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Biology Letters Jun 2024Red coralline algae create abundant, spatially vast, reef ecosystems throughout our coastal oceans with significant ecosystem service provision, but our understanding of...
Red coralline algae create abundant, spatially vast, reef ecosystems throughout our coastal oceans with significant ecosystem service provision, but our understanding of their basic physiology is lacking. In particular, the balance and linkages between carbon-producing and carbon-sequestering processes remain poorly constrained, with significant implications for understanding their role in carbon sequestration and storage. Using dual radioisotope tracing, we provide evidence for coupling between photosynthesis (which requires CO) and calcification (which releases CO) in the red coralline alga (previously )-a marine ecosystem engineer widely distributed across Atlantic mid-high latitudes. Of the sequestered HCO , 38 ± 22% was deposited as carbonate skeleton while 39 ± 14% was incorporated into organic matter via photosynthesis. Only 38 ± 2% of the sequestered HCO was transformed into CO, and almost 40% of that was internally recycled as photosynthetic substrate, reducing the net release of carbon to 23 ± 3% of the total uptake. The calcification rate was strongly dependent on photosynthetic substrate production, supporting the presence of photosynthetically enhanced calcification. The efficient carbon-recycling physiology reported here suggests that calcifying algae may not contribute as much to marine CO release as is currently assumed, supporting a reassessment of their role in blue carbon accounting.
Topics: Photosynthesis; Rhodophyta; Calcification, Physiologic; Carbon; Carbon Dioxide; Carbon Cycle; Carbon Sequestration
PubMed: 38889774
DOI: 10.1098/rsbl.2023.0598 -
The Journal of Clinical Investigation Jun 2024The β-secretase BACE1 is a central drug target for Alzheimer's disease. Clinically tested, BACE1-directed inhibitors also block the homologous protease BACE2. Yet,...
The β-secretase BACE1 is a central drug target for Alzheimer's disease. Clinically tested, BACE1-directed inhibitors also block the homologous protease BACE2. Yet, little is known about physiological BACE2 substrates and functions in vivo. Here, we identify BACE2 as the protease shedding the lymphangiogenic vascular endothelial growth factor receptor 3 (VEGFR3). Inactivation of BACE2, but not BACE1, inhibited shedding of VEGFR3 from primary human lymphatic endothelial cells (LECs) and reduced release of the shed, soluble VEGFR3 (sVEGFR3) ectodomain into the blood of mice, non-human primates and humans. Functionally, BACE2 inactivation increased full-length VEGFR3 and enhanced VEGFR3 signaling in LECs and also in vivo in zebrafish, where enhanced migration of LECs was observed. Thus, this study identifies BACE2 as a modulator of lymphangiogenic VEGFR3 signaling and demonstrates the utility of sVEGFR3 as a pharmacodynamic plasma marker for BACE2 activity in vivo, a prerequisite for developing BACE1-selective inhibitors for a safer prevention of Alzheimer's disease.
PubMed: 38888964
DOI: 10.1172/JCI170550 -
CNS Neuroscience & Therapeutics Jun 2024Impaired mitochondrial dynamics have been identified as a significant contributing factor to reduced neurogenesis under pathological conditions. However, the...
BACKGROUND
Impaired mitochondrial dynamics have been identified as a significant contributing factor to reduced neurogenesis under pathological conditions. However, the relationship among mitochondrial dynamics, neurogenesis, and spatial memory during normal development remains unclear. This study aims to elucidate the role of mitophagy in spatial memory mediated by neurogenesis during development.
METHODS
Adolescent and adult male mice were used to assess spatial memory performance. Immunofluorescence staining was employed to evaluate levels of neurogenesis, and mitochondrial dynamics were assessed through western blotting and transmission electron microscopy. Pharmacological interventions further validated the causal relationship among mitophagy, neurogenesis, and behavioral performance during development.
RESULTS
The study revealed differences in spatial memory between adolescent and adult mice. Diminished neurogenesis, accompanied by reduced mitophagy, was observed in the hippocampus of adult mice compared to adolescent subjects. Pharmacological induction of mitophagy in adult mice with UMI-77 resulted in enhanced neurogenesis and prolonged spatial memory retention. Conversely, inhibition of mitophagy with Mdivi-1 in adolescent mice led to reduced hippocampal neurogenesis and impaired spatial memory.
