, directly impacting radiotherapy benefit.

cancer biology↗

Elovl1 inhibition reduced very long chain fatty acids in a mouse model of adrenoleukodystrophy

Adrenoleukodystrophy (ALD) is a rare neurometabolic disease caused by mutations in the ABCD1 gene, which encodes for the peroxisomal very long chain fatty acid (VLCFAs) transporter. It is a debilitating disorder, which has a spectrum of clinical presentations. The most severe form is a rapidly progressing demyelinating disease called cerebral ALD or CALD. Patients with cALD have a life expectancy of 2-4 years after onset and symptoms often manifest in childhood. The other forms are adrenomyeloneuropathy or AMN, which is a slower progressing degeneration of the spinal cord, and adrenal insufficiency (Addison disease). Since the accumulation of VLCFAs are a common factor in all ALD pathologies, we identified therapeutic approach that could correct this metabolic defect. We developed a substrate reduction therapy (SRT) for ALD in the form of an inhibitor of the lipid elongase principally responsible for the generation of VLCFAs, Elovl1. This small molecule was able to successfully reduce the accumulation of VLCFA in the brain and spinal cord of ABCD1-/y mice. We used single nuclei RNA seq to identify the pathways altered in the ABCD1-/y mouse and corrected with Elovl1 inhibition. Though many lipid metabolism genes and pathways were indeed corrected, treatment with the Elovl1 inhibitor unexpectedly led to profound transcriptional changes beyond correction of pathways altered by loss of ABCD1. These data suggest that Elovl1 inhibition may have broader consequences in ABCD1-/y mice than correction of lipid homeostasis.

pharmacology and toxicology↗

Mechanistic insights into Rho/MRTF inhibition-induced apoptotic events and prevention of drug resistance in melanoma: Implications for the involvement of pirin

AimOvercoming therapy resistance is critical for effective melanoma control. Upregulation of Rho/MRTF signaling in human and mouse melanomas causes resistance to targeted therapies. Inhibition of this pathway by MRTFi, CCG-257081 resensitized resistant melanomas to BRAF and MEK inhibitors. It also prevented the development of resistance to vemurafenib (Vem). Here, we investigate the role of apoptosis and the protein pirin in CCG-257081-mediated suppression of drug resistance. MethodsUsing naive and resistant mouse YUMMER melanoma cells, we studied the effect of the BRAF inhibitor Vem with or without CCG-257081 on real-time growth and apoptosis (activation of caspase, Propidium iodide (PI) staining, and PARP cleavage). The effects of CCG-257081 on proliferation (Ki67) and caspase-3 activation were assessed in resistant YUMMER_R tumors in vivo. Finally, two CCG-257081 enantiomers were tested for pirin binding, inhibition of the Rho/MRTF-mediated activation of ACTA2 gene expression in fibroblasts, and the prevention of Vem resistance development by YUMMER_P cells. ResultsVem reduced growth of parental but not resistant cells, while CCG-257081 inhibited both. The combination was more effective than Vem alone. CCG-257081, but not Vem, induced activation of caspase-3 and -7 in resistant cells and increased PARP cleavage and PI staining. CCG-257081 reduced proliferation and activated caspase-3 in YUMMER_R melanoma tumors. Both CCG-257081 enantiomers robustly suppressed development of Vem-resistant colonies with the S isomer being more potent (1 M IC50). ConclusionCCG-257081 appears to target pre-resistant cells and Vem-induced resistant cells through enhanced apoptosis. Inhibition of pirin or the Rho/MRTF pathway can be employed to prevent melanoma resistance.

pharmacology and toxicology↗

A Computational Model of Mechanical Stretching of Cultured Cells on a Flexible Membrane

Mechanical forces applied to cells are known to regulate a wide variety of biological processes. Recent studies have supported that mechanical forces can cause nuclear deformation, leading to significant alterations in the gene expression and chromatin landscape of the cell. While the stresses and strains applied to cells is it is often known or controlled experimentally on a macroscopic length scale, it is often unclear what the actual forces and displacements are at the microscopic level of the cell. In this work, we created a model of cell deformation during application of mechanical stretch to cultured cells growth on a flexible membrane. This configuration is commonly used is in experimental studies as a means to apply controlled mechanical strains to adherent cultured cells. The parameters used in the study were used for application of strain to a mesenchymal stem cell stretched on a membrane. computational model was created to simulate the stresses and strains within the cell under a variety of stain amplitudes, waveforms and frequencies of mechanical loading with the range of commonly used experimental systems. The results demonstrate the connection between mechanical loading parameters applied through the flexible membrane and the resulting stresses and strains within the cell and nucleus. Using a viscoelastic model of chromatin, we connected the results provide to a rough model of resulting deformation within chromatin from the forces applied to the nucleus. Overall, the model is useful in providing insight between experimentally applied mechanical forces and the actual forces within the cell to better interpret the results of experimental studies. Statement of SignificanceIn this work, we created a computational model of the mechanical stretching of cell on a flexible membrane under cyclic mechanical loading. This model provides insight into the forces and displacements inside of cell that result from that application of stretch. As many experiments use this set up, our work is relevant to interpreting many studies that use mechanical stretch to stimulate mechanotransduction.

bioengineering↗

Mechanical Rejuvenation of Mesenchymal Stem Cells from Aged Patients

Mesenchymal stem cells (MSC) are an appealing therapeutic cell type for many diseases. However, patients with poor health or advanced age often have MSCs with poor regenerative properties. A major limiter of MSC therapies is cellular senescence, which is marked by limited proliferation capability, diminished multipotency, and reduced regenerative properties. In this work, we explored the ability of applied mechanical forces to reduce cellular senescence in MSCs. Our studies revealed that mechanical conditioning caused a lasting enhancement in proliferation, overall cell culture expansion potential, multipotency, and a reduction of senescence in MSCs from aged donors. Mechanistic studies suggested that these functional enhancements were mediated by oxidative stress and DNA damage repair signaling with mechanical load altering the expression of proteins of the sirtuin pathway, the DNA damage repair protein ATM, and antioxidant proteins. In addition, our results suggest a biophysical mechanism in which mechanical stretch leads to improved recognition of damaged DNA in the nucleus. Analysis of the cells through RNA-seq and ATAC-seq, demonstrated that mechanical loading alters the cells genetic landscape to cause broad shifts in transcriptomic patterns that related to senescence. Overall, our results demonstrate that mechanical conditioning can rejuvenate mesenchymal stem cells derived from aged patients and improve their potential as a therapeutic cell type. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/597781v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@a479d4org.highwire.dtl.DTLVardef@3a728eorg.highwire.dtl.DTLVardef@136dc3dorg.highwire.dtl.DTLVardef@b54d51_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

Phosphate overplus response in Chlamydomonas reinhardtii: polyphosphate dynamics to monitor phosphate uptake and turnover

Many micro-organisms store inorganic phosphate (Pi) in the form of polyphosphate (polyP) and exhibit in-cell polyP accumulation, a phenomenon known as phosphate overplus response, when resupplied with Pi after a period of deprivation. Quantitative and qualitative methods were used to follow the dynamics of polyP synthesis and turnover in four strains of Chlamydomonas reinhardtii during Pi deprivation followed by nutrient resupply. The lowest level of in-cell polyP during Pi deprivation, which also correlates with the cessation of growth, is the key parameter for the timing of Pi resupply to maximise the Pi overplus response Additional nutrients do not affect the size of the overplus response, but they are important for continued growth and maximal Pi removal from the media. Tracking polyP allows the correct time for nutrient resupply to be determined and therefore a reproducible Pi overplus response to be achieved. Depending on whether maximum cellular phosphorus (P) content or maximum Pi removal is desired different strategies may be required - e,g., Pi deprivation until growth cessation then resupplying complete nutrients gives the best trade-off between high in-cell P accumulation, high Pi uptake and algal biomass growth. Although polyP levels are maintained after Pi resupply, the polymer is dynamically remodelled. IP6 increases during this time. This increase does not precede polyP synthesis as predicted by a model where inositol phosphates switch on polyP synthesis. One strain tested, CC-5325, shows enhanced Pi uptake and levels of polyP and total in-cell P, suggesting that strain selection is also important. ImportanceThere is strong interest in using microalgae to sustainably control and recover nutrients, especially P, from wastewater. This would help to meet environmental discharge consents and recycle nutrients into agriculture or other applications. Like bacteria and yeasts, microalgae exhibit a Pi overplus phenomenon when Pi-deprived cells are resupplied with P, but microalgae do not require an additional carbon source and can simultaneously uptake nitrogen as well. Use of microalgae in wastewater treatment is limited by the unpredictability of their response and sensitivity to environmental factors, but engineered systems can greatly benefit from better understanding Pi dynamics and polyP accumulation. In the literature there is a lack of consensus regarding protocols to maximise the Pi overplus. In this work we provide robust measurements of quantitative physiological parameters, which should allow reproducibility in laboratory studies and provide design parameters for algal-based nutrient recovery systems from waste waters.

microbiology↗

Colchicine promotes atherosclerotic plaque stability independently of inflammation

Atherosclerosis is a chronic inflammatory disease which is driven in part by the aberrant trans-differentiation of vascular smooth muscle cells (SMCs). No therapeutic drug has been shown to reverse detrimental SMC-derived cell phenotypes into protective phenotypes, a hypothesized enabler of plaque regression and improved patient outcome. Herein, we describe a novel function of colchicine in the beneficial modulation of SMC-derived cell phenotype, independent of its conventional anti-inflammatory effects. Using SMC fate mapping in an advanced atherosclerotic lesion model, colchicine induced plaque regression by converting pathogenic SMC-derived macrophage-like and osteoblast-like cells into protective myofibroblast-like cells which thickened, and thereby stabilized, the fibrous cap. This was dependent on Notch3 signaling in SMC-derived plaque cells. These findings may help explain the success of colchicine in clinical trials relative to other anti-inflammatory drugs. Thus, we demonstrate the potential of regulating SMC phenotype in advanced plaque regression through Notch3 signaling, in addition to the canonical anti-inflammatory actions of drugs to treat atherosclerosis.

cell biology↗

Heart-on-a-chip model of immune-induced cardiac dysfunction reveals the involvement of free mitochondrial DNA and therapeutic effects of endothelial exosomes

Cardiovascular disease continues to take more human lives than all cancer combined, prompting the need for improved research models and treatment options. Despite a significant progress in development of mature heart-on-a-chip models of fibrosis and cardiomyopathies starting from induced pluripotent stem cells (iPSCs), human cell-based models of myocardial inflammation are lacking. Here, we bioengineered a vascularized heart-on-a-chip system with circulating immune cells to model SARS-CoV-2-induced acute myocarditis. Briefly, we observed hallmarks of COVID-19-induced myocardial inflammation in the heart-on-a-chip model, as the presence of immune cells augmented the expression levels of proinflammatory cytokines, triggered progressive impairment of contractile function and altered intracellular calcium transient activities. An elevation of circulating cell-free mitochondrial DNA (ccf-mtDNA) was measured first in the in vitro heart-on-a-chip model and then validated in COVID-19 patients with low left ventricular ejection fraction (LVEF), demonstrating that mitochondrial damage is an important pathophysiological hallmark of inflammation induced cardiac dysfunction. Leveraging this platform in the context of SARS-CoV-2 induced myocardial inflammation, we established that administration of human umbilical vein-derived EVs effectively rescued the contractile deficit, normalized intracellular calcium handling, elevated the contraction force and reduced the ccf- mtDNA and chemokine release via TLR-NF-kB signaling axis.

bioengineering↗

Inhibition of somatostatin enhances the long-term metabolic outcomes of sleeve gastrectomy in mice

Bariatric surgery is an effective obesity treatment, leading to weight loss and improvement in glycemia, that is characterized by hypersecretion of gastrointestinal hormones. However, weight regain and relapse of hyperglycemia are not uncommon. Here, we investigated the role of somatostatin (Sst) in bariatric surgery outcomes using a mouse model of sleeve gastrectomy (SG). Sst knockout (sst-ko) mice fed with a calorie-rich diet gained weight normally, and had a mild favorable metabolic phenotype compared to heterozygous sibling controls, including elevated plasma levels of Glp1. Mathematical modeling of the feedback inhibition between Sst and Glp1 showed that Sst exerts its maximal effect on Glp1 under conditions of high hormonal stimulation, such as following SG. Obese sst-ko mice that underwent SG had higher levels of Glp1 compared with heterozygous SG-operated controls. Accordingly, SG-sst-ko mice regained less weight than controls and maintained lower glycemia months after surgery. Obese wild-type mice that underwent SG and were treated daily with a Sst receptor inhibitor for two months, had higher Glp1 levels, regained less weight, and improved glycemia compared to saline- treated SG-operated controls. Our results suggest that Sst signaling inhibition enhances and maintains the long-term favorable metabolic outcomes of bariatric surgery.

physiology↗

Transmembrane Stem Factor Nanodiscs Enhanced Revascularization in a Hind Limb Ischemia Model in Diabetic, Hyperlipidemic Rabbits

Therapies to revascularize ischemic tissue have long been a goal for the treatment of vascular disease and other disorders. Therapies using stem cell factor (SCF), also known as a c-Kit ligand, had great promise for treating ischemia for myocardial infarct and stroke, however clinical development for SCF was stopped due to toxic side effects including mast cell activation in patients. We recently developed a novel therapy using a transmembrane form of SCF (tmSCF) delivered in lipid nanodiscs. In previous studies, we demonstrated tmSCF nanodiscs were able to induce revascularization of ischemia limbs in mice and did not activate mast cells. To advance this therapeutic towards clinical application, we tested this therapy in an advanced model of hindlimb ischemia in rabbits with hyperlipidemia and diabetes. This model has therapeutic resistance to angiogenic therapies and maintains long term deficits in recovery from ischemic injury. We treated rabbits with local treatment with tmSCF nanodiscs or control solution delivered locally from an alginate gel delivered into the ischemic limb of the rabbits. After eight weeks, we found significantly higher vascularity in the tmSCF nanodisc-treated group in comparison to alginate treated control as quantified through angiography. Histological analysis also showed a significantly higher number of small and large blood vessels in the ischemic muscles of the tmSCF nanodisc treated group. Importantly, we did not observe inflammation or mast cell activation in the rabbits. Overall, this study supports the therapeutic potential of tmSCF nanodiscs for treating peripheral ischemia.

bioengineering↗