Periodic Reporting for period 1 - 3DVasCMD (Development of novel 3D vascularized cardiac models to investigate Coronary Microvascular Disease)
Période du rapport: 2022-04-01 au 2024-09-30
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.
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.
The 3DVasCMD project aims to create advanced 3D models of vascularized cardiac tissue to better understand coronary microvascular disease (CMD). CMD is a serious condition affecting the small blood vessels in the heart, which can lead to heart disease. This project uses cutting-edge techniques to develop human in vitro models to study the disease.
Key Achievements
1. Creating Heart Vessel Models:
• We have successfully grown microvessels (capillaries) from donor-derived stem cells. These vessels are made using cells that have been genetically modified with a fluorescent reporter, making them easier to visualize and study by microscopy.
• We have also developed a method to create mini heart-like tissues with their own blood vessels, which can be used to study how heart muscle cells and blood vessels interact.
2. Improving Techniques for Studying Heart Disease:
• We have created a new way to grow and study heart-like tissue that includes both blood vessels and heart muscle cells. This model can be used to test how different conditions, like reduced blood flow, diabetes and hormonal changes, affect the heart.
• We have developed advanced methods to analyze how these blood vessels and heart tissues communicate with each other.
3. Innovative Use of Technology:
• We have developed a deep learning (AI) system that can analyze images of blood vessels without needing special dyes. This makes it easier and faster to study the structure and function of these tiny vessels.
• Another AI system we developed can predict the metabolic activity of these tissues just by looking at images, which is a groundbreaking way to study cell metabolism.
4. High-Throughput System Development:
• A new system has been designed to test many samples at once, which will speed up the process of finding new drugs for heart disease in the future. This system is currently being optimized to include precise control of fluid flow.
Significant Achievements
• The project has been showcased at several important scientific meetings, introducing our innovative methods and findings to the broader scientific community.
• We are in the process of publishing several scientific papers and filing a patent for our new AI-based analysis methods.
• The project has fostered collaborations with other researchers and institutions, enhancing the impact and reach of our work.
Key Achievements
1. Creating Heart Vessel Models:
• We have successfully grown microvessels (capillaries) from donor-derived stem cells. These vessels are made using cells that have been genetically modified with a fluorescent reporter, making them easier to visualize and study by microscopy.
• We have also developed a method to create mini heart-like tissues with their own blood vessels, which can be used to study how heart muscle cells and blood vessels interact.
2. Improving Techniques for Studying Heart Disease:
• We have created a new way to grow and study heart-like tissue that includes both blood vessels and heart muscle cells. This model can be used to test how different conditions, like reduced blood flow, diabetes and hormonal changes, affect the heart.
• We have developed advanced methods to analyze how these blood vessels and heart tissues communicate with each other.
3. Innovative Use of Technology:
• We have developed a deep learning (AI) system that can analyze images of blood vessels without needing special dyes. This makes it easier and faster to study the structure and function of these tiny vessels.
• Another AI system we developed can predict the metabolic activity of these tissues just by looking at images, which is a groundbreaking way to study cell metabolism.
4. High-Throughput System Development:
• A new system has been designed to test many samples at once, which will speed up the process of finding new drugs for heart disease in the future. This system is currently being optimized to include precise control of fluid flow.
Significant Achievements
• The project has been showcased at several important scientific meetings, introducing our innovative methods and findings to the broader scientific community.
• We are in the process of publishing several scientific papers and filing a patent for our new AI-based analysis methods.
• The project has fostered collaborations with other researchers and institutions, enhancing the impact and reach of our work.
We have established a unique vascularized cardiac model that allows for investigating cellular cross-talk between cardiac microvessels and muscle cells. This unprecedented model will enable us to investigate the combined cardiac-vascular response to alterations in the microenvironment (reduced flow, diabetes, and sex hormones) and may lead to new targets of coronary microvascular disease. Our focus now, is developing the complete model in a donor specific manner.
Our AI-based models already represent a significant advancement in the field. They allow for detailed analysis of morphologic features of blood vessels (an indicator of vascular health) without the need for traditional labeling techniques, which can be applied to various imaging technologies.
Our AI-based models already represent a significant advancement in the field. They allow for detailed analysis of morphologic features of blood vessels (an indicator of vascular health) without the need for traditional labeling techniques, which can be applied to various imaging technologies.