CONCLUSION
The observed decline in spatial memory in adult mice is associated with decreased mitophagy, which affects neurogenesis in the dentate gyrus. This underscores the therapeutic potential of enhancing mitophagy to counteract age- or disease-related cognitive decline.
Topics: Animals; Neurogenesis; Mitophagy; Spatial Memory; Hippocampus; Male; Mice; Mice, Inbred C57BL; Mitochondrial Dynamics; Quinazolinones
PubMed: 38887162
DOI: 10.1111/cns.14800 -
Stem Cell Research & Therapy Jun 2024Mechanical stimulation (MS) significantly increases the release of adenine and uracil nucleotides from bone marrow-derived mesenchymal stem cells (BM-MSCs) undergoing...
Mechanical stimulation-induced purinome priming fosters osteogenic differentiation and osteointegration of mesenchymal stem cells from the bone marrow of post-menopausal women.
BACKGROUND
Mechanical stimulation (MS) significantly increases the release of adenine and uracil nucleotides from bone marrow-derived mesenchymal stem cells (BM-MSCs) undergoing osteogenic differentiation. Released nucleotides acting via ionotropic P2X7 and metabotropic P2Y purinoceptors sensitive to ATP and UDP, respectively, control the osteogenic commitment of BM-MSCs and, thus, bone growth and remodelling. Yet, this mechanism is impaired in post-menopausal (Pm)-derived BM-MSCs, mostly because NTPDase3 overexpression decreases the extracellular accumulation of nucleotides below the levels required to activate plasma membrane-bound P2 purinoceptors. This prompted us to investigate whether in vitro MS of BM-MSCs from Pm women could rehabilitate their osteogenic commitment and whether xenotransplantation of MS purinome-primed Pm cells promote repair of critical bone defects in an in vivo animal model.
METHODS
BM-MSCs were harvested from the neck of femora of Pm women (70 ± 3 years old) undergoing total hip replacement. The cells grew, for 35 days, in an osteogenic-inducing medium either submitted (SS) or not (CTR) to MS (90 r.p.m. for 30 min) twice a week. Increases in alkaline phosphatase activity and in the amount of osteogenic transcription factors, osterix and osteopontin, denoted osteogenic cells differentiation, while bone nodules formation was ascertain by the alizarin red-staining assay. The luciferin-luciferase bioluminescence assay was used to quantify extracellular ATP. The kinetics of the extracellular ATP (100 µM) and UDP (100 µM) catabolism was assessed by HPLC. The density of P2Y and P2X7 purinoceptors in the cells was assessed by immunofluorescence confocal microscopy. MS-stimulated BM-MSCs from Pm women were xenotransplanted into critical bone defects drilled in the great trochanter of femora of one-year female Wistar rats; bone repair was assessed by histological analysis 10 days after xenotransplantation.
RESULTS
MS-stimulated Pm BM-MSCs in culture (i) release 1.6-fold higher ATP amounts, (ii) overexpress P2X7 and P2Y purinoceptors, (iii) exhibit higher alkaline phosphatase activity and overexpress the osteogenic transcription factors, osterix and osteopontin, and (iv) form larger bone nodules, than CTR cells. Selective blockage of P2X7 and P2Y purinoceptors with A438079 (3 µM) and MRS 2578 (0.1 µM), respectively, prevented the osteogenic commitment of cultured Pm BM-MSCs. Xenotransplanted MS purinome-primed Pm BM-MSCs accelerated the repair of critical bone defects in the in vivo rat model.
CONCLUSIONS
Data suggest that in vitro MS restores the purinergic cell-to-cell communication fostering the osteogenic differentiation and osteointegration of BM-MSCs from Pm women, a strategy that may be used in bone regeneration and repair tactics.
Topics: Female; Mesenchymal Stem Cells; Humans; Osteogenesis; Animals; Cell Differentiation; Aged; Postmenopause; Rats; Bone Marrow Cells; Mesenchymal Stem Cell Transplantation; Sp7 Transcription Factor; Cells, Cultured; Transcription Factors; Rats, Wistar
PubMed: 38886849
DOI: 10.1186/s13287-024-03775-4 -
Stem Cell Research & Therapy Jun 2024Cartilage is a kind of avascular tissue, and it is difficult to repair itself when it is damaged. In this study, we investigated the regulation of chondrogenic...
