Biology subjects

Price, J. M.

Publications and source records attributed to Price, J. M..

6 recordsLinked to original sources

bioRxiv2026

Infrapatellar Fat Pad Extracellular Vesicles Induce a Pro-Angiogenic VEGFAhigh/BMP4low Switch in Articular Chondrocytes: Implications for Chondrosarcoma

Chondrosarcoma is a hyper-vascularised, chemoresistant cartilage malignancy driven by VEGF-centred angiogenesis, and local adipose depots are increasingly recognised as paracrine drivers of tumour angiogenesis via adipokines and extracellular vesicles (EVs). The infrapatellar fat pad (IFP), an inflammatory adipose depot within the articular joint in direct cartilage contact, is a key local source of adipose-derived EVs, and thus a candidate driver of angiogenesis in chondrosarcoma. The aim of this study was to determine whether the IFP is a productive source of EVs, and whether IFP-derived EVs induce angiogenesis in articular chondrocytes. The IFP released significantly more EVs than subcutaneous fat (n = 8 per depot; p = 0.027). Treating primary human articular chondrocytes with IFP EVs for 24 h upregulated VEGFA (+1.6-fold, p = 0.036) and downregulated BMP4 (-2.4-fold, p = 0.011), engaging the VEGF/eNOS/ERK axis that drives chondrosarcoma angiogenesis. Re-analysis of a previously published phospho-kinase dataset from the same donor EVs, corroborated by a pooled donor-group analysis (n = 3), supported activation of eNOS, ERK1/2, PLC-{gamma}1 and HSP27. These findings identify the IFP as a dominant source of EVs within the articular joint, which can induce a pro-angiogenic, VEGF-axis switch in articular cartilage cells, supporting a signalling model relevant to chondrosarcoma angiogenesis.

cancer biology↗

bioRxiv2026

GLP-1 and GIP receptor agonism does not directly drive skeletal muscle atrophy or impair myogenesis in primary human myotubes

GLP-1 and GIP/GLP-1 receptor agonists produce substantial weight loss in clinical trials but significant loss of lean body mass is reported. Whether this reflects a direct pharmacological effect on skeletal muscle or an indirect consequence of caloric restriction and reduced mechanical loading is unknown. Primary myoblasts were isolated from skeletal muscle of older adults with obesity undergoing orthopaedic surgery. GIPR and GLP-1R expression was characterised by RT- qPCR and flow cytometry. Differentiated myotubes were treated with semaglutide or GIP peptide and assessed for atrophy-related gene expression (qPCR), secretome perturbation (Olink Reveal), mitochondrial and glycolytic bioenergetics (Seahorse XF Real-Time ATP Rate Assay, glucose uptake, lactate secretion) and myotube morphology and myogenesis (immunofluorescence). GIPR mRNA was consistently detected across all donors; GLP-1R mRNA was undetectable by PCR, though LUXendin645 flow cytometry identified low-level surface GLP-1R protein in 51-66% of myoblasts. Neither semaglutide nor GIP altered atrophy-related gene expression or the secretome, with no proteins reaching significance. Semaglutide reduced glycolytic and total ATP production rates, accompanied by reduced lactate secretion, suggesting modest suppression of glycolytic flux; mitochondrial parameters were unaffected. Neither treatment impaired myotube thickness or differentiation; GIP increased myotube thickness after 8 days. Direct GLP-1 and GIP receptor activation does not substantively perturb atrophic signalling, myogenesis, or the secretome of primary human skeletal muscle myotubes. These findings suggest that lean mass loss with incretin-based therapies is unlikely to be driven by direct pharmacological action on skeletal muscle - particularly relevant as these agents are increasingly used in older adults at risk of sarcopenia.

physiology↗

bioRxiv2025

Feeder-free generation of functional dendritic cells from human pluripotent stem cells

The scarcity of primary conventional dendritic cells (cDCs) and the limited effectiveness of monocyte-derived dendritic cells (moDCs) have long hindered progress in human dendritic cell research and immunotherapy. We developed a feeder-free differentiation platform that generates CD1c+CD141+ hPSC-cDCs phenotypically aligned with CD141+ tissue-resident cDC2 subsets found in human tissues. We further optimized the differentiation process using a Design-of-Experiments framework to refine cytokine and serum conditions, enhancing differentiation efficiency while reducing cytokine demand. These hPSC-cDCs exhibit efficient antigen uptake, defined cytokine responses, and robust priming of antigen-specific CD8+ T cell proliferation and effector differentiation, outperforming moDCs in direct comparison. Together, this work establishes a robust, and generalizable platform for mechanistic studies and translational development of dendritic cell-based vaccines and standardized ex vivo T cell expansion.

