Revolutionizing Heart Research: A New Dawn
Discover how new technologies are reshaping our understanding of heart diseases.
Meenakshi Suku, Jack F. Murphy, Sara Corbezzolo, Manus Biggs, Giancarlo Forte, Irene C. Turnbull, Kevin D. Costa, Lesley Forrester, Michael G Monaghan
― 7 min read
Table of Contents
- Old Research Methods
- A New Hope: Induced Pluripotent Stem Cells
- Building Heart Models
- Meet the Star Players: Macrophages and Cardiomyocytes
- Cardiomyocytes
- Macrophages
- Why They Matter
- The Challenge of Studying Macrophages
- iMacs: The New Players
- Giving iMacs a Cardiac Edge
- The Experiment
- Results of the Experiment
- Changes in iMacs
- The Heart’s Reaction
- Testing the Waters: Electrical Stimulation
- Results of Electrical Stimulation
- Creating 3D Engineered Cardiac Tissues
- The Process
- The Outcome
- Looking Ahead: The Future of Heart Research
- The Big Picture
- Conclusion: A Heartfelt Journey
- Original Source
Heart diseases are a big problem for people all over the world. They affect many lives and are one of the top reasons for deaths. Conditions can range from irregular heartbeats to heart failure, and they make it tough for those who are diagnosed. Scientists have been trying to figure out how to better understand and cure these heart problems, but traditional methods of research have often hit a wall.
Old Research Methods
For a long time, researchers used animals for experiments to learn about heart issues. However, this method has its flaws. The way a human heart works is different from how animal hearts function. Animal cells provide some insights, but they don’t show all the details that human heart cells do. This means that many important aspects could be missed.
Induced Pluripotent Stem Cells
A New Hope:Recently, a new technology called induced pluripotent stem cells (iPSCs) has come into play. This is a game changer! Scientists take adult cells and reprogram them to act like stem cells, which can turn into any type of cell in the body, including heart cells. This technique has opened up opportunities to study human heart cells outside of the body.
Building Heart Models
With iPSCs, researchers have begun creating models of human heart tissue in the lab. They try out different combinations of cells and materials to mimic how the heart behaves. These lab-made hearts can come in various forms, such as small clusters of cells (organoids), tiny devices that simulate heart functions (organ-on-a-chip), or larger engineered heart tissues.
Using these models, scientists can study how heart cells interact with each other and how they respond to various signals. The hope is that these experiments will lead to better treatments for heart diseases.
Macrophages and Cardiomyocytes
Meet the Star Players:Within the heart, there’s a team of cells that play crucial roles. Two important players are macrophages and cardiomyocytes. Let’s break these down:
Cardiomyocytes
Cardiomyocytes are the heart’s muscle cells. They help the heart pump blood and get oxygen to our organs. These cells need to mature properly to function well. When they're not fully developed, the heart can't work efficiently.
Macrophages
Macrophages are part of the immune system and act like the body’s cleanup crew. They help keep the heart healthy by clearing out damaged cells and helping with recovery after injuries like a heart attack. In the heart, a specific type of macrophage called cardiac resident macrophages (CRMs) is abundant.
Why They Matter
Both of these cell types are essential for heart health. Cardiomyocytes need to be in good shape to pump blood, and macrophages need to be ready to assist when things go wrong. If we wish to create heart tissues that work like a real heart, we need to understand both cell types and how to help them thrive.
The Challenge of Studying Macrophages
Despite their importance, studying CRMs has been tricky. Many researchers have had to rely on macrophages that come from blood, which don’t replicate the behaviors of CRMs very well. However, scientists are now looking into iPSC-derived macrophages (iMacs) as a potential golden ticket.
iMacs: The New Players
iMacs are derived from iPSCs and are thought to share characteristics with the CRMs found in the heart. They have the potential to mimic the functions of these heart macrophages better than traditional blood-derived macrophages.
Giving iMacs a Cardiac Edge
In the quest to make iMacs more like CRMs, researchers have tried several strategies. They decided to expose iMacs to special signals from cardiomyocytes, either through conditioned media (the liquid around cardiomyocytes that contains various growth factors) or by co-culturing them together (growing them side by side).
The Experiment
Here’s what they did: First, the researchers took iMacs and cardiomyocytes and brought them together. They looked at how the iMacs responded to various signals from the cardiomyocytes. They observed that the iMacs began to change their behavior, looking more like the CRMs in healthy hearts.
Results of the Experiment
The results were quite illuminating!
Changes in iMacs
When treated with cardiomyocyte signals, the iMacs showed noticeable changes. They began to express different markers that help identify them as true cardiac resident macrophages. They even became less reactive to inflammatory signals, showing they were more in tune with the peaceful environment of the heart.
The Heart’s Reaction
Not only did the iMacs change, but the cardiomyocytes also benefitted. The presence of iMacs helped the cardiomyocytes grow and mature better than they would on their own. They became more elongated and improved their ability to handle calcium, which is vital for heart contractions.
Testing the Waters: Electrical Stimulation
To test if they could push the cardiac cells even further, the researchers decided to use electrical stimulation on their heart models. This process mimics the natural electrical signals that occur in a healthy heart, so it was worth a shot to see if it would promote further maturation in both iMacs and cardiomyocytes.
