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Science (New York, N.Y.) Nov 2023Sexually dimorphic traits are common among mammals and are specified during development through the deployment of sex-specific genetic programs. Because little is known...
Sexually dimorphic traits are common among mammals and are specified during development through the deployment of sex-specific genetic programs. Because little is known about these programs, we investigated them using a resource of gene expression profiles in males and females throughout the development of five organs in five mammals (human, mouse, rat, rabbit, and opossum) and a bird (chicken). We found that sex-biased gene expression varied considerably across organs and species and was often cell-type specific. Sex differences increased abruptly around sexual maturity instead of increasing gradually during organ development. Finally, sex-biased gene expression evolved rapidly at the gene level, with differences between organs in the evolutionary mechanisms used, but more slowly at the cellular level, with the same cell types being sexually dimorphic across species.
Topics: Animals; Female; Humans; Male; Mice; Rabbits; Rats; Chickens; Evolution, Molecular; Gene Expression Regulation, Developmental; Mammals; RNA-Seq; Sex Characteristics; Transcriptome; Organogenesis
PubMed: 37917687
DOI: 10.1126/science.adf1046 -
Nature Communications Aug 2023The beneficial effects of physical activity on brain ageing are well recognised, with exerkines, factors that are secreted into the circulation in response to exercise,...
The beneficial effects of physical activity on brain ageing are well recognised, with exerkines, factors that are secreted into the circulation in response to exercise, emerging as likely mediators of this response. However, the source and identity of these exerkines remain unclear. Here we provide evidence that an anti-geronic exerkine is secreted by platelets. We show that platelets are activated by exercise and are required for the exercise-induced increase in hippocampal precursor cell proliferation in aged mice. We also demonstrate that increasing the systemic levels of the platelet-derived exerkine CXCL4/platelet factor 4 (PF4) ameliorates age-related regenerative and cognitive impairments in a hippocampal neurogenesis-dependent manner. Together these findings highlight the role of platelets in mediating the rejuvenating effects of exercise during physiological brain ageing.
Topics: Animals; Mice; Blood Platelets; Cognition; Hippocampus; Immunologic Factors; Neurogenesis; Platelet Factor 4; Aging; Cognitive Dysfunction
PubMed: 37587147
DOI: 10.1038/s41467-023-39873-9 -
Advanced Science (Weinheim,... Sep 2023In clinical practice, repairing osteochondral defects presents a challenge due to the varying biological properties of articular cartilages and subchondral bones. Thus,...
In clinical practice, repairing osteochondral defects presents a challenge due to the varying biological properties of articular cartilages and subchondral bones. Thus, elucidating how spatial microenvironment-specific biomimetic scaffolds can be used to simultaneously regenerate osteochondral tissue is an important research topic. Herein, a novel bioinspired double-network hydrogel scaffold produced via 3D printing with tissue-specific decellularized extracellular matrix (dECM) and human adipose mesenchymal stem cell (MSC)-derived exosomes is described. The bionic hydrogel scaffolds promote rat bone marrow MSC attachment, spread, migration, proliferation, and chondrogenic and osteogenic differentiation in vitro, as determined based on the sustained release of bioactive exosomes. Furthermore, the 3D-printed microenvironment-specific heterogeneous bilayer scaffolds efficiently accelerate the simultaneous regeneration of cartilage and subchondral bone tissues in a rat preclinical model. In conclusion, 3D dECM-based microenvironment-specific biomimetics encapsulated with bioactive exosomes can serve as a novel cell-free recipe for stem cell therapy when treating injured or degenerative joints. This strategy provides a promising platform for complex zonal tissue regeneration whilst holding attractive clinical translation potential.
Topics: Rats; Humans; Animals; Tissue Scaffolds; Osteogenesis; Hydrogels; Exosomes; Cartilage; Bone Regeneration; Printing, Three-Dimensional
PubMed: 37424038
DOI: 10.1002/advs.202303650 -
Cell Stem Cell Oct 2023Radial glial (RG) development is essential for cerebral cortex growth and organization. In humans, the outer radial glia (oRG) subtype is expanded and gives rise to...
