CXCL12
Stromal cell-derived factor 1 precursor (SDF-1) (hSDF-1) (C-X-C motif chemokine 12) (Intercrine reduced in hepatomas) (IRH) (hIRH) (Pre-B cell growth-stimulating factor) (PBSF) [Contains: SDF-1-beta(3-72); SDF-1-alpha(3-67)] [SDF1] [SDF1A] [SDF1B]
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Aging of the uterine endometrium is a critical factor that affects reproductive success, but the mechanisms associated with uterine aging are unclear. In this study, we conducted a qualitative examination of age-related changes in endometrial tissues and identified candidate genes as markers for uterine aging. Gene expression patterns were assessed by two RNA sequencing experiments using uterine tissues from wild type (WT) C57BL/6 mice. Gene expression data obtained by RNA-sequencing were validated by real-time PCR. Genes expressing the pro-inflammatory cytokines Il17rb and chemokines Cxcl12 and Cxcl14 showed differential expression between aged WT mice and a group of mice composed of 5 and 8 week-old WT (young) animals. Protein expression levels of the above-mentioned genes and of IL8, which functions downstream of IL17RB, were analysed by quantitative immunohistochemistry of unaffected human endometrium tissue samples from patients in their 20 s and 40 s (10 cases each). In the secretory phase samples, 3,3'- diaminobenzidine (DAB) staining intensities of IL17RB, CXCL12 and CXCL14 for patients in their 40 s were significantly higher than that for patients in their 20 s, as detected by a Mann Whitney U test. These results suggest that these genes are candidate markers for endometrial aging and for prediction of age-related infertility, although confirmation of these findings is needed in larger studies involving fertile and infertile women.
Keywords
- CXCL12
- CXCL14
- IL17RB
- endometrial cell aging
- infertility
- quantitative
immunohistochemistry
Classically considered short-lived and purely defensive leukocytes, neutrophils are unique in their fast and moldable response to stimulation. This plastic behavior may underlie variable and even antagonistic functions during inflammation or cancer, yet the full spectrum of neutrophil properties as they enter healthy tissues remains unexplored. Using a new model to track neutrophil fates, we found short but variable lifetimes across multiple tissues. Through analysis of the receptor, transcriptional, and chromatin accessibility landscapes, we identify varying neutrophil states and assign non-canonical functions, including vascular repair and hematopoietic homeostasis. Accordingly, depletion of neutrophils compromised angiogenesis during early age, genotoxic injury, and viral infection, and impaired hematopoietic recovery after irradiation. Neutrophils acquired these properties in target tissues, a process that, in the lungs, occurred in CXCL12-rich areas and relied on CXCR4. Our results reveal that tissues co-opt neutrophils en route for elimination to induce programs that support their physiological demands.
Keywords
- angiogenesis
- immune heterogeneity
- immune niche
- innate immunity
- neutrophil lifespan
- neutrophils
- single-cell analysis
- tissue-resident cells
Alzheimer's disease (AD) is one of the most common forms of dementia with still unknown pathogenesis. Several cytokines and chemokines are involved in the pathogenesis of AD. Among the chemokines, the CXCR4/CXCL12 complex has been shown to play an important role in the pathogenetic development of AD. We investigated the expression levels of CXCR4 / CXCL12 in fifteen brain regions of healthy non-demented subjects (NDHC) (2139 sample) and AD patients (1170 sample) stratified according to sex and age. Furthermore, we correlated their expressions with the Neurogranin (NRGN) and CHI3L1 levels, two inflamm-aging markers. We highlighted that CXCR4 gene expression levels were age-correlated in the brain of NDHC subjects and that AD nullified this correlation. A similar trend, but diametrically opposite was observed for CXCL12. Its expression was decreased during the aging in both sexes, and in the brains of AD patients, it underwent an inversion of the trend, only and exclusively in females. Brains of AD patients expressed high CXCR4 and CHI3L1, and low CXCL12 and Neurogranin levels compared to NDHC subjects. Both CXCR4 and CXCL12 correlated significantly with CHI3L1 and Neurogranin expression levels, regardless of disease. Furthermore, we showed a selective modulation of CXCL12 and CXCR4 only in specific brain regions. Taken together our results demonstrate that CXCL12 and CXCR4 are linked to Neurogranin and CHI3L1 expression levels and the relationship between postsynaptic damage and microglial activation in AD could be shown using all these genes. Further confirmations are needed to demonstrate the close link between these genes.
Keywords
- Aging
- Alzheimer’s disease
- Bioinformatics
- CHI3L1
- Chitinase
- NRGN
Periodontal ligament stem cells (PDLSCs) have many applications in the field of cytotherapy, tissue engineering, and regenerative medicine. However, the effect of age on the biological and immunological characteristics of PDLSCs remains unclear. In this study, we compared PDLSCs isolated from young and adult individuals. PDLSC proliferation was analyzed by Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) staining, and apoptosis level was detected by Annexin V-PE/7-ADD staining. PDLSC osteogenic/adipogenic/chondrogenic differentiation potentials were assessed by alkaline phosphatase (ALP), Alizarin Red, Oil Red O, Alcian Blue staining, and related quantitative analysis. PDLSC immunosuppressive capacity was determined by EdU and Annexin V-PE/7-ADD staining. To explore its underlying mechanism, microarray, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), and western blot analyses were performed to detect differentially expressed genes and proteins in PDLSCs. Our results demonstrated that with aging, the proliferation and osteogenic/adipogenic/chondrogenic differentiation potential of PDLSCs decreased, whereas apoptosis of PDLSCs increased. Moreover, the immunosuppressive ability of PDLSCs decreased with aging. Compared with PDLSCs from young subjects, analysis of mRNA expression revealed an upregulation of CCND3 and RC3H2, and a downregulation of Runx2, ALP, COL1A1, PPARγ2, CXCL12, FKBP1A, FKBP1B, NCSTN, P2RX7, PPP3CB, RIPK2, SLC11A1, and TP53 in those from adult individuals. Furthermore, protein expression levels of Runx2, ALP, COL1A1, and PPARγ2 in the adult group were decreased, whereas that of CCND3 increased. Taken together, aging influences the biological and immunological characteristics of PDLSCs, and thus, it is more appropriate to utilize PDLSCs from young individuals for tissue regeneration, post-aging treatment, and allotransplantation.
Keywords
- Aging
- Immunosuppression
- Osteogenic differentiation
- Periodontal ligament stem cells
- Peripheral blood mononuclear cells
- Tissue engineering
While intrinsic changes in aging hematopoietic stem cells (HSCs) are well characterized, it remains unclear how extrinsic factors affect HSC aging. Here, we demonstrate that cells in the niche-endothelial cells (ECs) and CXCL12-abundant reticular cells (CARs)-highly express the heme-degrading enzyme, heme oxygenase 1 (HO-1), but then decrease its expression with age. HO-1-deficient animals (HO-1 ) have altered numbers of ECs and CARs that produce less hematopoietic factors. HSCs co-cultured in vitro with HO-1 mesenchymal stromal cells expand, but have altered kinetic of growth and differentiation of derived colonies. HSCs from young HO-1 animals have reduced quiescence and regenerative potential. Young HO-1 HSCs exhibit features of premature exhaustion on the transcriptional and functional level. HO-1 HSCs transplanted into HO-1 recipients exhaust their regenerative potential early and do not reconstitute secondary recipients. In turn, transplantation of HO-1 HSCs to the HO-1 recipients recovers the regenerative potential of HO-1 HSCs and reverses their transcriptional alterations. Thus, HSC-extrinsic activity of HO-1 prevents HSCs from premature exhaustion and may restore the function of aged HSCs.
Keywords
- aging
- bone marrow
- cxcl12-abudant reticular cells
- endothelial cells
- niche
Bone marrow (BM) stromal cells provide the regulatory framework for hematopoiesis and contribute to developmental stage-specific niches, such as those preserving hematopoietic stem cells. Despite advances in our understanding of stromal function, little is known about the transcriptional changes that this compartment undergoes throughout lifespan and during adaptation to stress. Using RNA sequencing, we perform transcriptional analyses of four principal stromal subsets, namely CXCL12-abundant reticular, platelet-derived growth factor receptor (PDGFR)-α Sca1 , sinusoidal, and arterial endothelial cells, from early postnatal, adult, and aged mice. Our data reveal (1) molecular fingerprints defining cell-specific anatomical and functional features, (2) a radical reprogramming of pro-hematopoietic, immune, and matrisomic transcriptional programs during the transition from juvenile stages to adulthood, and (3) the aging-driven progressive upregulation of pro-inflammatory gene expression in stroma. We further demonstrate that transcriptomic pathways elicited in vivo by prototypic microbial molecules are largely recapitulated during aging, thereby supporting the inflammatory basis of age-related adaptations of BM hematopoietic function.
MeSH Terms
- Aging
- Animals
- Bone Marrow
- Bone Marrow Cells
- Cell Differentiation
- Cells, Cultured
- Cellular Microenvironment
- Chemokine CXCL12
- Embryonic Development
- Endothelial Cells
- Gene Expression Profiling
- Hematopoiesis
- Hematopoietic Stem Cells
- Inflammation
- Male
- Mesenchymal Stem Cells
- Mice
- Mice, Inbred C57BL
- Stem Cell Niche
- Transcriptome
Keywords
- aging
- bone marrow microenvironment
- hematopoietic stem cells
- inflammation
- niches
- stromal cells
- transcriptomics
Following the failure of acute neuroprotection therapies, major efforts are currently made worldwide to promote neurological recovery and brain plasticity in the subacute and post-acute phases of stroke. Currently, there is hope that stroke recovery might be promoted by cell-based therapies. The field of stem cell therapy for cerebral ischemia has made significant progress in the last five years. A variety of stem cells have been tested in animal models and humans including adipose stem cells, human umbilical cord blood-derived mesenchymal stem cells, human amnion epithelial cells, human placenta amniotic membrane-derived mesenchymal stem cells, adult human pluripotent-like olfactory stem cells, human bone marrow endothelial progenitor cells, electrically-stimulated human neuronal progenitor cells, or induced pluripotent stem cells (iPSCs) of human origin. Combination therapies in animal models include a mix of two or more therapeutic factors consisting of bone marrow stromal cells, exercise and thyroid hormones, endothelial progenitor cells overexpressing the chemokine CXCL12. Mechanisms underlying the beneficial effects of transplanted cells include the "bystander" effects, paracrine mechanisms, or extracellular vesicles-mediated restorative effects. Mitochondria transfer also appears to be a powerful strategy for regenerative processes. Studies in humans are currently limited to a small number of studies using autologous stem cells mainly aimed to assess tolerability and side-effects of human stem cells in the clinic.
