Dataset Information

Vulnerability of Progeroid Smooth Muscle Cells to biomechanical forces is mediated by MMP13

ABSTRACT: Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disease in children that leads to early death. Smooth muscle cells (SMCs) are the most affected cells in HGPS patients, although the reason for such vulnerability remains poorly understood. In this work, we developed a chip formed from HGPS-SMCs that were generated from induced pluripotent stem cells (iPSCs) to study their vulnerability to flow shear stress. HGPS-iPSC SMCs cultured under arterial flow conditions detached from the chip after a few days of culture; this process was mediated by the up-regulation of metalloprotease 13 (MMP13). Importantly, double mutant LmnaG609G/G609GMmp13-/- mice or LmnaG609G/G609GMmp13+/+ mice treated with a MMP inhibitor showed lower SMC loss in the aortic arch than controls. MMP13 up-regulation appears to be mediated by the up-regulation of heparan sulfate, a glycocalyx component. Our results offer a new platform for developing treatments for HGPS patients that may complement previous pre-clinical and clinical treatments.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Aorta

SUBMITTER: Alessandro Ori

LAB HEAD: Alessandro Ori

PROVIDER: PXD011652 | Pride | 2020-08-24

REPOSITORIES: Pride

ACCESS DATA

Publications

Vulnerability of progeroid smooth muscle cells to biomechanical forces is mediated by MMP13.

Pitrez Patricia R PR Estronca Luís L Monteiro Luís Miguel LM Colell Guillem G Vazão Helena H Santinha Deolinda D Harhouri Karim K Thornton Daniel D Navarro Claire C Egesipe Anne-Laure AL Carvalho Tânia T Dos Santos Rodrigo L RL Lévy Nicolas N Smith James C JC de Magalhães João Pedro JP Ori Alessandro A Bernardo Andreia A De Sandre-Giovannoli Annachiara A Nissan Xavier X Rosell Anna A Ferreira Lino L

Nature communications 20200817 1

Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disease in children that leads to early death. Smooth muscle cells (SMCs) are the most affected cells in HGPS individuals, although the reason for such vulnerability remains poorly understood. In this work, we develop a microfluidic chip formed by HGPS-SMCs generated from induced pluripotent stem cells (iPSCs), to study their vulnerability to flow shear stress. HGPS-iPSC SMCs cultured under arterial flow conditions detach from the ...[more]

PMID: 32807790

Similar Datasets

Project description:Inflammation is the natural defensive response of the immune system to an injury or infection and is regulated by small molecule mediators triggering different phases of the inflammatory process. In particular, lipid mediators (LM) and cytokines exhibit crucial regulatory functions in the progression and resolution of inflammation. Macrophages play a central role in this process and can adopt distinct phenotypes with specialized functions depending on their microenvironment: inflammatory M1 macrophages drive inflammation by the release of pro-inflammatory cytokines and LMs, like prostaglandins (PG) and leukotrienes (LT), while resolving M2 macrophages promote inflammation resolution and tissue regeneration by production of anti-inflammatory cytokines and specialized pro resolving mediators (SPM). Aging is associated with chronic and unresolved, low-grade inflammation (“inflammaging”) and aging-related dysfunction of macrophages in the resolution of inflammation and tissue maintenance has been reported. Yet, the underlying molecular mechanisms and functional consequences of latter processes remain poorly understood. Here, we show that polarization of peritoneal macrophages (PM) from geriatric mice towards an M2-like phenotype is impaired versus adult mice, resulting in aberrant LM formation and cytokine release. In PMs isolated from adult mice (PM-A) we observed a shift in LM formation from PGs and LTs to SPMs already after 4 h of polarization towards M2 with interleukin (IL) 4. In contrast, PMs from geriatric mice (PM-G) produced mainly LTs and PGs upon polarization. This pattern persists over the course of 48 h of polarization. Proteomic profiling revealed that polarization of PM A towards M2 yields a more distinct phenotype, clearly separated from M1, when compared to PM-G. We observed similar aging-related changes in the lipidome and cytokine profile of spleen, lung and liver tissue from mice. Hence, we hypothesize that during aging macrophage polarization towards M2 is impaired, which in turn drives chronic inflammation and disturbs tissue maintenance. By combining state-of-the art lipidomic and proteomic profiling we aim to uncover new molecular targets for pharmaceutical interventions to improve therapeutic strategies for elderly patients with chronic inflammatory diseases.

Project description:Metformin is a type 2 diabetes medication which extends life span across species when given from young adulthood onwards; late life effects of metformin are not well understood. Here we used C. elegans to investigate the outcome of metformin treatment initiated late in life. We found that, contrary to young age administration, old age metformin treatment interferes with energy homeostasis and shortens life span by aggravating age-associated mitochondrial dysfunction. Nematode mutants defective in mitochondrial respiration, mitochondrial biogenesis and mitochondrial quality control were highly susceptible to metformin killing already at young age while insulin receptor deficient nematodes carrying healthier mitochondria were protected from late life metformin toxicity. In the mammalian cell culture model of replicative senescence metformin killing correlated with loss of mitochondrial membrane potential and strong reduction of systemic ATP levels. Reduced ATP levels and depletion of lipid stores consistent with energy deficit were observed also in nematodes following late life metformin treatment. At the molecular level young animals responded to metformin by inducing adaptive stress responses and longevity-assurance pathways while old nematodes demonstrated a protein expression signature consistent with lipid turnover and energy deficit. Ectopic ATP supplementation was sufficient to alleviate metformin toxicity in human skin fibroblasts highlighting the key contribution of energy deficit to the detrimental effect of metformin. Also, co-exposure with rapamycin, known to stabilize cellular ATP levels under conditions of mitochondrial failure, significantly reduced metformin-inflicted lethality in both cells and old animals. In summary we uncovered a novel negative synergism between metformin treatment and mitochondrial dysfunction which gains importance late in life and may limit therapeutic benefits of metformin for older patients; these side effects can partially be overcome by co-treatment with agents stabilizing cellular ATP levels such as rapamycin.

Dataset Information

Vulnerability of Progeroid Smooth Muscle Cells to biomechanical forces is mediated by MMP13

Publications

Vulnerability of progeroid smooth muscle cells to biomechanical forces is mediated by MMP13.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure