Endothelial-Smooth Muscle Cell Interactions in a Shear-Exposed Intimal Hyperplasia on-a-Dish Model to Evaluate Therapeutic Strategies

Andreia Fernandes, Arnaud Miéville, Franziska Grob, Tadahiro Yamashita, Julia Mehl, Vahid Hosseini, Maximilian Y. Emmert, Volkmar Falk, Viola Vogel

研究成果: Article査読

抄録

Intimal hyperplasia (IH) represents a major challenge following cardiovascular interventions. While mechanisms are poorly understood, the inefficient preventive methods incentivize the search for novel therapies. A vessel-on-a-dish platform is presented, consisting of direct-contact cocultures with human primary endothelial cells (ECs) and smooth muscle cells (SMCs) exposed to both laminar pulsatile and disturbed flow on an orbital shaker. With contractile SMCs sitting below a confluent EC layer, a model that successfully replicates the architecture of a quiescent vessel wall is created. In the novel IH model, ECs are seeded on synthetic SMCs at low density, mimicking reendothelization after vascular injury. Over 3 days of coculture, ECs transition from a network conformation to confluent 2D islands, as promoted by pulsatile flow, resulting in a “defected” EC monolayer. In defected regions, SMCs incorporated plasma fibronectin into fibers, increased proliferation, and formed multilayers, similarly to IH in vivo. These phenomena are inhibited under confluent EC layers, supporting therapeutic approaches that focus on endothelial regeneration rather than inhibiting proliferation, as illustrated in a proof-of-concept experiment with Paclitaxel. Thus, this in vitro system offers a new tool to study EC-SMC communication in IH pathophysiology, while providing an easy-to-use translational disease model platform for low-cost and high-content therapeutic development.

本文言語English
論文番号2202317
ジャーナルAdvanced Science
9
28
DOI
出版ステータスPublished - 2022 10月 5

ASJC Scopus subject areas

  • 医学(その他)
  • 化学工学(全般)
  • 材料科学(全般)
  • 生化学、遺伝学、分子生物学(その他)
  • 工学(全般)
  • 物理学および天文学(全般)

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