BACKGROUND
Cartilage is a kind of avascular tissue, and it is difficult to repair itself when it is damaged. In this study, we investigated the regulation of chondrogenic differentiation and vascular formation in human jaw bone marrow mesenchymal stem cells (h-JBMMSCs) by the long-chain noncoding RNA small nucleolar RNA host gene 1 (SNHG1) during cartilage tissue regeneration.
METHODS
JBMMSCs were isolated from the jaws via the adherent method. The effects of lncRNA SNHG1 on the chondrogenic differentiation of JBMMSCs in vitro were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), Pellet experiment, Alcian blue staining, Masson's trichrome staining, and modified Sirius red staining. RT-qPCR, matrix gel tube formation, and coculture experiments were used to determine the effect of lncRNA SNHG1 on the angiogenesis in JBMMSCs in vitro. A model of knee cartilage defects in New Zealand rabbits and a model of subcutaneous matrix rubber suppositories in nude mice were constructed for in vivo experiments. Changes in mitochondrial function were detected via RT-qPCR, dihydroethidium (DHE) staining, MitoSOX staining, tetramethyl rhodamine methyl ester (TMRM) staining, and adenosine triphosphate (ATP) detection. Western blotting was used to detect the phosphorylation level of signal transducer and activator of transcription 3 (STAT3).
RESULTS
Alcian blue staining, Masson's trichrome staining, and modified Sirius Red staining showed that lncRNA SNHG1 promoted chondrogenic differentiation. The lncRNA SNHG1 promoted angiogenesis in vitro and the formation of microvessels in vivo. The lncRNA SNHG1 promoted the repair and regeneration of rabbit knee cartilage tissue. Western blot and alcian blue staining showed that the JAK inhibitor reduced the increase of STAT3 phosphorylation level and staining deepening caused by SNHG1. Mitochondrial correlation analysis revealed that the lncRNA SNHG1 led to a decrease in reactive oxygen species (ROS) levels, an increase in mitochondrial membrane potential and an increase in ATP levels. Alcian blue staining showed that the ROS inhibitor significantly alleviated the decrease in blue fluorescence caused by SNHG1 knockdown.
CONCLUSIONS
The lncRNA SNHG1 promotes chondrogenic differentiation and angiogenesis of JBMMSCs. The lncRNA SNHG1 regulates the phosphorylation of STAT3, reduces the level of ROS, regulates mitochondrial energy metabolism, and ultimately promotes cartilage regeneration.
Topics: RNA, Long Noncoding; Humans; Animals; Cell Differentiation; Rabbits; Mitochondria; Mesenchymal Stem Cells; Chondrogenesis; Mice; Mice, Nude; Regeneration; Neovascularization, Physiologic; Cartilage; STAT3 Transcription Factor; Angiogenesis
PubMed: 38886785
DOI: 10.1186/s13287-024-03793-2 -
Cell Death & Disease Jun 2024The regeneration of the mammalian skeleton's craniofacial bones necessitates the action of intrinsic and extrinsic inductive factors from multiple cell types, which...
The regeneration of the mammalian skeleton's craniofacial bones necessitates the action of intrinsic and extrinsic inductive factors from multiple cell types, which function hierarchically and temporally to control the differentiation of osteogenic progenitors. Single-cell transcriptomics of developing mouse calvarial suture recently identified a suture mesenchymal progenitor population with previously unappreciated tendon- or ligament-associated gene expression profile. Here, we developed a Mohawk homeobox (Mkx; R26R) reporter mouse and demonstrated that this reporter identifies an adult calvarial suture resident cell population that gives rise to calvarial osteoblasts and osteocytes during homeostatic conditions. Single-cell RNA sequencing (scRNA-Seq) data reveal that Mkx suture cells display a progenitor-like phenotype with expression of teno-ligamentous genes. Bone injury with Mkx cell ablation showed delayed bone healing. Remarkably, Mkx gene played a critical role as an osteo-inhibitory factor in calvarial suture cells, as knockdown or knockout resulted in increased osteogenic differentiation. Localized deletion of Mkx in vivo also resulted in robustly increased calvarial defect repair. We further showed that mechanical stretch dynamically regulates Mkx expression, in turn regulating calvarial cell osteogenesis. Together, we define Mkx cells within the suture mesenchyme as a progenitor population for adult craniofacial bone repair, and Mkx acts as a mechanoresponsive gene to prevent osteogenic differentiation within the stem cell niche.