Results of Electrical Stimulation
Sure enough, when they applied electrical signals, the cardiomyocytes matured even more, displaying stronger contractions and more adult-like characteristics. Meanwhile, the iMacs also showed improved behaviors, reacting positively to the stimulation without becoming overly aggressive or inflammatory.
Creating 3D Engineered Cardiac Tissues
Having seen success with the 2D models, the researchers wanted to take things a step further. They set out to create 3D engineered cardiac tissues (ECTs) using iMacs and cardiomyocytes. With ECTs, the hope was to create a model that better mimicked the actual heart.
The Process
The researchers mixed iMacs and cardiomyocytes with special gels to create a gel-like structure, allowing the cells to grow together in a 3D space. This setup is crucial because it allows for better cell contact and communication, which are key for healthy tissue function.
The Outcome
The engineered tissues with iMacs exhibited improved alignment and structure compared to those without. They were also better at beating in sync, which is essential for a functioning heart. In other words, the addition of iMacs not only made for a more robust tissue but also improved its function.
Looking Ahead: The Future of Heart Research
This study paves the way for better understanding and modeling of heart cells, especially how to manage and treat heart diseases. By using iPSC technology, researchers can study human heart cells directly, leading to more effective therapies. Additionally, the integration of different cell types, like iMacs, can provide insights into the complex interplay between various cells in the heart.
The Big Picture
Ultimately, the goal is to create heart models that can be used for drug testing, studying disease mechanisms, and eventually helping to regenerate damaged heart tissues. With this knowledge, the hope is to offer patients better treatment options and improve outcomes for those with heart diseases.
Conclusion: A Heartfelt Journey
In the quest to understand heart diseases and improve treatments, this study highlights the potential of using iPSC-derived cells. By bringing together macrophages and cardiomyocytes, scientists have taken steps towards creating a functioning heart model. Not only does this research offer new hope for understanding heart health, but it also provides a fun peek into the future of regenerative medicine.
In short, the heart keeps on beating, and with these new methods and models, researchers are hopeful they can keep it pumping for many more years to come! Thank you for joining this journey into the world of heart cells. Who knew studying the heart could be so exciting?
Title: Synergistic generation of cardiac resident-like macrophages and cardiomyocyte maturation in tissue engineered platforms
Abstract: Cardiovascular disease stands as the leading cause of death globally, claiming approximately 19million lives in 2020. On the contrary, the development of cardiovascular drugs is experiencing a decline, largely due to the bottleneck in understanding the pathophysiology of various heart diseases and assessing the effects of drugs on healthy human hearts. The development of induced pluripotent stem cell (iPSC) technology and the availability of cardiac cell types in vitro, has resulted in a surge in efforts to fabricate human cardiac models for disease modelling and drug discovery applications. Although numerous attempts evidence successful fabrication of 3 dimensional (3D) engineered heart tissues, the innate immune cell population of the myocardium - particularly cardiac macrophages, was until recently, overlooke. With increasing appreciation of the interactions between cardiomyocytes and macrophages in the myocardium, in this work, isogenic populations of cardiac resident-like macrophages and cardiomyocytes were generated using iPSCs, to understand the interactions between the two cell types in both 2D and 3D settings, and subjected to electric stimulation. After characterizing iPSC-derived macrophages (iMacs) and iPSC-derived cardiomyocytes (iCMs) in depth, the conditioning of iMacs to align to a cardiac resident macrophage-like phenotype in the presence of iCMs in 2D culture was explored. In co-culture with iCMs, iMacs upregulated known genes expressed by cardiac resident macrophages. Additionally, in co-culture with iMacs, iCMs displayed an elongated morphology, improved calcium function and an increase in known maturation genes such as the ratio between MYH7 and MYH6 as well as SERCA2. In a 2D setting, iMacs showed the ability to electrically couple with iCMs and facilitate synchronous beating in iCM cultures. The 2D characterisation was translated into an engineered cardiac tissue model, wherein, improvement in tissue characteristics in the presence of iMacs was demonstrated in terms of increased cell alignment, enhanced cardiomyocyte elongation, physiologically relevant beat rates and improved tissue compaction. Taken together, these findings may open new avenues to use iMacs in engineered cardiac tissue models, not only as an innate immune cell source, but also as a support cell type to improve cardiomyocyte function and maturation.
Authors: Meenakshi Suku, Jack F. Murphy, Sara Corbezzolo, Manus Biggs, Giancarlo Forte, Irene C. Turnbull, Kevin D. Costa, Lesley Forrester, Michael G Monaghan
Last Update: Dec 7, 2024
Language: English
Source URL: https://www.biorxiv.org/content/10.1101/2024.12.04.626684
Source PDF: https://www.biorxiv.org/content/10.1101/2024.12.04.626684.full.pdf
Licence: https://creativecommons.org/licenses/by-nc/4.0/
Changes: This summary was created with assistance from AI and may have inaccuracies. For accurate information, please refer to the original source documents linked here.
Thank you to biorxiv for use of its open access interoperability.