Embryologic origin influences smooth muscle cell phenotype modulation signatures in Marfan syndrome aortic aneurysm
by Roxanna Van Norman
October 5, 2022
A study led by a team of researchers at the Stanford School of Medicine has shown that smooth muscle cells activate different genes depending on their embryologic origins, which may help explain why localized aortic root aneurysms form, in particular, in patients with Marfan syndrome.
"Our laboratory is trying to explore novel, high-risk ideas to address aortic aneurysm development and therapeutics. No current drug therapies reliably affect human Marfan syndrome aneurysm growth, perhaps due to limitations in understanding underlying mechanisms,” said Michael Fischbein, MD, PhD, Associate Professor in the Stanford Department of Cardiothoracic Surgery and the senior author of the study. “There is an urgent need to dissect the pathway(s) involved in Marfan syndrome aortic wall matrix breakdown so that mechanistic-based therapies can be developed.”
The researchers hypothesized that normal heart developmental programs might impart a genetic "memory" on cells that may influence their behavior in patients with Marfan syndrome, an inherited connective tissue disorder caused by a genetic mutation. The researchers utilized a lineage-tracing strategy in aortic aneurysm models and applied integrated, lineage-stratified single-cell transcriptomics/epigenomics.
The study was published in Arteriosclerosis, Thrombosis, and Vascular Biology and selected as the featured article for September issue.
Aortic aneurysm research
Citing previous studies, the researchers recognized that cells from different embryologic origins populate the aortic root. They wanted to understand further how cells from distinct lineages behave during aortic aneurysm development, said Albert James (A.J.) Pedroza, MD, a postdoctoral research fellow in Fischbein's Thoracic Aortic Research Laboratory. He is the lead author of the paper.
"This is the first study to integrate single-cell RNA sequencing (gene expression) and DNA accessibility (epigenetics) in aortic aneurysm models," said Pedroza. From this study, the researchers identified new gene regulatory pathways involved in Marfan syndrome smooth muscle cell reprogramming. "This powerful combination enables us to identify critical regulatory genes that may promote aneurysm disease."
As the paper noted, future studies will be necessary to target these regulators and assess their specific functions in aneurysm disease. These studies continue to be the subject of ongoing research in the Fischbein Laboratory.
The paper's authors included Alex R. Dalal, Rohan Shad, Nobu Yokoyama, Ken Nakamura, Paul Cheng, Robert C. Wirka, Olivia Mitchel, Michael Baiocchi, William Hiesinger, and Thomas Quertermous.
This work was supported by various grants from the National Institutes of Health, a Human Cell Atlas grant from the Chan Zuckerberg Foundation, and the American Heart Association.
Michael Fischbein, MD, PhD
AJ Pedroza, MD