Radial glial (RG) development is essential for cerebral cortex growth and organization. In humans, the outer radial glia (oRG) subtype is expanded and gives rise to diverse neurons and glia. However, the mechanisms regulating oRG differentiation are unclear. oRG cells express leukemia-inhibitory factor (LIF) receptors during neurogenesis, and consistent with a role in stem cell self-renewal, LIF perturbation impacts oRG proliferation in cortical tissue and organoids. Surprisingly, LIF treatment also increases the production of inhibitory interneurons (INs) in cortical cultures. Comparative transcriptomic analysis identifies that the enhanced IN population resembles INs produced in the caudal ganglionic eminence. To evaluate whether INs could arise from oRGs, we isolated primary oRG cells and cultured them with LIF. We observed the production of INs from oRG cells and an increase in IN abundance following LIF treatment. Our observations suggest that LIF signaling regulates the capacity of oRG cells to generate INs.
Topics: Humans; Ependymoglial Cells; Cell Differentiation; Neurogenesis; Cerebral Cortex; Interneurons
PubMed: 37673072
DOI: 10.1016/j.stem.2023.08.009 -
Proceedings of the National Academy of... Nov 2023Spinal cord injury (SCI) can lead to iron overloading and subsequent neuronal ferroptosis, which hinders the recovery of locomotor function. However, it is still unclear...
Spinal cord injury (SCI) can lead to iron overloading and subsequent neuronal ferroptosis, which hinders the recovery of locomotor function. However, it is still unclear whether the maintenance of neuronal iron homeostasis enables to revitalize intrinsic neurogenesis. Herein, we report the regulation of cellular iron homeostasis after SCI via the chelation of excess iron ions and modulation of the iron transportation pathway using polyphenol-based hydrogels for the revitalization of intrinsic neurogenesis. The reversed iron overloading can promote neural stem/progenitor cell differentiation into neurons and elicit the regenerative potential of newborn neurons, which is accompanied by improved axon reinnervation and remyelination. Notably, polyphenol-based hydrogels significantly increase the neurological motor scores from ~8 to 18 (out of 21) and restore the transmission of sensory and motor electrophysiological signals after SCI. Maintenance of iron homeostasis at the site of SCI using polyphenol-based hydrogels provides a promising paradigm to revitalize neurogenesis for the treatment of iron accumulation-related nervous system diseases.
Topics: Humans; Infant, Newborn; Neurons; Neurogenesis; Spinal Cord Injuries; Hydrogels; Iron; Iron Overload; Polyphenols; Homeostasis; Spinal Cord
PubMed: 37948584
DOI: 10.1073/pnas.2220300120 -
Nature Genetics Jul 2023Spatiotemporal orchestration of gene expression is required for proper embryonic development. The use of single-cell technologies has begun to provide improved...
Spatiotemporal orchestration of gene expression is required for proper embryonic development. The use of single-cell technologies has begun to provide improved resolution of early regulatory dynamics, including detailed molecular definitions of most cell states during mouse embryogenesis. Here we used Slide-seq to build spatial transcriptomic maps of complete embryonic day (E) 8.5 and E9.0, and partial E9.5 embryos. To support their utility, we developed sc3D, a tool for reconstructing and exploring three-dimensional 'virtual embryos', which enables the quantitative investigation of regionalized gene expression patterns. Our measurements along the main embryonic axes of the developing neural tube revealed several previously unannotated genes with distinct spatial patterns. We also characterized the conflicting transcriptional identity of 'ectopic' neural tubes that emerge in Tbx6 mutant embryos. Taken together, we present an experimental and computational framework for the spatiotemporal investigation of whole embryonic structures and mutant phenotypes.
Topics: Mice; Animals; Transcriptome; Organogenesis; Embryonic Development; Embryo, Mammalian; Phenotype; Gene Expression Regulation, Developmental; T-Box Domain Proteins
PubMed: 37414952
DOI: 10.1038/s41588-023-01435-6 -
Nature Communications Jul 2023Mammalian embryos exhibit sophisticated cellular patterning that is intricately orchestrated at both molecular and cellular level. It has recently become apparent that...
Mammalian embryos exhibit sophisticated cellular patterning that is intricately orchestrated at both molecular and cellular level. It has recently become apparent that cells within the animal body display significant heterogeneity, both in terms of their cellular properties and spatial distributions. However, current spatial transcriptomic profiling either lacks three-dimensional representation or is limited in its ability to capture the complexity of embryonic tissues and organs. Here, we present a spatial transcriptomic atlas of all major organs at embryonic day 13.5 in the mouse embryo, and provide a three-dimensional rendering of molecular regulation for embryonic patterning with stacked sections. By integrating the spatial atlas with corresponding single-cell transcriptomic data, we offer a detailed molecular annotation of the dynamic nature of organ development, spatial cellular interactions, embryonic axes, and divergence of cell fates that underlie mammalian development, which would pave the way for precise organ engineering and stem cell-based regenerative medicine.
