Biomechanical Stress and Inflammation Linked Using Muscle Cells

A team of biomedical engineers used induced pluripotent stem cells from patients with Hutchinson-Gilford progeria syndrome (HGPS) to investigate the relationship between biomechanical stress and inflammation in an organ-on-a-chip device that mimicked the microenvironment of the cardiovascular system.

HGPS is a premature aging disease showing accelerated vascular aging, leading to the death of patients at an early age due to cardiovascular diseases. The syndrome targets primarily vascular cells, which reside in mechanically active tissues. It has been difficult to study vascular aging in the laboratory, as most models fail to mimic the biomechanics that cells experience in the body.

Investigators at Brigham and Women's Hospital developed an organ-on-a-chip model system that enabled the effects of biomechanical strain to be examined in the context of vascular aging and disease. The device consisted of a top fluidic channel and underlying vacuum channel, which mimicked, upon pressure, the mechanical stretching that cells experience within blood vessels.

The investigators loaded the device with smooth muscle cells (SMCs) derived from pluripotent stem cells taken from either normal donors or from patients with HGPS. They reported in the February 17, 2017, online edition of the journal Small that physiological strain induced a contractile phenotype in primary smooth muscle cells, while a pathological strain induced a hypertensive phenotype similar to that of angiotensin II treatment. SMCs derived from human induced pluripotent stem cells of HGPS donors (HGPS iPS-SMCs), but not from healthy donors, showed an exacerbated inflammatory response to strain. In particular, increased levels of inflammation markers as well as DNA damage were observed. Drug treatment reversed the strain-induced damage by shifting the gene expression profile away from inflammation.

The progeria-on-a-chip model was deemed to be 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. "Vascular diseases and aging are intimately linked yet rarely studied in an integrated approach," concluded the investigators. "Gaining a deeper understanding of the molecular pathways regulating inflammation during vascular aging might pave the way for new strategies to minimizing cardiovascular risk with age."