immunology↗

bioRxiv2025

Matrix viscoelasticity regulates dendritic cell migration and immune priming

The tumor microenvironment shapes immune surveillance through its mechanical properties, yet the role of matrix viscoelasticity remains unclear. Here, we used a collagen system with tunable viscoelasticity to define how matrix relaxation directs dendritic cell (DC) behavior. Elastic matrices impaired DC migration by limiting actomyosin-driven collagen remodeling, thereby reducing DC-T cell encounters and weakening T cell priming, activation, proliferation, and tumor killing. Blocking DC migration in fast-relaxing gels recapitulated key aspects of the impaired T cell priming seen in elastic matrices. Prolonged confinement in elastic extracellular matrix induced a mechanomemory state, locking DCs into reduced motility even after transfer to viscoelastic environments, corresponding to altered chromatin accessibility. Finally, studies with patient-derived ependymoma samples confirmed these findings, identifying viscoelasticity as a barrier to antitumor immunity with implications for therapeutic intervention.

bioengineering↗

bioRxiv2025

Dose-dependent, opioid-induced sleep disruption is partially mediated by motor activity but not by body temperature in C57BL/6J mice

States of sleep and wakefulness, motor activity, and body temperature are temporally linked, yet these variables are often studied independently. Here we report novel results from male C57BL/6J mice (n = 24) that quantify the causal and correlational relationships between these temporally linked measures. The initial experiments used 12 mice to identify the lowest antinociceptive doses of fentanyl (0.1 mg/kg) and morphine (1 mg/kg). Twelve additional mice were implanted with telemeters to simultaneously record EEG, electromyogram, motor activity, and subcutaneous body temperature. Doses of fentanyl (0.1, 0.3, 1, 3 mg/kg) and morphine (1, 3, 10, 30 mg/kg) caused significant (P<0.05) increases in wakefulness and decreases in NREM and REM sleep. Fentanyl (0.1 to 3 mg/kg) and morphine (3 to 30 mg/kg) significantly increased motor activity. Body temperature during wakefulness was significantly decreased by fentanyl (1, 3 mg/kg). Morphine increased (3 mg/kg) and decreased (30 mg/kg) body temperature. Mediation analyses showed that the increase in wakefulness caused by fentanyl and morphine was partially mediated by motor activity, but not by changes in body temperature. These results provide the first complete dose-response data for effects of fentanyl and morphine on simultaneously acquired measures of sleep/wake states, body temperature, and motor activity. Compared to human data, these results from mice reveal similarities (sleep disruption, hyperthermia and hypothermia) and differences (increased motor activity) caused by fentanyl and morphine. The results also demonstrate the power of mediation analyses for providing nuanced insights into opioid effects on clinically relevant neurobehavioral phenotypes. Significance StatementSleep disruption is an undesired, clinically significant effect of opioids prescribed to manage pain. Sleep disruption exacerbates pain and can lead to increased opioid requirement, as well as increased risk of addiction relapse. The significance of this study is the discovery that in mice, even the lowest doses of fentanyl and morphine that caused antinociception also caused sleep disruption. Thus, in mice, it is not possible to provide antinociception using fentanyl or morphine without causing sleep disruption.

pharmacology and toxicology↗

bioRxiv2020

The vitamin A ester retinyl propionate has a unique metabolic profile and higher retinoid-related bioactivity over retinol and retinyl palmitate in human skin models.

Human skin is exposed daily to environmental stressors, which cause acute damage and inflammation. Over time this leads to morphological and visual appearance changes associated with premature aging. Topical vitamin A derivatives such as retinol (ROL), retinyl palmitate (RPalm), and retinyl propionate (RP) have been used to reverse these changes and improve the appearance of skin. This study investigated a stoichiometric comparison of these retinoids using in vitro and ex vivo skin models. Skin biopsies were treated topically to compare skin penetration and metabolism. Treated keratinocytes were evaluated for transcriptomics profiling and hyaluronic acid (HA) synthesis and treated 3D epidermal skin equivalents were stained for epidermal thickness, Ki67, and filaggrin. A retinoic acid receptor-alpha (RAR) reporter cell line was used to compare retinoid activation levels. Results from ex vivo skin found that RP and ROL have higher penetration levels compared to RPalm. RP is metabolized primarily into ROL in the viable epidermis and dermis whereas ROL is esterified into RPalm and metabolized into the inactive retinoid 14-hydroxy-4,14-retro-retinol (14-HRR). RP treatment yielded higher RAR activation and HA synthesis levels than ROL whereas RPalm had a null effect. In keratinocytes, RP and ROL stimulated similar gene expression patterns and pathway theme profiles. In conclusion, RP and ROL show a similar response directionality whereas RPalm response was inconsistent. Additionally, RP has a consistently higher magnitude of response compared with ROL or RPalm.

biochemistry↗