Active Research Programs:

1) hiPSC Disease Modeling of Thoracic Aortic Aneurysm

Thoracic aortic aneurysm (TAA) is one of the leading causes of death in the United States. The current treatment is limited to surgical intervention, and there is an urgent need for a better understanding of the molecular mechanisms underlying TAA formation and progression. We use human induced pluripotent stem cells, gene editing and lineage-specific cell differentiation to understand the molecular and cellular mechanisms of TAA formation.

2) Characterization of Genetic Variants associated with Congenital Heart Defects using Genomics Approaches

We aim to identify protein-coding and regulatory genetic variants associated with congenital heart defects including bicuspid aortic valve (BAV) which affects 1-2% of the population. We also functionally characterize the role of these variants in disease formation using in vitro models.

We have adapted single cell approaches to reveal the molecular defects caused by disease variants both in vitro and in vivo. Recently, we demonstrated the heterogeneity of smooth muscle cells derived from conventional differentiation protocols and characterized the global transcriptional changes caused by an LDS-associated mutation. Furthermore, we are applying spatial transcriptomics approaches to map transcriptional changes in surgical specimens from patients with various aortic diseases.

3) Bioengineered blood vessels to model Thoracic Aortic Aneurysm

A major obstacle in TAA research is that human tissue is not available in the early clinically-silent phase of the disease, and end-stage tissue collected during surgical repair is likely to have endured cellular and molecular changes over many years, obscuring the early molecular causes of the disease. Development of better models is essential in uncovering the temporal molecular changes during aneurysm formation and to ultimately screen drugs. To model aortic aneurysms, we seed SMCs derived from isogenic control (WT) and knock-in (KI) hiPSCs on polyglycolide (PGA) mesh, and culture them in vitro. Both WT and KI iPSC-TEBVs appear opaque, and have mechanical properties similar to native vessels after 8 weeks. We also obtain primary SMCs from normal donor and diseased aortic tissues, and use them for TEBV generation to model aortic aneurysm.

In collaboration with CAMTraST, we use immunodeficient rabbit and rat models to implant the TEBVs, and to capture clinical aneurysm features. We are utilizing this powerful platform to screen drugs against pathogenic variants associated with thoracic aortic aneurysm.

4) Outcome based Clinical Research

Our clinical team focuses on developing novel and effective techniques to improve the surgical outcome of various procedures targeting thoracic aortic aneurysm and dissection. We have built large databases and tissue banks of patients with aortic dissection and BAV to follow long-term outcomes and for subsequent molecular studies.

Relevant Publications:

Zhou et al., Circulation 2021: hiPSC Modeling of Lineage-Specific Smooth Muscle Cell Defects Caused by TGFBR1A230T Variant, and its Therapeutic Implications for Loeys-Dietz Syndrome.

Navarro et al., Biomaterials 2021: Biomimetic tubular scaffold with heparin conjugation for rapid degradation in in situ regeneration of a small diameter neoartery.

Yang JCTVS Tech. 2021: A novel simple technique to enlarge the aortic annulus by two valve sizes.

Song et al., Stem Cell Reports 2021: Development of the Nude Rabbit Model.

Gong et al., ATVB 2020: In Vitro Lineage-Specific Differentiation of Vascular Smooth Muscle Cells in Response to SMAD3 Deficiency.

Yang et al., Circulation 2018: Endovascular Fenestration/Stenting First Followed by Delayed Open Aortic Repair for Acute Type A Aortic Dissection With Malperfusion Syndrome.

Yang et al., Nature Communications 2017: Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve.