Human iPSCs-Derived 3D-Perfused Model of Vascular Malformation
Abstract
Topic Area: This proposal targets vascular malformations, which is one of the topic areas of the FY21 Peer Reviewed Medical Research Program (PRMRP). The Critical Problem to Be Addressed: Vascular malformations (VMs) refer to malformed blood vessels. They are heterogeneous groups of diseases affecting a large population. VMs are caused by genetic mutations (either inherited at birth or occur after birth) in genes involved in blood vessel development. Because blood vessels are everywhere in the body, disorganized blood vessels can cause a variety of symptoms from mild to life-threatening, depending on the affected tissue/organ. VMs have a major impact on the quality of life of patients; they are painful and disfiguring, and many lead to bleeding, recurrent infections, thrombosis, organ dysfunction, and even death. Current therapies for VMs are very limited; the only options are laser treatment and surgery. However, these treatments are insufficient, and patients often experience a high risk of recurrence and progression. In addition, surgical treatment cannot be applied to tissues that are critical for normal function such as certain areas of the brain. Therefore, there is a critical need to develop pharmacological treatment for VMs. However, doing so requires the development of in vivo or in vitro models of VMs that recreate the disease pathology of human VMs. The Innovation of the Idea: Currently, the only available models to study VMs are mice or zebrafish. However, they do not fully replicate the disease and therapeutic response in humans. There is no human cell-based model of VMs. This proposal brings three innovative areas to address unmet needs to create humanized model of VMs: (1) 3D bioprinting technology to create multiscale perfused vasculature, which allows native vascular remodeling with flow perfused through the vascular lumen; (2) brain-specific microvasculature, which mimics brain tissue microenvironment; (3) induced pluripotent stem cell-derived endothelial cells with fluorescent reporter to allow real-time monitoring of vascular formation and respond to drug treatment. The Ultimate Applicability and Impact of the Research: This project will lead to several VM models using human cells that allow identifying novel drug targets, screening existing drugs, and/or elucidating the pathogenesis of the disease. In the future, other types of VMs caused by various mutations can be easily established and studied. In addition, VMs models can be established directly using patient-derived cells, without knowing the specific mutation. This will allow personalized medicine to quickly test candidate therapies for specific patients, even before the molecular mechanisms are fully understood for a particular VM.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210022
Entities
People
- Guohao Dai
Organizations
- Northeastern University
- United States Army