Topics: Animals; Mice; Homeodomain Proteins; Osteogenesis; Skull; Cell Differentiation; Osteoblasts; Cranial Sutures; Stem Cells; Biomarkers
PubMed: 38886383
DOI: 10.1038/s41419-024-06813-4 -
Frontiers in Endocrinology 2024Osteoporosis (OP) is a chronic systemic bone metabolism disease characterized by decreased bone mass, microarchitectural deterioration, and fragility fractures. With the... (Review)
Review
Osteoporosis (OP) is a chronic systemic bone metabolism disease characterized by decreased bone mass, microarchitectural deterioration, and fragility fractures. With the demographic change caused by long lifespans and population aging, OP is a growing health problem. The role of miRNA in the pathogenesis of OP has also attracted widespread attention from scholars in recent years. Type H vessels are unique microvessels of the bone and have become a new focus in the pathogenesis of OP because they play an essential role in osteogenesis-angiogenesis coupling. Previous studies found some miRNAs regulate type H vessel formation through the regulatory factors, including platelet-derived growth factor-BB (PDGF-BB), hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), and so on. These findings help us gain a more in-depth understanding of the relationship among miRNAs, type H vessels, and OP to find a new perspective on treating OP. In the present mini-review, we will introduce the role of type H vessels in the pathogenesis of OP and the regulation of miRNAs on type H vessel formation by affecting regulatory factors to provide some valuable insights for future studies of OP treatment.
Topics: Animals; Humans; Bone and Bones; MicroRNAs; Microvessels; Neovascularization, Pathologic; Osteogenesis; Osteoporosis
PubMed: 38883597
DOI: 10.3389/fendo.2024.1394785 -
Drug Design, Development and Therapy 2024Autologous stem cell transplantation has emerged as a promising strategy for bone repair. However, the osteogenic potential of mesenchymal stem cells derived from...
Extracellular Vesicles Derived from HO-Stimulated Adipose-Derived Stem Cells Alleviate Senescence in Diabetic Bone Marrow Mesenchymal Stem Cells and Restore Their Osteogenic Capacity.
INTRODUCTION
Autologous stem cell transplantation has emerged as a promising strategy for bone repair. However, the osteogenic potential of mesenchymal stem cells derived from diabetic patients is compromised, possibly due to hyperglycemia-induced senescence. The objective of this study was to assess the preconditioning effects of extracellular vesicles derived from HO-stimulated adipose-derived stem cells (ADSCs) and non-modified ADSCs on the osteogenic potential of diabetic bone marrow mesenchymal stem cells (BMSCs).
METHODS
Sprague-Dawley (SD) rats were experimentally induced into a diabetic state through a high-fat diet followed by an injection of streptozotocin, and diabetic BMSCs were collected from the bone marrow of these rats. Extracellular vesicles (EVs) were isolated from the conditioned media of ADSCs, with or without hydrogen peroxide (HO) preconditioning, using density gradient centrifugation. The effects of HO preconditioning on the morphology, marker expression, and particle size of the EVs were analyzed. Furthermore, the impact of EV-pretreatment on the viability, survivability, migration ability, osteogenesis, cellular senescence, and oxidative stress of diabetic BMSCs was examined. Moreover, the expression of the Nrf2/HO-1 pathway was also assessed to explore the underlying mechanism. Additionally, we transplanted EV-pretreated BMSCs into calvarial defects in diabetic rats to assess their in vivo bone formation and anti-senescence capabilities.
RESULTS
Our study demonstrated that pretreatment with EVs from ADSCs significantly improved the viability, senescence, and osteogenic differentiation potential of diabetic BMSCs. Moreover, in-vitro experiments revealed that diabetic BMSCs treated with HO-activated EVs exhibited increased viability, reduced senescence, and enhanced osteogenic differentiation compared to those treated with non-modified EVs. Furthermore, when transplanted into rat bone defects, diabetic BMSCs treated with HO-activated EVs showed improved bone regeneration potential and enhanced anti-senescence function t compared to those treated with non-modified EVs. Both HO-activated EVs and non-modified EVs upregulated the expression of the Nrf2/HO-1 pathway in diabetic BMSCs, however, the promoting effect of HO-activated EVs was more pronounced than that of non-modified EVs.
CONCLUSION
Extracellular vesicles derived from HO-preconditioned ADSCs mitigated senescence in diabetic BMSCs and enhanced their bone regenerative functions via the activation of the Nrf2/HO-1 pathway.
