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Purpose of the Review <p>Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by mutations in <i>FBN1</i>, leading to cardiovascular complications, including aortic aneurysms and dissections. Progress in discovering pharmacological treatments to prevent or delay these manifestations has been limited because current models, including animal models and human aortic tissue samples, fail to capture MFS's genetic and phenotypic heterogeneity. Induced pluripotent stem cell (iPSC)-derived vascular models offer a promising alternative. iPSCs retain patient-specific genetic backgrounds and can differentiate into relevant vascular cell types, including endothelial cells and vascular smooth muscle cells.</p> Recent Findings <p>iPSC-derived models have uncovered novel therapeutic targets, including integrin αV and GSK3β, and enabled high-throughput drug screening platforms. Additionally, 3D bioengineered vascular constructs and microfluidic artery-on-a-chip platforms are advancing the field by integrating biomechanical forces and tissue architecture to better mimic the aortic wall's complexity. Despite these advancements, the immaturity and heterogeneity of iPSC-derived vascular cells remain significant challenges.</p> Summary <p>We discuss the challenges of studying MFS and strategies to enhance current iPSC models by developing multicellular 3D vascular models that more accurately mimic the structure and biomechanics of the aorta. Future research is needed to improve iPSC vascular cell maturation and develop multilayered 3D vascular models to better understand disease pathogenesis and advance precision medicine approaches for MFS.</p>

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Harnessing iPSCs to Model Marfan Syndrome: Advancing Clinical Diagnosis and Drug Discovery

  • 期刊论文

  • 发表日期：

    2025年2月12日

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  • Zina Zein Abdin,
  • Hao Yin,
  • Caitlin Giannis,
  • Ryan Hsieh,
  • J. Geoffrey Pickering,
  • Mark Chandy

摘要

Purpose of the Review

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by mutations in FBN1, leading to cardiovascular complications, including aortic aneurysms and dissections. Progress in discovering pharmacological treatments to prevent or delay these manifestations has been limited because current models, including animal models and human aortic tissue samples, fail to capture MFS's genetic and phenotypic heterogeneity. Induced pluripotent stem cell (iPSC)-derived vascular models offer a promising alternative. iPSCs retain patient-specific genetic backgrounds and can differentiate into relevant vascular cell types, including endothelial cells and vascular smooth muscle cells.

Recent Findings

iPSC-derived models have uncovered novel therapeutic targets, including integrin αV and GSK3β, and enabled high-throughput drug screening platforms. Additionally, 3D bioengineered vascular constructs and microfluidic artery-on-a-chip platforms are advancing the field by integrating biomechanical forces and tissue architecture to better mimic the aortic wall's complexity. Despite these advancements, the immaturity and heterogeneity of iPSC-derived vascular cells remain significant challenges.

Summary

We discuss the challenges of studying MFS and strategies to enhance current iPSC models by developing multicellular 3D vascular models that more accurately mimic the structure and biomechanics of the aorta. Future research is needed to improve iPSC vascular cell maturation and develop multilayered 3D vascular models to better understand disease pathogenesis and advance precision medicine approaches for MFS.