MeSH Terms
- Animals
- Brain Ischemia
- Cell Separation
- Disease Models, Animal
- Exercise Therapy
- Humans
- Stem Cell Transplantation
- Stem Cells
- Stroke
- Thyroid Hormones
Keywords
- aging
- cerebral ischemia
- human stem cells
- restorative therapies
- rodent stem cells
Reduced quantity and quality of stem cells in aged individuals hinders cardiac repair and regeneration after injury. We used young bone marrow (BM) stem cell antigen 1 (Sca-1) cells to reconstitute aged BM and rejuvenate the aged heart, and examined the underlying molecular mechanisms. BM Sca-1 or Sca-1 cells from young (2-3 months) or aged (18-19 months) GFP transgenic mice were transplanted into lethally irradiated aged mice to generate 4 groups of chimeras: young Sca-1 , young Sca-1 , old Sca-1 , and old Sca-1 . Four months later, expression of rejuvenation-related genes (Bmi1, Cbx8, PNUTS, Sirt1, Sirt2, Sirt6) and proteins (CDK2, CDK4) was increased along with telomerase activity and telomerase-related protein (DNA-PKcs, TRF-2) expression, whereas expression of senescence-related genes (p16 , P19 , p27 ) and proteins (p16 , p27 ) was decreased in Sca-1 chimeric hearts, especially in the young group. Host cardiac endothelial cells (GFP CD31 ) but not cardiomyocytes were the primary cell type rejuvenated by young Sca-1 cells as shown by improved proliferation, migration, and tubular formation abilities. C-X-C chemokine CXCL12 was the factor most highly expressed in homed donor BM (GFP ) cells isolated from young Sca-1 chimeric hearts. Protein expression of Cxcr4, phospho-Akt, and phospho-FoxO3a in endothelial cells derived from the aged chimeric heart was increased, especially in the young Sca-1 group. Reconstitution of aged BM with young Sca-1 cells resulted in effective homing of functional stem cells in the aged heart. These young, regenerative stem cells promoted aged heart rejuvenation through activation of the Cxcl12/Cxcr4 pathway of cardiac endothelial cells.
MeSH Terms
- Animals
- Antigens, Ly
- Bone Marrow Cells
- Cellular Senescence
- Female
- Heart
- Membrane Proteins
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Rejuvenation
Keywords
- Sca-1
- aging
- heart
- reconstitution
- rejuvenation
- stem cells
Alzheimer's disease (AD) is one of the most common and devastating aging related neurodegenerative diseases. Aging is a natural physiological process, a progressive deterioration of the overall homeostatic brain mechanisms, accompanied by cognitive decline. CXCL12/CXCR4 chemokine signaling plays a critical role in modulating various nervous system developmental processes and in regulating synaptic plasticity. In this article, we have firstly shown that CXCR4 is critical for cell proliferation and cytotoxicity in the SH-SY5Y cell model. Moreover, it has been firstly demonstrated that CXCR4 colocalized with AKT on the membrane and regulated the AKT activation to prevent aging and AD. In a word, we supply a novel pathway that CXCR4 pathway stimulated by CXCL12 regulated AKT activation, CREB phosphorylation and P53 level to affect the process of aging and AD. Therefore, CXCR4 may be a novel target and biomarker for the diagnosis and treatment of AD and aging.
MeSH Terms
- Aging
- Alzheimer Disease
- Biomarkers
- Cell Line
- Cell Proliferation
- Chemokine CXCL12
- Cyclic AMP Response Element-Binding Protein
- Humans
- Phosphorylation
- Protein Transport
- Proto-Oncogene Proteins c-akt
- RNA Interference
- RNA, Small Interfering
- Receptors, CXCR4
- Signal Transduction
- Tumor Suppressor Protein p53
Keywords
- AKT
- Alzheimer’s disease (AD)
- CXCR4
- SH-SY5Y
- aging
Sinusoidal endothelial cells and mesenchymal CXCL12-abundant reticular cells are principal bone marrow stromal components, which critically modulate haematopoiesis at various levels, including haematopoietic stem cell maintenance. These stromal subsets are thought to be scarce and function via highly specific interactions in anatomically confined niches. Yet, knowledge on their abundance, global distribution and spatial associations remains limited. Using three-dimensional quantitative microscopy we show that sinusoidal endothelial and mesenchymal reticular subsets are remarkably more abundant than estimated by conventional flow cytometry. Moreover, both cell types assemble in topologically complex networks, associate to extracellular matrix and pervade marrow tissues. Through spatial statistical methods we challenge previous models and demonstrate that even in the absence of major specific interaction forces, virtually all tissue-resident cells are invariably in physical contact with, or close proximity to, mesenchymal reticular and sinusoidal endothelial cells. We further show that basic structural features of these stromal components are preserved during ageing.
MeSH Terms
- Aging
- Animals
- Bone Marrow
- Bone Marrow Cells
- Cell Count
- Cell Movement
- Cellular Microenvironment
- Endothelial Cells
- Extracellular Matrix
- Femur
- Hematopoiesis
- Hematopoietic Stem Cells
- Imaging, Three-Dimensional
- Mesenchymal Stem Cells
- Mice
- Mice, Inbred C57BL
- Microscopy
- Stem Cell Niche
The tumor microenvironment plays pivotal roles in various human neoplasms. However, that of benign tumor, particularly hormone-secreting endocrine tumors, has remained virtually unknown. Therefore, we firstly attempted to analyze the tumor microenvironment of autonomous hormone-secreting adrenocortical adenomas. We first histologically evaluated 21 cortisol-producing adrenocortical adenoma (CPA) and 13 aldosterone-producing adrenocortical adenoma (APA) cases. Quantitative histologic analysis revealed that intratumoral immune cell infiltration (ICI) was more pronounced in CPAs than in APAs. We then evaluated the cytokine and chemokine profiles using polymerase chain reaction arrays in APAs and CPAs. Angiogenic chemokines, C-X-C motif chemokine ligand (CXCL) 1 and CXCL2, were significantly more abundant in CPAs than in APAs using subsequent quantitative polymerase chain reaction and immunohistochemical analyses. We then examined the vascular density between these 2 adenomas, and the density was significantly higher in overt CPAs than in APAs. Of particular interest, CXCL12-positive vessels were detected predominantly in CPAs, and their infiltrating immune cells were C-X-C motif chemokine receptor 4 (CXCR4) positive. These results above indicated that CXCL12-CXCR4 signaling could partly account for ICI detected predominantly in CPAs. We then further explored the etiology of ICI in CPAs by evaluating the senescence of tumor cells possibly caused by excessive cortisol in CPAs. The status of senescence markers, p16 and p21, was significantly more abundant in CPAs than in APAs. In addition, all CPA cases examined were positive for senescence-associated β-galactosidase. These results all indicated that exposure to local excessive cortisol could result in senescence of tumors cells and play essential roles in constituting the characteristic tissue microenvironment of CPAs.
