The influence of the geroprotective cytokine on the transcriptome of young and old mesenchymal stem cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE287646 | GEO | 2025/04/30
REPOSITORIES: GEO
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Project description:Replicative senescence hampers application of mesenchymal stromal cells (MSCs) because it limits culture expansion, impairs differentiation potential, and hinders reliable standardization of cell products. MSCs can be rejuvenated by reprogramming into induced pluripotent stem cells (iPSCs), which is associated with complete erasure of age- and senescence-associated DNA methylation (DNAm) patterns. However, this process is also associated with erasure of cell-type and tissue-specific epigenetic characteristics that are not recapitulated upon re-differentiation towards MSCs. In this study, we therefore followed the hypothesis that overexpression of pluripotency factors under culture conditions that do not allow full reprogramming might reset senescence-associated changes without entering a pluripotent state. MSCs were transfected with episomal plasmids and either successfully reprogrammed into iPSCs or cultured in different media with continuous passaging every week. Overexpression of pluripotency factors without reprogramming did neither prolong culture expansion nor ameliorate molecular and epigenetic hallmarks of senescence. Notably, transfection resulted in immortalization of one cell preparation with gain of large parts of the long arm of chromosome 1. Taken together, premature termination of reprogramming does not result in rejuvenation of MSCs and harbours the risk of transformation. This approach is therefore not suitable to rejuvenate cells for cellular therapy.
2019-05-21 | GSE115666 | GEO
Project description:We report a novel licensing strategy to improve the immunosuppressive capacity of MSCs. Licensing murine MSCs with TGF-β1 (TGF-β MSC) significantly improved their ability to modulate both the phenotype and secretome of inflammatory bone marrow-derived macrophages and significantly increased the numbers of regulatory T lymphocytes (Tregs) following co-culture assays. These TGF-β MSC-expanded Tregs also expressed significantly higher levels of PD-L1 and CD73, indicating enhanced suppressive potential. Detailed analysis of T lymphocyte co-cultures revealed modulation of secreted factors, most notably, elevated prostaglandin E2 (PGE2). Furthermore, TGF-β MSCs could significantly prolong rejection-free survival (69.2% acceptance rate compared to 21.4% for un-licensed MSC treated recipients) in a murine corneal allograft model. Mechanistic studies revealed that (i) therapeutic efficacy of TGF-β MSCs is Smad2/3-dependent; (ii) TGF-β MSC’s enhanced immunosuppressive capacity is contact-dependent and (iii) enhanced secretion of PGE2 (via prostaglandin EP4 receptor) by TGF-β MSCs is the predominant mediator of Treg expansion and T cell activation and is associated with corneal allograft survival. Collectively, we provide compelling evidence for the use of TGF-β1 licensing as an unconventional strategy for enhancing MSC immunosuppressive capacity.
2020-08-31 | GSE150008 | GEO
Project description:Here, we use single cell transcriptomics to characterize a dynamic senescence process of in vitro expanded MSC products from adipose tissue (AD), bone marrow (BM), placenta membrane (PM) and umbilical cord (UC). We found that cultured MSCs underwent progressive cell aging. As compared to perinatal MSCs (derived from PM and UC), adult MSCs (derived from AD and BM) showed higher degree of senescence and impaired immunosuppressive function. Moreover, we identified the transcriptional network regulating the intra-population functional diversity, which provides us guidance to drive reprogramming of determined MSCs lineage with specific cellular functions for a particular therapeutic intent.
2023-06-19 | GSE200161 | GEO
Project description:Transcriptional profiling of human control and Néstor-Guillermo Progeria Syndrome (NGPS) mesenchymal stem cells (MSCs). Somatic cell reprogramming involves rejuvenation of adult cells and relies on the ability to erase age-associated molecular marks. Accordingly, reprogramming efficiency declines with ageing, and age-associated features such as genetic instability, cell senescence or telomere shortening negatively affect this process. However, the regulatory mechanisms that constitute age-associated barriers for cell reprogramming remain largely unknown. Here, by using cells from patients with premature ageing, we demonstrate that NF-κB activation is a critical barrier for the generation of induced pluripotent stem cells (iPSCs) in ageing. We show that NF-κB repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-κB hyperactivation impairs generation of iPSCs by eliciting reprogramming repressors DOT1L and YY1, reinforcing cell senescence signals and down-regulating pluripotency genes. We also show that genetic and pharmacological NF-κB inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Néstor-Guillermo Progeria Syndrome (NGPS) and Hutchinson-Gilford Progeria Syndrome (HGPS) patients, as well as from normal aged donors. Finally, we demonstrate that DOT1L inhibition in vivo ameliorates the accelerated ageing phenotype and extends lifespan in a progeroid animal model. Collectively, our results provide evidence for a novel role of NF-κB in the control of cell fate transitions and reinforce the interest of studying age-associated molecular impairments to implement cell reprogramming methodologies, and to identify new targets of rejuvenation strategies. Control and NGPS MSCs were differentiated into bone in the presence or absence of sodium salicylate. Total RNA was extracted and global gene expression was analyzed.
2015-07-01 | E-GEOD-65172 | biostudies-arrayexpress
Project description:The efficient clearance of dead and dying cells, also known as efferocytosis, is critical to maintain tissue homeostasis. In the bone marrow microenvironment (BMME), this role is primarily fulfilled by professional bone marrow macrophages, but recent work has shown that mesenchymal stromal cells (MSCs) act as a non-professional phagocyte within the BMME. However, little is known about the mechanism and impact of efferocytosis on MSCs in the BMME and on their function. To investigate this, we performed flow cytometric analysis of neutrophil uptake by ST2 cells, a murine bone marrow-derived stromal cell line, and in murine primary bone marrow-derived stromal cells. Transcriptional analysis showed that MSCs possess the necessary receptors and internal processing machinery to conduct efferocytosis, with Axl and Tyro3 serving as the main receptors, while MerTK was not expressed. Moreover, the expression of these receptors was modulated by efferocytic behavior, regardless of apoptotic target. MSCs derived from human bone marrow also demonstrated efferocytic behavior, showing that MSC efferocytosis is conserved. In all MSCs, efferocytosis impaired osteoblastic differentiation. Transcriptional analysis and functional assays identified downregulation in MSC mitochondrial function upon efferocytosis. Experimentally, efferocytosis induced mitochondrial fission in MSCs. Pharmacologic inhibition of mitochondrial fission in MSCs not only decreased efferocytic activity but also rescued osteoblastic differentiation, demonstrating that efferocytosis-mediated mitochondrial remodeling plays a critical role in regulating MSC differentiation. This work describes a novel function of MSCs as non-professional phagocytes within the BMME and demonstrates that efferocytosis by MSCs plays a key role in directing mitochondrial remodeling and MSC differentiation. Efferocytosis by MSCs may therefore be a novel mechanism of dysfunction and senescence. Since our data in human MSCs show that MSC efferocytosis is conserved, the consequences of MSC efferocytosis may impact the behavior of these cells in the human skeleton, including osteoporosis in aging.
2023-07-14 | GSE223281 | GEO
Project description:The efficient clearance of dead and dying cells, also known as efferocytosis, is critical to maintain tissue homeostasis. In the bone marrow microenvironment (BMME), this role is primarily fulfilled by professional bone marrow macrophages, but recent work has shown that mesenchymal stromal cells (MSCs) act as a non-professional phagocyte within the BMME. However, little is known about the mechanism and impact of efferocytosis on MSCs in the BMME and on their function. To investigate this, we performed flow cytometric analysis of neutrophil uptake by ST2 cells, a murine bone marrow-derived stromal cell line, and in murine primary bone marrow-derived stromal cells. Transcriptional analysis showed that MSCs possess the necessary receptors and internal processing machinery to conduct efferocytosis, with Axl and Tyro3 serving as the main receptors, while MerTK was not expressed. Moreover, the expression of these receptors was modulated by efferocytic behavior, regardless of apoptotic target. MSCs derived from human bone marrow also demonstrated efferocytic behavior, showing that MSC efferocytosis is conserved. In all MSCs, efferocytosis impaired osteoblastic differentiation. Transcriptional analysis and functional assays identified downregulation in MSC mitochondrial function upon efferocytosis. Experimentally, efferocytosis induced mitochondrial fission in MSCs. Pharmacologic inhibition of mitochondrial fission in MSCs not only decreased efferocytic activity but also rescued osteoblastic differentiation, demonstrating that efferocytosis-mediated mitochondrial remodeling plays a critical role in regulating MSC differentiation. This work describes a novel function of MSCs as non-professional phagocytes within the BMME and demonstrates that efferocytosis by MSCs plays a key role in directing mitochondrial remodeling and MSC differentiation. Efferocytosis by MSCs may therefore be a novel mechanism of dysfunction and senescence. Since our data in human MSCs show that MSC efferocytosis is conserved, the consequences of MSC efferocytosis may impact the behavior of these cells in the human skeleton, including osteoporosis in aging.
2023-07-14 | GSE223279 | GEO
Project description:Growth differentiation factor 11 (GDF11), also known as bone morphogenetic protein 11 (BMP11) is a member of the Growth differentiation factors (GDFs), a subfamily of proteins belonging to the transforming growth factor-beta (TGF-β) superfamily (Katoh and Katoh 2006). ). In the past 7-8 years, several high profile studies, showed that systemic restoration of GDF11 levels reverses age-related phenotypes and rejuvenated heart and skeletal muscle in aged mice (Loffredo, Steinhauser et al. 2013, Sinha, Jang et al. 2014), improves insulin sensitivity via restoring pancreatic β-cell function in diabetic mice (Li, Li et al. 2017), and increases proliferation of brain capillary endothelial cells thereby improving the vascular and neurogenic rejuvenation in the brain of aged mice (Katsimpardi, Litterman et al. 2014, Finkenzeller, Stark et al. 2015, Zhang, Guo et al. 2018). Nonetheless, the possible rejuvenation effect of GDF11 was questioned over past years by several other studies. These reports doubted the age-associated decrease of circulating GDF11 level and related phenotypes in the muscle, the heart and the brain (Egerman, Cadena et al. 2015, Rodgers and Eldridge 2015); moreover, restoration of GDF11 levels in old mice had no positive effect on heart structure or function (Smith, Zhang et al. 2015). Increase of GDF11 levels had deleterious effects on aging skeletal muscle regeneration (Egerman, Cadena et al. 2015), suggesting also that supraphysiological levels could lead to cachexia (Hammers, Merscham-Banda et al. 2017). In the field of liver diseases, GDF11 was shown to exhibit tumor suppressive properties in HCC cells (Zhang, Pan et al. 2018, Gerardo-Ramírez, Lazzarini-Lechuga et al. 2019) and to worsen hepatocellular injury and liver regeneration after liver ischemia reperfusion injury (Liu, Dong et al. 2018). From these controverted studies, it is clear that the systemic effects of GDF11 in health and disease are not yet clearly and fully delineated. The aim of the present study was to specifically characterize the role of GDF11 in lipid metabolism and in the progression of the NAFLD disease spectrum, which is currently unknown. We thus aimed at investigating the potential effect of GDF11 on lipid droplet formation in human hepatocytes. Our data strongly suggest that GDF11 supplementation exacerbates, both in presence or absence of FFA, lipid droplet accumulation in two hepatic cell models (HepG2 and Hep3B) by impinging on ALK5/SMAD2/3 dependent signaling pathway.
