Vascular Organoids to Model Inherited Vascular Diseases
Abstract
Introduction: Pulmonary hypertension (PH) is a devastating disease with a very poor prognosis, mostly affecting young adult women. It is characterized by narrowing of the arteries leading from the heart to the lungs that results in elevation in pressure. If left untreated, this cardiopulmonary condition can lead to failure of the right heart and premature death. Dysfunction of the pulmonary endothelial cells that covers the inner layer of the blood vessel and an imbalance between molecules that promote vasodilation (nitric oxide), and vasoconstriction (Endothelin) are believed to be the major contributors to PH. In addition, excessive proliferation (i.e., a rapid increase in cell numbers) of the pulmonary artery smooth muscle cells (SMC), impaired apoptosis (i.e., cell death), mutations in activin receptor-like kinase 1 (ACVRL1 or ALK1) and inflammation have all been implicated in the process of vascular remodeling commonly seen in PH. Over the past 20 years, significant advances have been made in the treatment of PH, and there are now more than 10 drugs targeting the endothelin, nitric oxide and prostacyclin pathway with tremendous impact on patient prognosis and quality of life. Yet, despite these progresses, there is no cure for PH, and there is no treatment that can halt the process of vascular arterial remodeling (VAR) seen in this condition. One of the major barriers into making major inroads in the treatment of PH or enabling a deeper understanding of its causes is the lack of readily accessible human tissue samples. For the most part, PH research has relied on tissue explanted at the time of lung transplantation or autopsy samples that are usually collected from patients with end-stage PH and as such are reflective of very advanced disease. Laboratory animal models or heterologous cell systems (i.e., cells belonging to different organisms) have been used to validate some of the observations from human tissues, but because their physiology is distinctly non-human, they lack direct human translational potential and are often poorly predictive of patient outcomes. The ability to generate human species-specific, and even patient-specific, induced-pluripotent stem cells (iPSCs) that can be transformed into a variety of cell types including smooth muscle cells (SMCs) and endothelial cells (ECs) now provides the opportunity to examine the underlying mechanisms of many disease in derived human cells. Using iPSC, many forms of hereditary diseases have been successfully recapitulated in vitro (inherited mutations causing cardiac disease, muscular dystrophy, and a variety of neurodegenerative diseases), allowing for insights into their mechanisms and potential for targeted therapeutic options. Summary of Goals and Objectives: The objective of this proposal is to apply the iPSC platform to study pulmonary vascular disease by generating vascular organoids from patient-specific iPSCs that harbor the ALK1 mutations identified in subjects with hereditary PH, and to compare those cells to similar ones obtained from healthy control subjects, matched for age and sex. The ALK1 mutation is particularly important because carriers of this genetic abnormalities develop the syndrome of hereditary hemorrhagic telangiectasia (HHT) where in addition to VAR characteristic of PH, vascular malformations of the arteries and the veins known as arteriovenous malformations (AVMs) are also seen in lung, liver, spleen, or brain. These AVMs are susceptible to rupture and hemorrhage, leading to major morbidity and mortality from recurrent bleeding or stroke. No molecular therapy is presently available for carriers of these mutation. With this platform, the goal is to recapitulate the disease in vitro and create a new model system for this condition. The research is centered on characterizing iPSC-derived 3D vascular organoids harboring the ALK1 mutation both in a dish (i.e., in vitro) as well as in vivo after transplantation in a receptive host, wher
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210679
Entities
People
- Maria Trivieri
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army