MeSH Terms
- Adenoma
- Adrenal Cortex Neoplasms
- Adrenocortical Adenoma
- Adult
- Aldosterone
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Male
- Middle Aged
- RNA, Messenger
- Tumor Microenvironment
Keywords
- Adrenocortical adenoma
- Cellular senescence
- Immune cell infiltration
- Steroids
- Tumor microenvironment
Current studies have revealed that aging is a negative factor that suppresses granulosa cell functions and causes low fertility in women. However, the difference in gene expression between normal and aging granulosa cells remains undefined. Therefore, the aim of this study was to investigate the gene expression profiles of granulosa cells during aging. Granulosa cells from young healthy porcine ovaries were aged [i]in vitro[/i] by prolonging the culture time (for 48h). First, the extracellular ultrastructure was observed by scanning electron microscopy followed by RNA-seq and KEGG pathway analysis. The results showed that the extracellular ultrastructure was significantly altered by aging; cell membranes were rough, and cavitations were found. Moreover, the formations of filopodia were greatly reduced. RNA-seq data revealed that 3411 genes were differentially expressed during aging, of which 2193 genes were up-regulated and 1218 genes were down-regulated. KEGG pathway analysis revealed that 25 pathways including pathway in cancer, PI3K-Akt signaling pathway, focal adhesion, proteoglycans in cancer, and cAMP signaling pathway were the most changed. Moreover, several high differentially expressed genes (CEBPB, CXCL12, ANGPT2, IGFBP3, and BBOX1) were identified in aging granulosa cells, The expressions of these genes and genes associated with extracellular matrix remodeling associated genes (TIMP3, MMP2, MMP3, and CTGF), energy metabolism associated genes (SLC2A1, PPARγ) and steroidogenesis associated genes (StAR, CYP11A1 and LHCGR) were confirmed by quantitative PCR. This study identifies the differently changed pathways and their related genes, contributes to the understanding of aging in granulosa cells, and provides an important foundation for further studies.
Keywords
- Gerotarget
- RNA-seq
- aging
- gene expression
- granulosa cell
- porcine
To understand strain-specificities of immune system in aged rats and their immunopathological implications, CD4 T lymphocyte-mediated neuroinflammation in experimental autoimmune encephalomyelitis (EAE) was studied in two strains. Upon immunization for EAE, 22-24-month-old Albino Oxford (AO) rats developed milder neurological deficit of prolonged duration compared with their Dark Agouti (DA) counterparts. Consistently, they exhibited: (i) diminished neuroantigen-specific CD4 T lymphocyte generation in draining lymph nodes (reflecting lower density of high-affinity IL-2 receptor complex on their surface and higher CD4 FoxP3 CD25 regulatory cell frequency); (ii) less favorable spinal cord expression of CXCL12 and CCL2, and consequently diminished infiltration of neuroantigen-specific CD4 T lymphocytes, including highly pathogenic IL-17 IFN-γ ones, and inflammatory monocytes into the spinal cord and (iii) subsequently impaired CD4 T lymphocyte reactivation/survival and differentiation into highly pathogenic IL-17 cells (reflecting downregulated expression of IL-1β, IL-6 and IL-23/p19). On the other hand, when the neurological deficit reached maximum/plateau, in AO rat spinal cord was found lower CD4 FoxP3 CD25 cell frequency followed by higher frequency of IL-10-producing CD8 T cells, which most likely also belong to regulatory T lymphocytes. Thus, the altered relation between regulatory T cell and effector CD4 T cell subsets was linked with persistence of mild neuroinflammation in AO rat EAE model.
MeSH Terms
- Aging
- Animals
- CD8-Positive T-Lymphocytes
- Cytokines
- Encephalomyelitis, Autoimmune, Experimental
- Female
- Rats
- Receptors, Interleukin-2
- Species Specificity
- Spinal Cord
- T-Lymphocytes, Regulatory
Keywords
- Aged rats
- EAE
- IL-10-producing T cells
- IL-17 IFN-γ T lymphocytes
- Rat strain differences
Recent evidence suggests that high dose and/or long term use of proton pump inhibitors (PPIs) may increase the risk of adverse cardiovascular events in older patients, but mechanisms underlying these detrimental effects are not known. Taking into account that the senescent endothelial cells have been implicated in the genesis or promotion of age-related cardiovascular disease, we hypothesized an active role of PPIs in senescent cells. The aim of this study is to investigate the changes in gene expression occurring in senescent and non-senescent human coronary artery endothelial cells (HCAECs) following Omeprazole (OPZ) or Lansoprazole (LPZ) treatment. Here, we show that atherogenic response is among the most regulated processes in PPI-treated HCAECs. PPIs induced down-regulation of anti-atherogenic chemokines (CXCL11, CXCL12 and CX3CL1) in senescent but not in non-senescent cells, while the same chemokines were up-regulated in untreated senescent cells. These findings support the hypothesis that up-regulated anti-atherogenic chemokines may represent a defensive mechanism against atherosclerosis during cellular senescence, and suggest that PPIs could activate pro-atherogenic pathways by changing the secretory phenotype of senescent HCAECs. Moreover, the genes coding for fatty acid binding protein 4 (FABP4) and piezo-type mechanosensitive ion channel component 2 (PIEZO2) were modulated by PPIs treatment with respect to untreated cells. In conclusions, our results show that long-term and high dose use of PPI could change the secretory phenotype of senescent cells, suggesting one of the potential mechanisms by which use of PPI can increase adverse outcomes in older subjects.