2019-08-14 | GSE135796 | GEO
Project description:Obesity is a health problem characterized by large expansion of adipose tissue. During this expansion, genotoxic stressors can be accumulated and negatively affect the Mesenchymal Stem Cells (MSCs) of adipose tissue. Due to the oxidative stress generated by these genotoxic stressors, senescence phenotype might be observed in adipose tissue MSCs. Senescent MSCs lose their proliferations and differentiation properties and secrete senescence-associated molecules to their niche thus triggering senescence for the rest of the tissue. Accumulation of senescent cells in adipose tissue results in decreased tissue regeneration and functional impairment not only in the close vicinity but also in the other tissues. Here we hypothesized that declined tissue regeneration might be associated with loss of stemness in MSCs population. We analyzed the expression of several stemness genes in adipose tissue MSCs of high-fat diet and normal diet mice models. Since the MSCs population covers a small percentage of the pluripotent stem cells, a role in proliferation and tissue regeneration, we measured the percentage of these cells via TRA-1-60 surface antigen. Additionally, by conducting a shotgun proteomic approach using LC-MS/MS, whole cell proteome of the adipose tissue MSCs of high-fat diet and normal diet mice were analyzed and identified proteins were evaluated via Gene Ontology and PPI network analysis. MSCs of obese mice showed senescent phenotype and altered cell cycle distribution due to a hostile environment with oxidative stress in adipose tissue where they reside. Additionally, the number of pluripotent markers expressing cells declined in the MSC population of the high-fat diet mice. Gene expression analysis evidenced the loss of stemness with a decrease in the expression of stemness-associated genes. Of the proteomic comparison of the normal and the high-fat diet group, MSCs revealed that stemness-associated molecules were decreased while inflammation and senescence-associated phenotypes emerged in obese mice MSCs. Our results showed us that the MSCs of adipose tissue may lose their stemness properties due to obesity-associated stress conditions.
2024-10-17 | PXD050811 | Pride
Project description:Cellular senescence is characterised by a state of permanent cell cycle arrest. While cellular senescence is a recognised driver of organismal ageing, the extent of heterogeneity within and between different senescent cell populations remains largely unclear. Here we combined cell biological and single cell RNA-sequencing approaches to investigate heterogeneity of replicative senescence in human ESC-derived mesenchymal stem cells (esMSCs) as MSCs are the cell type of choice for the majority of current stem cell herapies and senescence of MSC is a recognized driver of organismal ageing. We identified three senescing esMSC subpopulations and their associated maker genes, allowing us to identify potential drug targets that may delay the emergence of senescent MSCs in vitro and perhaps in vivo in the future.
2023-04-30 | GSE200157 | GEO
Project description:<p><strong>BACKGROUND:</strong> Perioperative neurocognitive disorder (PND) is a key complication affecting older individuals after anesthesia and surgery. Failure to translate multiple pharmacological therapies for PND from preclinical studies to clinical settings has necessitated the exploration of novel therapeutic strategies. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) treatment has emerged as a promising therapeutic strategy for treating neurodegenerative diseases and has the potential to translate basic science into clinical practice. In this study, we investigated the effects and underlying mechanism of hUC-MSCs on PND in aged mice.</p><p><strong>METHODS:</strong> hUC-MSCs were isolated from an infant umbilical cord and identified using flow cytometry and differentiation assays. We established PND model by undergoing aseptic laparotomy under isoflurane anesthesia maintaining spontaneous ventilation in 18-month-old male C57BL/6 mice. hUC-MSCs were slowly injected into mice by coccygeal vein before anesthesia. Cognitive function, neuroinflammation, neuroplasticity, endogenous neurogenesis and brain-derived neurotrophic factor (BDNF) were assessed. To determine the mechanisms underlying by which hUC-MSCs mediate their neuroprotective effects in PND, K252a, an antagonist of BDNF receptor, was administered intraperitoneally before surgery. Hippocampal BDNF/TrkB/CREB signaling pathway and metabolomic signatures were evaluated.</p><p><strong>RESULTS:</strong> hUC-MSC treatment ameliorated the learning and memory impairment in aged mice with PND. The downstream effects were the suppression of neuroinflammatory responses and restoration of neurogenesis and neuroplasticity dysregulation. Interestingly, the level of mature BDNF, but not that of proBDNF, was increased in the hippocampus after hUC-MSC treatment. Further analysis revealed that the improved cognitive recovery and the restoration of neurogenesis and neuroplasticity dysregulation elicited by exposure to hUC-MSCs were, at least partially, mediated by the activation of the BDNF/TrkB/CREB signaling pathway. Untargeted metabolomic further identified lipid metabolism dysfunction as potential downstream of the BDNF/TrkB/CREB signaling pathway in hUC-MSC-mediated neuroprotection for PND.</p><p><strong>CONCLUSIONS:</strong> Our study highlights the beneficial effects of hUC-MSC treatment on PND and provides a justification to consider the potential use of hUC-MSCs in the perioperative period.</p>
2023-07-25 | MTBLS7759 | MetaboLights