Featured Poster: Utilizing an induced pluripotent stem cell platform to model arterial calcification resulting from deficiency of CD73

Friday, September 8, 2023

4:30 PM – 4:45 PM EDT

Location: Constitution Foyer

Speaker(s)

Chikage Noishiki, MD, PhD (she/her/hers)

Postdoctoral Scholar
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford University, Stanford, CA 94304, USA
Mountain View, California, United States

Co-Author(s)

TA

Tom Alsaigh, MD

Vascular Medicine Fellow
Division of Vascular Surgery, Stanford University School of Medicine, Stanford, CA 94304, USA, United States
DW

David Wu, BS

Life Science Research Professional
Stanford Cardiovascular Institute, Stanford University, Stanford, CA 94305, USA, United States
SA

Shaunak Adkar, MD, PhD

Vascular Surgery Resident
Division of Vascular Surgery, Stanford University School of Medicine, Stanford University, Stanford, CA 94304, USA, United States
VC

Venita Chandra, MD

Clinical Professor
Division of Vascular Surgery, Stanford University School of Medicine, Stanford University, Stanford, CA 94304, USA, United States
DK

Derek Klarin, MD

Assistant Professor
Division of Vascular Surgery, Stanford University School of Medicine, Stanford University, Stanford, CA 94304, USA, United States
JL

Jason Lee, MD

Professor
Division of Vascular Surgery, Stanford University School of Medicine, Stanford University, Stanford, CA 94304, USA, United States
Eri Fukaya, MD, PhD

Clinical Associate Professor, Vascular Surgery and Medicine
Stanford University
Palo Alto, California, United States
NL

Nicholas Leeper

Stanford Vascular Surgery
NS

Nazish Sayed, MD, PhD

Assistant Professor
Stanford Cardiovascular Institute, Division of Vascular Surgery, Stanford University School of Medicine, Stanford, CA 94304, USA, United States

Description of Background: Vascular calcification is prevalent in atherosclerosis, diabetes and chronic kidney disease, and affected patients often suffer from significant morbidity and mortality related to complications of disease progression. The pathophysiology is not well known, and studies suggest involvement of a complex dynamic process between bone development and metabolism. The protein encoded by CD73 (NT5E) is involved in the conversion of AMP to Adenosine, a pathway necessary to block physiologic calcification and mutations in NT5E have been associated with arterial calcification. Arterial Calcification due to Deficiency of CD73 (ACDC) is a rare and poorly understood adult-onset vasculopathy consisting of large build-up of calcium.

Methods: We perform whole genome sequencing (WGS) of arterial tissue from a patient with severe arterial calcification of unknown etiology requiring serial limb amputations in the setting of poor extremity perfusion. We identified three culprit variant NT5E gene mutations known to affect patients with ACDC. Furthermore, to understand the ACDC pathophysiology in-a-dish, we generated induced pluripotent stem cells (iPSC) from the patient’s PBMCs and differentiated them to endothelial (ECs) and smooth muscle cells (SMCs).

Results: Patient-specific iPSC-ECs exhibited endothelial dysfunction as evident by their decreased capacity to form vascular networks or generate nitric oxide.

Conclusion: These results lay the groundwork to unravel the mechanisms underlying ACDC by conducting genome editing experiments to precisely identify the NT5E variant responsible for disease severity. Importantly, our iPSC platform provides an opportunity to set up drug screening experiments to evaluate treatment options for afflicted patients.

Learning Objective: 1. Understand the pathophysiology of arterial calcification due to deficiency of CD73 (ACDC) and its association with the NT5E gene mutations.
2. Learn about the use of whole genome sequencing (WGS) and induced pluripotent stem cells (iPSCs) to study the ACDC pathophysiology in-a-dish.
3. Understand the potential of iPSCs as a platform for drug screening experiments to evaluate treatment options for patients with ACDC.