MeSH Terms
- Cells, Cultured
- Cellular Senescence
- Coronary Vessels
- Cytokines
- Dose-Response Relationship, Drug
- Endothelial Cells
- Gene Expression Regulation, Developmental
- Humans
- Lansoprazole
- Omeprazole
- Proton Pump Inhibitors
- Transcriptional Activation
- Transcriptome
Keywords
- Gene expression
- HCAECs
- Proton pump inhibitors
- SASP
- Senescence
Old age and sex steroid deficiency are the two most critical factors for the development of osteoporosis. It remains unknown, however, whether the molecular culprits of the two conditions are similar or distinct. We show herein that at 19.5 months of age-a time by which the age-dependent decline of cortical and cancellous bone mass and cortical porosity were fully manifested in C57BL/6J mice-these animals remained functionally estrogen sufficient. Transgenic mice with conditional expression of mitochondria-targeted catalase-a potent H O inactivating enzyme-in cells of the myeloid lineage (mitoCAT;LysM-Cre mice) were protected from the loss of cortical, but not cancellous, bone caused by gonadectomy in either sex. Consistent with these findings, in vitro studies with ERα-deficient Prx1 cells and gonadectomized young adult mice showed that in both sexes decreased ERα signaling in Prx1 cells leads to an increase in SDF1, a.k.a. CXCL12, an osteoclastogenic cytokine whose effects were abrogated in macrophages from mitoCAT;LysM-Cre mice. In contrast to sex steroid deficiency, the adverse effects of aging on either cortical or cancellous bone were unaffected in mitoCAT;LysM-Cre mice. On the other hand, attenuation of H O generation in cells of the mesenchymal lineage targeted by Prx1-Cre partially prevented the loss of cortical bone caused by old age. Our results suggest the effects of sex steroid deficiency and aging on the murine skeleton are independent and result from distinct mechanisms. In the former, the prevailing mechanism of the cortical bone loss in both sexes is increased osteoclastogenesis caused by estrogen deficiency; this is likely driven, at least in part, by mesenchymal/stromal cell-derived SDF1. Decreased osteoblastogenesis, owing in part to increased H O combined with increased osteoclastogenesis caused by aging mechanisms independent of estrogen deficiency, are the prevailing mechanisms of the loss of cortical bone with old age. © 2016 American Society for Bone and Mineral Research.
MeSH Terms
- Aging
- Animals
- Biomechanical Phenomena
- Bone Resorption
- Bone and Bones
- Calcification, Physiologic
- Cancellous Bone
- Cell Count
- Cell Lineage
- Chemokine CXCL12
- Cortical Bone
- Estrogen Receptor alpha
- Estrogens
- Female
- Gonadal Steroid Hormones
- Hydrogen Peroxide
- Male
- Mesenchymal Stem Cells
- Mice, Inbred C57BL
- Myeloid Cells
- Osteoclasts
- Ovariectomy
- Porosity
Keywords
- AGING
- MOLECULAR PATHWAYS-REMODELING
- OSTEOBLASTS
- OSTEOCLASTS
- SEX STEROIDS
Autophagy is triggered in vascular smooth muscle cells (VSMCs) of diseased arterial vessels. However, the role of VSMC autophagy in cardiovascular disease is poorly understood. Therefore, we investigated the effect of defective autophagy on VSMC survival and phenotype and its significance in the development of postinjury neointima formation and atherosclerosis. Tissue-specific deletion of the essential autophagy gene Atg7 in murine VSMCs (atg7 VSMCs) caused accumulation of SQSTM1/p62 and accelerated the development of stress-induced premature senescence as shown by cellular and nuclear hypertrophy, [[CDKN2A]]-RB-mediated G proliferative arrest and senescence-associated GLB1 activity. Transfection of SQSTM1-encoding plasmid DNA in Atg7 VSMCs induced similar features, suggesting that accumulation of SQSTM1 promotes VSMC senescence. Interestingly, atg7 VSMCs were resistant to oxidative stress-induced cell death as compared to controls. This effect was attributed to nuclear translocation of the transcription factor NFE2L2 resulting in upregulation of several antioxidative enzymes. In vivo, defective VSMC autophagy led to upregulation of MMP9, TGFB and CXCL12 and promoted postinjury neointima formation and diet-induced atherogenesis. Lesions of VSMC-specific atg7 knockout mice were characterized by increased total collagen deposition, nuclear hypertrophy, [[CDKN2A]] upregulation, RB hypophosphorylation, and GLB1 activity, all features typical of cellular senescence. To conclude, autophagy is crucial for VSMC function, phenotype, and survival. Defective autophagy in VSMCs accelerates senescence and promotes ligation-induced neointima formation and diet-induced atherogenesis, implying that autophagy inhibition as therapeutic strategy in the treatment of neointimal stenosis and atherosclerosis would be unfavorable. Conversely, stimulation of autophagy could be a valuable new strategy in the treatment of arterial disease.
Keywords
- atherosclerosis
- autophagy
- neointima formation
- senescence
- sequestosome 1/p62
- vascular smooth muscle cells
The expression of signaling molecules MMP2, MMP9, ERBB3, CXCL12, Nkx2.5, CD90 (the markers of remodeling intracellular matrix and cell differentiation) in human buccal epithelium in ageing has been studied. The expression of molecular markers MMP2, MMP9, CD90 end ERBB3 has shown a decrease during ageing, especially in old people compared with persons of mature age. These data have demonstrated, that buccal epithelium may be considered as a perspective object to study the aging processes in organism as a whole (on the decrease of cell for differentiation and remodeling intracellular matrix).
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Cell Differentiation
- Epithelium
- Female
- Humans
- Male
- Matrix Metalloproteinases
- Middle Aged
- Mouth Mucosa
IL-15 is a cytokine critical for development, maintenance, and response of T cells, natural killer (NK) cells, NK T cells, and dendritic cells. However, the identity and distribution of IL-15-expressing cells in lymphoid organs are not well understood. To address these questions, we established and analyzed IL-15-CFP knock-in mice. We found that IL-15 was highly expressed in thymic medulla, and medullary thymic epithelial cells with high MHC class II expression were the major source of IL-15. In bone marrow, IL-15 was detected primarily in VCAM-1( )PDGFRβ( )CD31(-)Sca-1(-) stromal cells, which corresponded to previously described CXCL12-abundant reticular cells. In lymph nodes, IL-15-expressing cells were mainly distributed in the T-cell zone and medulla. IL-15 was expressed in some fibroblastic reticular cells and gp38(-)CD31(-) double-negative stromal cells in the T-cell zone. Blood endothelial cells, including all high endothelial venules, also expressed high IL-15 levels in lymph nodes, whereas lymphatic endothelial cells (LECs) lacked IL-15 expression. In spleen, IL-15 was expressed in VCAM-1( ) stromal cells, where its expression increased as mice aged. Finally, IL-15 expression in blood and LECs of peripheral lymphoid organs significantly increased in LPS-induced inflammation. Overall, we have identified and characterized several IL-15-expressing cells in primary and secondary lymphoid organs, providing a unique perspective of IL-15 niche in immune microenvironment. This study also suggests that some stromal cells express IL-7 and IL-15 differentially and suggests a way to functionally classify different stromal cell subsets.
MeSH Terms
- Aging
- Animals
- Bone Marrow Cells
- Endothelial Cells
- Gene Knock-In Techniques
- Inflammation
- Interleukin-15
- Lipopolysaccharides
- Lymph Nodes
- Lymphoid Tissue
- Mesoderm
- Mice
- Mucous Membrane
- Spleen
- Stromal Cells
- T-Lymphocytes
- Thymus Gland
Keywords
- aging
- differentiation
- homeostasis
- thymus
Multiple sclerosis (MS) is characterized by episodes of inflammatory demyelination with progressive failure of remyelination. Prior studies using murine models of MS indicate that remyelination within the adult central nervous system (CNS) requires the expression and activity of TNFR2 and CXCR4 by oligodendrocyte progenitor cells (OPCs), promoting their proliferation and differentiation into mature oligodendrocytes. Here, we extend these studies by examining the role of TNFR2 in the expression of the CXCR4 ligand, CXCL12, within the corpus callosum (CC) during cuprizone (CPZ) intoxication and by demonstrating that lentiviral-mediated gene delivery of CXCL12 to the demyelinated CC improves OPC proliferation and myelin expression during remyelination. Activated astrocytes and microglia express both TNFR1 and TNFR2 within the demyelinated CC. However, CPZ intoxicated TNFR2-/- mice exhibit loss of up-regulation of CXCL12 in astrocytes with concomitant decreases in numbers of CXCR4 NG2 OPCs within the CC. While CXCR4 antagonism does not affect OPC migration from subventricular zones into the CC, it decreases their proliferation and differentiation within the CC. Stereotactic delivery of lentivirus expressing CXCL12 protein into the CC of acutely demyelinated TNFR2-/- mice increases OPC proliferation and expression of myelin. In contrast, chronically demyelinated wild-type mice, which exhibit significant loss of astrocytes and OPCs, are unable to be rescued via CXCL12 lentivirus alone but instead required engraftment of CXCL12-expressing astrocytes for increased myelin expression. Our results show that TNFR2 activation induces CXCL12 expression in the demyelinated CC via autocrine signaling specifically within astrocytes, which promotes OPC proliferation and differentiation. In addition, gene delivery of critical pro-myelinating proteins might be a feasible approach for the treatment of remyelination failure in MS.
MeSH Terms
- Aging
- Animals
- Astrocytes
- Cell Differentiation
- Cell Proliferation
- Central Nervous System
- Chemokine CXCL12
- Corpus Callosum
- Demyelinating Diseases
- Disease Models, Animal
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Multiple Sclerosis
- Myelin Sheath
- Oligodendroglia
- Receptors, Tumor Necrosis Factor, Type II
- Stem Cells
Chemokine-dependent migration of T lymphocytes assures recirculation of naïve T cells to secondary lymphoid organs and tissue-specific trafficking of memory-effector T cells. Previous studies carried out in rodents have demonstrated age-associated modulation of the expression of chemokine receptors such as CXCR4 and CCR5; however, little is known about the molecular mechanisms that regulate receptor expression and turnover in T cells, during advancing age in humans. Our recent results demonstrating increased chemotactic migration in response to CXCL12 in CD4( ) T cells obtained from the elderly, as compared to those from young donors, led us to hypothesize that increase in surface expression, because of altered endocytic regulation of CXCR4 on T cells during aging, might be directly responsible for increased migration toward CXCL12. Studies presented here demonstrate a significant increase in the surface expression of CXCR4 in CD4( ) T cells from elderly human donors, relative to those from the young. Additionally, CXCL12-mediated endocytosis of CXCR4 was differentially regulated during aging, which could be attributed to alterations in the ubiquitination of CXCR4. Thus, altered ubiquitination of CXCR4 may contribute to the increased surface expression and enhanced T-cell migration to chemotactic stimuli in the elderly.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- CD4-Positive T-Lymphocytes
- Chemokine CXCL12
- Chemotaxis, Leukocyte
- Gene Expression Regulation
- Humans
- In Vitro Techniques
- Ligands
- Lymphocyte Activation
- Receptors, CCR5
- Receptors, CXCR4
- Signal Transduction
- Ubiquitin Thiolesterase
- Ubiquitination
- Young Adult
Natural killer (NK) cells are granular lymphocytes that are generated from hematopoietic stem cells and play vital roles in the innate immune response against tumors and viral infection. Generation of NK cells is known to require several cytokines, including interleukin-15 (IL-15) and Fms-like tyrosine kinase 3 ligand, but not IL-2 or IL-7. Here we investigated the in vivo role of CXC chemokine ligand-12 (CXCL12) and its primary receptor CXCR4 in NK-cell development. The numbers of NK cells appeared normal in embryos lacking CXCL12 or CXCR4; however, the numbers of functional NK cells were severely reduced in the bone marrow, spleen, and peripheral blood from adult CXCR4 conditionally deficient mice compared with control animals, probably resulting from cell-intrinsic CXCR4 deficiency. In culture, CXCL12 enhanced the generation of NK cells from lymphoid-primed multipotent progenitors and immature NK cells. In the bone marrow, expression of IL-15 mRNA was considerably higher in CXCL12-abundant reticular (CAR) cells than in other marrow cells, and most NK cells were in contact with the processes of CAR cells. Thus, CXCL12-CXCR4 chemokine signaling is essential for NK-cell development in adults, and CAR cells might function as a niche for NK cells in bone marrow.