Topics: Animals; Hydrogen Peroxide; Extracellular Vesicles; Rats, Sprague-Dawley; Mesenchymal Stem Cells; Rats; Osteogenesis; Diabetes Mellitus, Experimental; Cellular Senescence; Male; Cells, Cultured; Adipose Tissue; Oxidative Stress; Streptozocin
PubMed: 38882044
DOI: 10.2147/DDDT.S454509 -
Orthopaedic Journal of Sports Medicine Jun 2024Medial patellar facet lesions have been well-described in the setting of patellar instability. However, relatively little is known about risk factors for atraumatic...
BACKGROUND
Medial patellar facet lesions have been well-described in the setting of patellar instability. However, relatively little is known about risk factors for atraumatic medial patellar facet lesions.
PURPOSE/HYPOTHESIS
To identify clinical and radiographic risk factors for medial patellar facet lesions in patients without a history of trauma or patellar instability. It was hypothesized that a posterior tibial tubercle relative to the trochlear groove would be a risk factor for atraumatic medial patellar facet lesions.
STUDY DESIGN
Case-control study; Level of evidence, 3.
METHODS
A total of 37 patients with atraumatic medial patellar facet lesions were matched by age, sex, and body mass index with 37 control patients without a history of patellofemoral dysplasia. Demographic and imaging characteristics were compared between groups. Plain radiography was used to evaluate Wiberg type, and magnetic resonance imaging was used to calculate Caton-Deschamps index, tibial tubercle-trochlear groove distance, trochlear facet asymmetry ratio, patellotrochlear index, sulcus depth, patellar bisect ratio, and tibial tubercle height. Statistically significant variables from univariate analysis were used as inputs to the multivariate regression model to assess independent risk factors.
RESULTS
There were no differences between groups with respect to Wiberg type, Caton-Deschamps index, tibial tubercle-trochlear groove distance, sulcus depth, or patellotrochlear index ( > .05 for all). The medial facet lesion group had a larger medial trochlear facet (trochlear facet asymmetry ratio, 0.72 ± 0.11 vs 0.60 ± 0.09; < .001), a more medial-lying patella in the trochlear groove (patellar bisect ratio, 0.57 ± 0.06 vs 0.55 ± 0.07; = .035), and a more posterior tibial tubercle relative to the trochlear groove (tibial tubercle height, -3.13 ± 5.21 vs -0.23 ± 5.93 mm; = .030) compared with the control group. Multivariate regression analysis identified trochlear facet asymmetry and tibial tubercle height as independent risk factors for medial patellar facet lesions (relative risk = 97.3 [95% CI, 14.9-635.1], < .001 and relative risk = 0.95 [95% CI, 0.92-0.98], = .004, respectively).
CONCLUSION
A relatively larger medial trochlear facet and a more posterior tibial tubercle relative to the trochlear groove were found to be risk factors for medial patellar facet lesions in patients without a history of trauma or patellar instability.
PubMed: 38881850
DOI: 10.1177/23259671241255681 -
Molecular Biology and Evolution Jun 2024Although evolution is driven by changes in how regulatory pathways control development, we know little about the molecular details underlying these transitions. The...
Although evolution is driven by changes in how regulatory pathways control development, we know little about the molecular details underlying these transitions. The TRA-2 domain that mediates contact with TRA-1 is conserved in Caenorhabditis. By comparing the interaction of these proteins in two species, we identified a striking change in how sexual development is controlled. Identical mutations in this domain promote oogenesis in Caenorhabditis elegans but promote spermatogenesis in Caenorhabditis briggsae. Furthermore, the effects of these mutations involve the male-promoting gene fem-3 in C. elegans but are independent of fem-3 in C. briggsae. Finally, reciprocal mutations in these genes show that C. briggsae TRA-2 binds TRA-1 to prevent expression of spermatogenesis regulators. By contrast, in C. elegans TRA-1 sequesters TRA-2 in the germ line, allowing FEM-3 to initiate spermatogenesis. Thus, we propose that the flow of information within the sex determination pathway has switched directions during evolution. This result has important implications for how evolutionary change can occur.
Topics: Animals; Caenorhabditis elegans Proteins; Sex Determination Processes; Caenorhabditis elegans; Male; Spermatogenesis; Female; Caenorhabditis; Biological Evolution; RNA-Binding Proteins; Mutation; Oogenesis; Evolution, Molecular; Self-Fertilization; DNA-Binding Proteins; Transcription Factors
PubMed: 38880992
DOI: 10.1093/molbev/msae101