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Inhibition of longevity regulator PAPP-A modulates tissue homeostasis via restraint of mesenchymal stromal cells [Fig. 1]

ABSTRACT: Reducing insulin-like growth factor (IGF) signaling is one of the best conserved and characterized mechanisms to extend longevity. Pregnancy associated plasma protein A (PAPP-A) is a secreted metalloprotease that increases IGF availability by cleaving IGF binding proteins. PAPP-A inhibition reduces local IGF signaling, limits the progression of multiple age-related diseases, and extends lifespan, but the mechanisms behind these pleiotropic effects remains unknown. Here, we developed and utilized a PAPP-A neutralizing antibody to discover that adulthood inhibition of this protease reduced collagen and extracellular matrix (ECM) gene expression in multiple tissues in mice. Using bone marrow to explore this effect, we identified mesenchymal stromal cells (MSCs) as the source of PAPP-A and primary responders to PAPP-A inhibition. Short-term treatment with anti-PAPP-A reduced IGF signaling in MSCs, altered MSC expression of collagen/ECM, and decreased MSC number. This affected MSC-dependent functions, decreasing myelopoiesis and osteogenesis. Our data demonstrate that PAPP-A inhibition reduces the activity and number of IGF-dependent mesenchymal progenitor cells and their differentiated progeny, and that this reduction leads to functional changes at the tissue level. MSC-like cells are present in virtually all tissues, and aberrant collagen and ECM production from mesenchymal cells drives aspects of aging and age-related diseases, thus this may be a mechanism by which PAPP-A deficiency enhances lifespan and healthspan.

ORGANISM(S): Mus musculus

PROVIDER: GSE144615 | GEO | 2021/02/01

REPOSITORIES: GEO

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Inhibition of longevity regulator PAPP-A modulates tissue homeostasis via restraint of mesenchymal stromal cells [Fig. 2]

Project description:Reducing insulin-like growth factor (IGF) signaling is one of the best conserved and characterized mechanisms to extend longevity. Pregnancy associated plasma protein A (PAPP-A) is a secreted metalloprotease that increases IGF availability by cleaving IGF binding proteins. PAPP-A inhibition reduces local IGF signaling, limits the progression of multiple age-related diseases, and extends lifespan, but the mechanisms behind these pleiotropic effects remains unknown. Here, we developed and utilized a PAPP-A neutralizing antibody to discover that adulthood inhibition of this protease reduced collagen and extracellular matrix (ECM) gene expression in multiple tissues in mice. Using bone marrow to explore this effect, we identified mesenchymal stromal cells (MSCs) as the source of PAPP-A and primary responders to PAPP-A inhibition. Short-term treatment with anti-PAPP-A reduced IGF signaling in MSCs, altered MSC expression of collagen/ECM, and decreased MSC number. This affected MSC-dependent functions, decreasing myelopoiesis and osteogenesis. Our data demonstrate that PAPP-A inhibition reduces the activity and number of IGF-dependent mesenchymal progenitor cells and their differentiated progeny, and that this reduction leads to functional changes at the tissue level. MSC-like cells are present in virtually all tissues, and aberrant collagen and ECM production from mesenchymal cells drives aspects of aging and age-related diseases, thus this may be a mechanism by which PAPP-A deficiency enhances lifespan and healthspan.

2021-02-01 | GSE144616 | GEO

NFAT signalling in human mesenchymal stromal cells affects extracellular matrix metabolism and anti-fungal immune responses

Project description:Mesenchymal stromal cells (MSCs) combined with calcineurin-NFAT (CN-NFAT) inhibitors are being tested as a treatment for graft versus host disease (GvHD). The immunosuppressive properties of MSCs seem beneficial; however, their response during fungal infection, which is an important cause of mortality in GvHD patients, is unknown. We report that MSCs phagocytose the fungal component zymosan, resulting in phosphorylation of Syk kinase, increase in cytosolic calcium levels and ultimately, in NFAT1 nuclear translocation. RNA-sequencing analysis of zymosan-treated MSCs showed that CN-NFAT inhibition affects extracellular matrix (ECM) genes, but not cytokine expression that is under the control of the NF-κB pathway. When co-culturing MSCs or decellularized MSC-ECM with human peripheral blood mononuclear cells (PBMCs), selective NFAT inhibition in MSCs decreased cytokine expression by PBMCs. These findings reveal a dual mechanism underlying the MSC response to zymosan: while NF-κB directly controls inflammatory cytokine expression, NFAT impacts immune-cell functions by regulating ECM remodelling.

2021-06-14 | GSE157981 | GEO

Engineered ECMs modulate the expression profile of bone marrow-derived human MSC: implications for HSC self-renewal

Project description:The bone marrow harbours multipotent mesenchymal stromal cells (MSCs) that nurture haematopoietic stem cells (HSCs). The extracellular matrix (ECM) is an integral part of the bone marrow, and the aim of this study was therefore to (a) examine the effect of engineered ECM substrates on MSC gene expression over time, and (b) to determine the functional ability of ECM-cultured MSCs to support HSCs. ECMs were surface immobilised using films of maleic anhydride to covalently immobilise tropocollagen or fibrillar collagen type I to the substrate. Where indicated, collagen type 1 fibrils were supplemented with heparin or hyaluronic acid. All surfaces maintained MSC viability, though cell expansion was ECM dependent. Microarray analysis indicated that both time in culture and culture substrate were important factors regulating gene expression. Surprisingly, a number of MSC genes critical for the support of HSC self-renewal were down regulated during the study period. The functional effects of the different substrates were quantitatively assessed by determining cobblestone area-forming cell frequencies and colony-forming units (CFUs). Progenitor frequencies were similar for all substrates during the first 3 weeks in culture, but thereafter the reference material, plasma-treated polystyrene (PTP), outperformed ECM-based culture substrates, as predicted from expression studies. Likewise, PTP was able to maintain CFUs for extended periods, whereas HSCs rapidly exhausted themselves when cultured on any of the ECM substrates tested. The ability to regulate the expression of stromal factors using reconstituted ECM is exciting and warrants further studies to identify the ECM components/combinations that maximise the expansion of clonogenic HSCs. Keywords: time course, human MSC, extracellular matrix

2009-08-01 | GSE12635 | GEO

Human osteoblast-derived extracellular matrix with high homology to human bone proteome is osteopromotive for mesenchymal stromal cells

Project description:Efficient osteogenic differentiation of mesenchymal stem cells (MSCs) is crucial to accelerate bone formation. In this context, the use of extracellular matrix (ECM) as natural 3D-framework mimicking in vivo tissue architecture is of interest. The aim of this study was to generate a devitalized human osteogenic MSC-derived ECM and to investigate its impact on MSC osteogenic differentiation to improve MSC properties in bone regeneration. The devitalized ECM significantly enhanced MSC adhesion and proliferation. Osteogenic differentiation and mineralization of MSCs on the ECM was quicker than in standard conditions. The presence of ECM promoted in vivo bone formation by MSCs in a mouse model of ectopic-calcification. We analyzed the ECM composition by mass spectrometry, detecting 846 proteins. Of these, 473 proteins were shared with the human bone proteome we previously described, demonstrating high homology to an in vivo microenvironment. Bioinformatic analysis of the 846 proteins showed involvement in adhesion and osteogenic differentiation, confirming the ECM composition as key modulator of MSC behaviour. In addition to known ECM-components, proteomic analysis revealed novel ECM functions, which could improve culture conditions. In summary, this study provides a simplified method to obtain an in vitro MSC-derived ECM that enhances osteogenic differentiation, and could be applied as natural biomaterial to accelerate bone regeneration.

2022-02-24 | PXD006865 | Pride

Mesenchymal stem cell integrin-associated complexes

Project description:The composition and stiffness of the extracellular matrix (ECM) environment that surrounds Multipotent mesenchymal stem cells (MSCs) stem cells dictates transcriptional programming, thereby affecting stem cell lineage decision-making. Cells sense force between themselves and their microenvironment controlling the capability of MSCs to differentiate into adipocytes, osteocytes and chondrocytes. Force sensing is transmitted by integrin receptors and their associated adhesion signalling complexes. To identify regulators of MSC force sensing we sought to catalogue MSC adhesion complex composition. Therefore we isolated integrin-associated adhesion complexes formed in MSCs plated on the ECM ligand fibronectin. We identifed proteins using mass spectrometry that define a MSC specific subset of adhesion complex proteins consisting of key linkages to the actin cytoskeleton together with integrin signalling and force sensing components.

