title: Biomechanical Strain Exacerbates Inflammation on a Progeria-on-a-Chip Model.
abstract: Organ-on-a-chip platforms seek to recapitulate the complex microenvironment of human organs using miniaturized microfluidic devices. Besides modeling healthy organs, these devices have been used to model diseases, yielding new insights into pathophysiology. Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease showing accelerated vascular aging, leading to the death of patients due to cardiovascular diseases. HGPS targets primarily vascular cells, which reside in mechanically active tissues. Here, a progeria-on-a-chip model is developed and the effects of biomechanical strain are examined in the context of vascular aging and disease. Physiological strain induces a contractile phenotype in primary smooth muscle cells (SMCs), while a pathological strain induces a hypertensive phenotype similar to that of angiotensin II treatment. Interestingly, SMCs derived from human induced pluripotent stem cells of HGPS donors (HGPS iPS-SMCs), but not from healthy donors, show an exacerbated inflammatory response to strain. In particular, increased levels of inflammation markers as well as DNA damage are observed. Pharmacological intervention reverses the strain-induced damage by shifting gene expression profile away from inflammation. The progeria-on-a-chip is a relevant platform to study biomechanics in vascular biology, particularly in the setting of vascular disease and aging, while simultaneously facilitating the discovery of new drugs and/or therapeutic targets.
authors.affiliation: Biomaterials Innovation Research Center, Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, 02139, USA.|Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.|Doctoral Program in Experimental Biology and Biomedicine, Center for Neuroscience and Cell Biology, Institute for Interdisciplinary Research, University of Coimbra, 3030-789, Coimbra, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Ribas
authors.affiliation: Biomaterials Innovation Research Center, Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, 02139, USA.|Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors.forename: Yu Shrike
authors.initials: YS
authors.lastname: Zhang
authors.affiliation: CNC-Centre for Neuroscience and Cell Biology, University of Coimbra, 3030-789, Coimbra, Portugal.|Institute for Interdisciplinary Research, University of Coimbra, 3030-789, Coimbra, Portugal.
authors.forename: Patrícia R
authors.initials: PR
authors.lastname: Pitrez
authors.affiliation: Biomaterials Innovation Research Center, Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, 02139, USA.|Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.|Department of Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, 7500, AE Enschede, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Leijten
authors.affiliation: Biomaterials Innovation Research Center, Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, 02139, USA.|Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Miscuglio
authors.affiliation: Department of Biomechanical Engineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, 7500, AE Enschede, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Rouwkema
authors.affiliation: Biomaterials Innovation Research Center, Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, 02139, USA.|Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors.forename: Mehmet Remzi
authors.initials: MR
authors.lastname: Dokmeci
authors.affiliation: CECS, INSERM U861, I-STEM, AFM, Institute for Stem Cell Therapy and Exploration of Monogenic Diseases, 28 Rue Henri Desbrueres, 91100, Corbeil-Essones, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Nissan
authors.affiliation: CNC-Centre for Neuroscience and Cell Biology, University of Coimbra, 3030-789, Coimbra, Portugal.|Institute for Interdisciplinary Research, University of Coimbra, 3030-789, Coimbra, Portugal.
authors.forename: Lino
authors.initials: L
authors.lastname: Ferreira
authors.affiliation: Biomaterials Innovation Research Center, Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, 02139, USA.|Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.|Department of Physics, King Abdulaziz University, Jeddah, 21569, Saudi Arabia.|Department of Bioindustrial Technologies, College of Animal Bioscience and Technology, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul, 143-701, Republic of Korea.
authors.forename: Ali
authors.initials: A
authors.lastname: Khademhosseini
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D001696:Biomechanical Phenomena; D001808:Blood Vessels / Q000473:pathology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D007249:Inflammation / Q000473:pathology*; D056656:Lab-On-A-Chip Devices; D008148:Lovastatin / Q000494:pharmacology; D044085:Microfluidics; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D011371:Progeria / Q000503:physiopathology*
chemical_list: D000804:Angiotensin II; D008148:Lovastatin
keywords: aging; mechanotransduction; organ-on-a-chip; progeria; vascular disease