Development of novel 3D vascularized cardiac models to investigate Coronary Microvascular Disease
Coronary microvascular disease (CMD) is a significant healthcare challenge, contributing to ischemic heart disease, the leading global cause of mortality. CMD is associated with dysfunction of small coronary vessels due to aging, obesity, and metabolic diseases, leading to reduced blood flow and oxygenation in the heart (Figure on background). Despite its widespread impact on health, our understanding of CMD is limited to animal studies, which do not accurately replicate human pathophysiology and fail to reveal cellular interactions in a controlled manner. Consequently, there is an urgent need for a humanized in vitro model to mimic CMD.
The primary objective of the 3DVasCMD project is to develop novel, physiologically accurate, in vitro tool to understand the pathophysiology of CMD. By leveraging advances in organ-on-chip and induced pluripotent stem cell (iPSC) technologies, along with state-of-the-art 3D humanized vascular models, this project aims to investigate CMD more effectively. The specific goals are to (Overview figure):
1. Develop and characterize a 3D vascularized cardiac model.
2. Determine the impact of known risk factors on CMD pathophysiology.
3. Create a high-throughput system for cardiovascular drug screening.
Our approach involves integrating autologously-differentiated iPSCs (cells from the same donor) in a controlled fluidic environment, enabling unprecedented studies of ischemia (reduced blood flow), diabetes, and sex-hormone contributions to CMD using 3D in vitro tissues. Ultimately, a high-throughput version of our model, combined with machine learning, will predict the effectiveness of therapeutic targets.
Expected Impact
3DVasCMD will significantly advance our understanding of how microenvironmental and heritable risk factors contribute to CMD. This model will provide a comprehensive tool for studying multiple facets of vascular disease, offering insights into pathological mechanisms and potential therapeutic targets. The expected impacts of the project include:
1. Improved Understanding of CMD: By developing a humanized in vitro model, we will bridge the gap between current animal models and human physiology, offering more relevant insights into this common condition.
2. Drug Discovery and Testing: The high-throughput system will facilitate cardiovascular drug screening, identifying effective therapeutic compounds and predicting off-target effects, thereby accelerating drug development.
3. Precision Medicine: Our model will enable personalized treatment approaches by accounting for patient-specific factors such as genetic background and sex-specific differences, ultimately improving clinical outcomes.
4. Scientific and Clinical Integration: The interdisciplinary nature of 3DVasCMD, combining tissue engineering, stem cell biology, and advanced imaging, will foster collaborations between scientific and clinical communities, enhancing the translational potential of our findings.
By addressing these critical aspects, 3DVasCMD aims to revolutionize CMD research and treatment, contributing to reduced mortality and improved quality of life for patients worldwide.