Topics: Animals; Mice; Organogenesis; Transcriptome; Gene Expression Profiling; Embryo, Mammalian; Stem Cells; Mammals
PubMed: 37524711
DOI: 10.1038/s41467-023-40155-7 -
International Journal of Molecular... Dec 2023The TAM (TYRO3, MERTK, and AXL) family of receptor tyrosine kinases are pleiotropic regulators of adult tissue homeostasis maintaining organ integrity and self-renewal.... (Review)
Review
The TAM (TYRO3, MERTK, and AXL) family of receptor tyrosine kinases are pleiotropic regulators of adult tissue homeostasis maintaining organ integrity and self-renewal. Disruption of their homeostatic balance fosters pathological conditions like autoinflammatory or degenerative diseases including rheumatoid arthritis, lupus erythematodes, or liver fibrosis. Moreover, TAM receptors exhibit prominent cell-transforming properties, promoting tumor progression, metastasis, and therapy resistance in various cancer entities. Emerging evidence shows that TAM receptors are involved in bone homeostasis by regulating osteoblastic bone formation and osteoclastic bone resorption. Therefore, TAM receptors emerge as new key players of the regulatory cytokine network of osteoblasts and osteoclasts and represent accessible targets for pharmacologic therapy for a broad set of different bone diseases, including primary and metastatic bone tumors, rheumatoid arthritis, or osteoporosis.
Topics: Adult; Humans; Osteoblasts; Osteoclasts; Bone Diseases; Osteogenesis; Arthritis, Rheumatoid; Bone Resorption
PubMed: 38203403
DOI: 10.3390/ijms25010233 -
European Journal of Medical Research Oct 2023Increased lymphangiogenesis and lymph node (LN) metastasis are thought to be important steps in cancer metastasis, and are associated with patient's poor prognosis.... (Review)
Review
Increased lymphangiogenesis and lymph node (LN) metastasis are thought to be important steps in cancer metastasis, and are associated with patient's poor prognosis. There is increasing evidence that the lymphatic system may play a crucial role in regulating tumor immune response and limiting tumor metastasis, since tumor lymphangiogenesis is more prominent in tumor metastasis and diffusion. Lymphangiogenesis takes place in embryonic development, wound healing, and a variety of pathological conditions, including tumors. Tumor cells and tumor microenvironment cells generate growth factors (such as lymphangiogenesis factor VEGF-C/D), which can promote lymphangiogenesis, thereby inducing the metastasis and diffusion of tumor cells. Nevertheless, the current research on lymphangiogenesis in gastric cancer is relatively scattered and lacks a comprehensive understanding. Therefore, in this review, we aim to provide a detailed perspective on molecules and signal transduction pathways that regulate gastric cancer lymphogenesis, which may provide new insights for the diagnosis and treatment of cancer.
Topics: Humans; Lymphangiogenesis; Stomach Neoplasms; Lymphatic Metastasis; Signal Transduction; Tumor Microenvironment
PubMed: 37803421
DOI: 10.1186/s40001-023-01298-x -
The Journal of International Medical... Aug 2023Sclerostin, a protein encoded by the sclerostin () gene, is mostly expressed in osteocytes. First described in the pathogenesis of three disorders, sclerosteosis, van... (Review)
Review
Sclerostin, a protein encoded by the sclerostin () gene, is mostly expressed in osteocytes. First described in the pathogenesis of three disorders, sclerosteosis, van Buchem's disease, and craniodiaphyseal dysplasia, sclerostin has been identified as an important regulator of bone homeostasis, controlling bone formation by osteoblasts through inhibition of the canonical Wnt signaling pathway. Recent studies have highlighted a hypothetical role of sclerostin in myogenesis, thus modulating the interaction between bone and muscle. This narrative review provides an overview of the clinical implications of sclerostin modulation on skeletal muscle mass and function, and bone metabolism. Improving knowledge about muscle-bone crosstalk may represent a turning point in the development of therapeutic strategies for musculoskeletal disorders, particularly osteosarcopenia.
Topics: Humans; Hyperostosis; Knowledge; Muscles; Osteoblasts; Osteogenesis
PubMed: 37632438
DOI: 10.1177/03000605231193293