MeSH Terms
- Aging
- Animals
- Cell Differentiation
- Cell Separation
- Chemokine CXCL12
- Flow Cytometry
- Hematopoiesis
- Immunohistochemistry
- Killer Cells, Natural
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Receptors, CXCR4
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction
CXCR4 is a chemokine receptor implicated in the metastatic process. The CXCR4 ligand, CXCL12, was shown to bind also the CXCR7 receptor, a recently deorphanized chemokine receptor whose signalling pathway and function are still controversial. This study was conducted to determine patients clinic-pathological factors and outcome according to the expressions of CXCR4 and CXCR7 in renal cell carcinoma (RCC). CXCR4 and CXCR7 expression was evaluated in 223 RCC patients through immunohistochemistry; moreover CXCR4 and CXCR7 was detected in 49 others consecutive RCC patients trough RT- PCR. CXCR4 expression was low in 42/223 RCC (18.8%), intermediate in 71/223 (31.9%) and high in 110/223 (49.3%). CXCR7 expression was low in 44/223 RCC patients (19.8%), intermediate in 65/223 (29.1%) and high in 114/223 (51.1%). High CXCR4 and high CXCR7 expression predicted shorter disease free survival. In multivariate analysis, high CXCR4 expression (p= 0.0061), high CXCR7 (p= 0.0194) expression and the concomitant high expression of CXCR4 and CXCR7 (p= 0.0235) are independent prognosis factors. Through RT-PCR, CXCR4 was overexpressed in 36/49 and CXCR7 in 33/49 samples correlating with symptoms at diagnosis and lymph nodes status. So we can hypothesize that CXCR4 and CXCR7, singularly evaluated and in combination, are valuable prognostic factors in RCC patients.
MeSH Terms
- Aged
- Aging
- Carcinoma, Renal Cell
- Disease-Free Survival
- Female
- Humans
- Immunohistochemistry
- Kidney
- Kidney Neoplasms
- Lymphatic Metastasis
- Male
- Neoplasm Recurrence, Local
- Neoplasm Staging
- Prognosis
- RNA, Messenger
- Receptors, CXCR
- Receptors, CXCR4
- Reverse Transcriptase Polymerase Chain Reaction
- Survival Analysis
CXCL12 is an important CXC chemokine involved in numerous biological processes. We had previously demonstrated the synergistic participation of CXCL12 and IL-7 in the control of both survival and proliferation of CD34( ) human thymic lymphoid progenitors. On this basis, we hypothesize a presumptive role for CXCL12 and its receptor, CXCR4, in the thymus involution. In this respect, in the current report we describe the expression of both molecules in the human thymus during aging. Our results demonstrate that, despite the profound alterations observed in the thymic epithelial microenvironment of aged thymuses, the proportions of different CD4/CD8 thymocyte subsets do not undergo significant variations. Remarkably, a strong CXCL12 expression was found in older thymuses, which appeared in the same locations as in younger thymuses: the subcapsulary and medullary areas. The proportions of CXCR4( ) cells, most of them belonging to the CD3(-) compartment, showed no important variations in the older thymuses. However, within the CD34( ) cell population, a significant reduction in the expression of CXCR4 molecules was observed.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- Antigens, CD34
- Atrophy
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Cell Differentiation
- Cell Proliferation
- Chemokine CXCL12
- Homeostasis
- Humans
- Immunohistochemistry
- Middle Aged
- Receptors, CXCR4
- Stem Cells
- T-Lymphocytes
- Thymus Gland
- Young Adult
Alzheimer's disease (AD) is characterized by massive neuronal cell loss in the brain. Stem cell factor (SCF) is a hematopoietic growth factor (HGF) that promotes neuroprotective effects and supports neurogenesis in the brain. In the present study, we found significantly lower SCF plasma levels in 30 early AD patients (908.5 /- 181.7 pg/ml) in comparison with 30 age-matched healthy controls (1058.3 /- 221.5 pg/ml; p = 0.006). SCF plasma levels in AD patients showed a significant inverse correlation with dementia severity as measured by ADAS-Cog (r = -0.289; p = 0.037). AD patients showed significantly lower SCF levels in cerebrospinal fluid (CSF) (131.60 /- 43.03 pg/ml) in comparison with 15 age- and gender-matched patients with other non-inflammatory neurological disease (NIND) (166.03 /- 42.5 pg/ml; p = 0.017). In addition, we found significant positive correlations between SCF and CXCL12 (also known as SDF-1) plasma levels in healthy controls (r = 0.341; p = 0.008) and between SCF and CXCL12 CSF levels in AD patients (r = 0.487; p < 0.001). In conclusion, decreased SCF plasma and CSF levels in early AD patients may contribute to a deficient hematopoietic brain support with putative pathogenic and clinical relevance. Further studies are needed to examine whether a manipulation of HGFs such as SCF could be a promising new therapeutic strategy for AD.
MeSH Terms
- Aged
- Aging
- Alzheimer Disease
- Amyloid beta-Peptides
- Chemokine CXCL12
- Data Interpretation, Statistical
- Female
- Hematopoiesis
- Humans
- Male
- Neuropsychological Tests
- Peptide Fragments
- Stem Cell Factor
- tau Proteins
Exercise is a treatment paradigm that can ameliorate cognitive dysfunction in Alzheimer disease (AD) and AD mouse models. Since exercise is also known to alter the peripheral immune response, one potential mechanism for the cognitive improvement following exercise may be by modulating the inflammatory repertoire in the central nervous system. We investigated the effects of voluntary exercise in the Tg2576 mouse model of AD at a time-point at which pathology has already developed. Inflammatory mRNA markers are increased in sedentary Tg2576 mice versus non-transgenic controls. We demonstrate that short-term voluntary wheel running improved spatial learning in aged transgenic mice as compared to sedentary Tg2576 controls. Inflammatory profiles of the Tg2576 and non-transgenic mice were different following exercise with the non-transgenic mice showing a broader response as compared to the Tg2576. Notably, exercising Tg2576 exhibited increases in a few markers including CXCL1 and CXCL12, two chemokines that may affect cognition.
MeSH Terms
- Aging
- Alzheimer Disease
- Amyloid beta-Peptides
- Amyloid beta-Protein Precursor
- Animals
- Behavior, Animal
- Chemokine CXCL1
- Chemokine CXCL2
- Cognition
- Disease Models, Animal
- Enzyme-Linked Immunosorbent Assay
- Gene Expression Regulation
- Inflammation
- Maze Learning
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Microarray Analysis
- RNA, Messenger
- Time Factors
Alzheimer disease (AD) is characterized by the presence of plaques and tangles in parallel with progressive cognitive decline. The underlying cause of the cognitive decline is unknown. The purpose of this study was to identify factors that could affect learning and memory using the Tg2576 mouse model of AD. Un-biased GeneChip analysis at the time-point coinciding with the onset of behavioral deficits but prior to plaque deposition revealed that Tg2576 show altered gene expression for a number of molecules including the chemokine CXCL12. We show that this chemokine's mRNA, protein and receptor are downregulated in this mouse model coinciding with cognitive deficits. Furthermore, we demonstrate that CXCL12 levels are decreased in AD patients as compared to controls. To determine if CXCL12 might be related to impaired learning and memory, we chronically treated young non-transgenic mice with an antagonist to the CXCL12 receptor to simulate the reduction seen in transgenic animals. Treated animals showed selectively impaired learning and memory suggesting a potential role for this chemokine in cognitive functioning.
MeSH Terms
- Aging
- Alzheimer Disease
- Amyloid beta-Peptides
- Animals
- Biomarkers
- Brain
- Chemokine CXCL12
- Disease Models, Animal
- Down-Regulation
- Encephalitis
- Gene Expression Regulation
- Heterocyclic Compounds
- Hippocampus
- Humans
- Learning Disabilities
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Plaque, Amyloid
- RNA, Messenger
- Receptors, CXCR4
- Synaptic Transmission
The functions of a chemokine CXC chemokine ligand (CXCL) 12/stromal cell-derived factor-1/pre-B cell growth stimulating factor and its physiologic receptor CXCR4 in T cell development are controversial. In this study, we have genetically further characterized their roles in fetal and adult T cell development using mutant and chimeric mice. In CXCL12(-/-) or CXCR4(-/-) embryos on a C57BL/6 background, accumulation of T cell progenitors in the outer mesenchymal layer of the thymus anlage during initial colonization of the fetal thymus was comparable with that seen in wild-type embryos. However, the expansion of CD3(-)CD4(-)CD8(-) triple-negative T cell precursors at the CD44(-)CD25( ) and CD44(-)CD25(-) stages, and CD4( )CD8( ) double-positive thymocytes was affected during embryogenesis in these mutants. In radiation chimeras competitively repopulated with CXCR4(-/-) fetal liver cells, the reduction in donor-derived thymocytes compared with wild-type chimeras was much more severe than the reduction in donor-derived myeloid lineage cells in bone marrow. Triple negative CD44( )CD25( ) T cell precursors exhibited survival response to CXCL12 in the presence of stem cell factor as well as migratory response to CXCL12. Thus, it may be that CXCL12 and CXCR4 are involved in the expansion of T cell precursors in both fetal and adult thymus in vivo. Finally, enforced expression of bcl-2 did not rescue impaired T cell development in CXCR4(-/-) embryos or impaired reconstitution of CXCR4(-/-) thymocytes in competitively repopulated mice, suggesting that defects in T cell development caused by CXCR4 mutation are not caused by reduced expression of bcl-2.
MeSH Terms
- Aging
- Animals
- B-Lymphocyte Subsets
- Bone Marrow Cells
- Bone Marrow Transplantation
- Cell Differentiation
- Cell Division
- Cell Movement
- Cell Survival
- Cells, Cultured
- Chemokine CXCL12
- Chemokines, CXC
- Embryonic and Fetal Development
- Fetal Tissue Transplantation
- Hematopoietic Stem Cells
- Liver Transplantation
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Transgenic
- Mutation
- Proto-Oncogene Proteins c-bcl-2
- Radiation Chimera
- Receptors, CXCR4
- T-Lymphocyte Subsets
- Thymus Gland