DEVELOPMENT OF A TISSUE ENGINEERED INTESTINE

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Induced pluripotent stem cell-derived vascular networks to screen nano-bio interactions

Publication . Estronca, Luís; Francisco, Vitor; Pitrez, Patrícia; Honório, Inês; Carvalho, Lara; Vazão, Helena; Blersch, Josephine; Rai, Akhilesh; Nissan, Xavier; Simon, Ulrich; Grãos, Mário; Saúde, Leonor; Ferreira, Lino

The vascular bioactivity/safety of nanomaterials is typically evaluated by animal testing, which is of low throughput and does not account for biological differences between animals and humans such as ageing, metabolism and disease profiles. The development of personalized human in vitro platforms to evaluate the interaction of nanomaterials with the vascular system would be important for both therapeutic and regenerative medicine. A library of 30 nanoparticle (NP) formulations, in use in imaging, antimicrobial and pharmaceutical applications, was evaluated in a reporter zebrafish model of vasculogenesis and then tested in personalized humanized models composed of human-induced pluripotent stem cell (hiPSC)-derived endothelial cells (ECs) with ‘‘young’’ and ‘‘aged’’ phenotypes in 3 vascular network formats: 2D (in polystyrene dish), 3D (in Matrigel) and in a blood vessel on a chip. As a proof of concept, vascular toxicity was used as the main readout. The results show that the toxicity profile of NPs to hiPSC-ECs was dependent on the ‘‘age’’ of the endothelial cells and vascular network format. hiPSC-ECs were less susceptible to the cytotoxicity effect of NPs when cultured in flow than in static conditions, the protective effect being mediated, at least in part, by glycocalyx. Overall, the results presented here highlight the relevance of in vitro hiPSC-derived vascular systems to screen vascular nanomaterial interactions.

2021-02-12Artigo científico

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

Publication . Pitrez, Patricia R.; Estronca, Luís; Monteiro, Luís Miguel; Colell, Guillem; Vazão, Helena; Santinha, Deolinda; Harhouri, Karim; Thornton, Daniel; Navarro, Claire; Egesipe, Anne-Laure; Carvalho, Tânia; Dos Santos, Rodrigo L.; Lévy, Nicolas; Smith, James C.; de Magalhães, João Pedro; Ori, Alessandro; Bernardo, Andreia; De Sandre-Giovannoli, Annachiara; Nissan, Xavier; Rosell, Anna; Ferreira, Lino

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 chip after a few days of culture; this process is mediated by the upregulation of metalloprotease 13 (MMP13). Importantly, double-mutant LmnaG609G/G609GMmp13-/- mice or LmnaG609G/G609GMmp13+/+ mice treated with a MMP inhibitor show lower SMC loss in the aortic arch than controls. MMP13 upregulation appears to be mediated, at least in part, by the upregulation of glycocalyx. Our HGPS-SMCs chip represents a platform for developing treatments for HGPS individuals that may complement previous pre-clinical and clinical treatments.

2020Artigo científico

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Entidade financiadora

Fundação para a Ciência e a Tecnologia

Número da atribuição

SFRH/BD/71042/2010