Modeling Thoracic Aortic Dissection Using Patient-Specific iPSCs Reveals VSMC Dysfunction and Extracellular Matrix...

Area of Science:

• Cardiovascular Biology
• Stem Cell Biology
• Genetics

Background:

• Thoracic aortic dissection (TAD) is a fatal condition with poorly understood mechanisms.
• Vascular smooth muscle cell (VSMC) dysfunction is a key feature of TAD.
• Currently, no effective medical therapies exist for TAD.

Purpose of the Study:

• To generate patient-specific induced pluripotent stem cells (iPSCs) from TAD patients.
• To model TAD pathogenesis using iPSC-derived VSMCs.
• To investigate the molecular mechanisms underlying TAD.

Main Methods:

• Generated iPSCs from TAD patients and healthy controls using nonintegrated episomal vectors.
• Differentiated iPSCs into VSMCs.
• Performed whole-exome sequencing to identify genetic mutations.
• Analyzed VSMC contractility, extracellular matrix (ECM) protein expression, and TGF-β signaling.

Main Results:

• TAD-iPSC-derived VSMCs showed significantly reduced contractility.
• A COL4A2 gene mutation (c.392G>T, p. R131M) was identified in TAD-iPSCs.
• TAD-VSMCs exhibited altered collagen expression (decreased Collagen IV, increased Collagen I/III) and hyperactivated TGF-β signaling with elevated MMP9.

Conclusions:

• Patient-specific iPSC-derived VSMCs provide a model for TAD.
• Dysfunctional VSMC contractility, ECM remodeling, and aberrant TGF-β signaling contribute to TAD pathogenesis.
• These findings offer insights into TAD mechanisms and potential therapeutic strategies.