2016-07-20 | MSV000079956 | MassIVE

Mesenchymal stem cell integrin-associated complexes

2015-07-20 | PXD001809 | Pride

Quantitative proteomics analysis of different sources of hMSCs

Project description:Mesenchymal stem cells (MSCs) are an attractive therapeutic tool for tissue engineering and re-generative medicine due to their regenerative and trophic properties. The best-known and most widely used are bone marrow MSCs, but they are now being harvested and developed from a wide range of adult and perinatal tissues. MSCs from different sources are believed to have dif-ferent secretion potentials and production, which may influence their therapeutic effects. To prove it, we performed a quantitative proteomic analysis based on the TMT technique of MSCs from 3 different sources: wharton’s jelly (WJ), dental pulp (DP) and bone marrow (BM). Our analysis has focused on MSC biological properties of interest for tissue engineering. We identified a total of 611 human proteins differentially expressed. WJ-MSCs shown the greatest variation compared to the other sources. WJ produced more extra-cellular matrix (ECM) proteins and ECM-affiliated proteins and appeared to more able to modulate the inflammatory and immune response. BM-MSCs display enhanced differentiation and paracrine communication capabilities. DP-MSC appeared to promote exosome production. The results obtained confirm the existence of differences between WJ, DP and BM-MSC and the need to select the MSC origin according to the therapeutic objective sought.

2023-09-20 | PXD043912 | Pride

RhoA Determines Lineage Fate of MSCs by Modulating CTGF-VEGF Complex in Extracellular Matrix

Project description:Mesenchymal stem cells (MSCs) participate in the repair/remodeling of many tissues, where MSCs commit to different lineages dependent on the cues in the local microenvironment. Here we show that TGFβ-activated RhoA/ROCK functions as a molecular switch regarding the fate of MSCs in arterial repair/remodeling after injury. MSCs differentiate into myofibroblasts when RhoA/ROCK is turned on, endothelial cells when turned off. The former is pathophysiologic resulting in intimal hyperplasia, whereas the latter is physiological leading to endothelial repair. Further analysis revealed that MSC RhoA activation promotes formation of an extracellular matrix (ECM) complex consisting of connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF). Inactivation of RhoA/ROCK in MSCs induces matrix metalloproteinase-3-mediated CTGF cleavage, resulting in VEGF release and MSC endothelial differentiation. Our findings uncover a novel mechanism by which cell-ECM interactions determine stem cell lineage specificity and offer additional molecular targets to manipulate MSC-involved tissue repair/regeneration.

2016-03-01 | GSE73557 | GEO

Epigenetic rewiring towards mesenchymal-epithelial transformation in ovarian cancer-associated mesenchymal stem cells drives metastasis

Project description:Ovarian cancer develops early intra-peritoneal metastasis establishing a pro-tumorigenic tumor microenvironment (TME) through reprogramming normal mesenchymal stem cells into carcinoma-associated mesenchymal stem cells (CA-MSCs). CA-MSCs are the stromal stem cell of the TME, supporting cancer growth, increasing desmoplasia, angiogenesis and chemotherapy resistance. We demonstrate epigenetic rewiring drives CA-MSC formation via enhancer-enriched DNA hypermethylation, altered chromatin accessibility and differential histone modifications inducing a partial mesenchymal to epithelial transition (MET) increasing tumor cell adhesion. Direct CA-MSC:tumor cell interactions, confirmed in patient ascites, facilitate ovarian cancer metastasis through co-migration. WT1, a developmental mediator of MET, and EZH2, mediate CA-MSC epigenetic reprogramming. WT1 overexpression induces CA-MSC conversion while WT1 knock-down, in combination with EZH2 inhibition, blocks CA-MSC formation. EZH2 inhibition subsequently decreases intra-abdominal metastasis.

2020-12-22 | GSE138072 | GEO

Intracellular proteome (SDS/Na-DoC) extract from EP/LP MSCs grown on soft/stiff hydrogels for 4 days

Project description:Tissues are maintained by homeostatic feedback mechanisms in which cells can respond to, but also modify, the chemical and mechanical properties of the surrounding extracellular matrix (ECM). Mechano-sensitive mesenchymal stem cells (MSCs) resident in the marrow niche experience a diverse mechanical environment, but ageing can affect the composition and quality of bone and marrow tissues. Here we quantified the compounded effects of substrate stiffness and replication-induced senescence on MSC morphology and their ability to modify their environments through secretion of ECM proteins. The ECM proteome was found to be sensitive to substrate stiffness, but pharmacological inhibition of cellular contractility perturbed this response, decreasing levels of tenascin-C, fibulins and fibronectin. A corresponding change in the ECM of senescent cells, concomitant with a loss of mechano-responsive morphological features, suggested a decoupling of mechanotransduction pathways. Intracellular proteomic and transcriptomic analyses confirmed a decrease in all components of the cytoskeletal protein homeostasis machinery in senescent MSCs. These results demonstrate a senescence-mediated perturbation to cytoskeletal homeostasis, pathways of mechanotransduction and the secretion of ECM proteins considered necessary for tissue maintenance.

2022-10-10 | PXD013240 | Pride

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