Interwoven heart muscle cells (cardiomyocytes) and supporting cells (fibroblasts).

Decoding Heart Health: How Fibroblasts and Cardiomyocytes Team Up (and Clash) in Engineered Tissue

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Kai Mendoza in Health & Wellness November 2026 • 4 min read.

"Unlocking the secrets of heart tissue engineering: A look at the surprising roles of fibroblasts and cardiomyocytes in creating functional heart muscle."


For years, scientists have strived to recreate the complex structure and function of the human heart in the lab. One promising approach is engineered heart muscle (EHM), which involves building functional heart tissue from cells and supportive materials. But how do these components work together to create a beating, force-generating tissue?

Recent research has shed light on the surprising roles of two key cell types: fibroblasts and cardiomyocytes. Cardiomyocytes are the heart muscle cells responsible for contraction, while fibroblasts are cells that provide structural support and produce the extracellular matrix (ECM), the scaffolding that holds cells together. It turns out that these cells have a complex and sometimes conflicting relationship that's crucial for EHM development.

This article explores the fascinating interplay between fibroblasts and cardiomyocytes in EHM, diving into the latest findings on how they influence tissue stiffening, cell organization, and overall heart muscle function. Understanding this cellular dance could pave the way for better heart disease treatments and regenerative therapies.

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From Feasibility to First-in-Human Study

A January 29, 2025 report describes feasibility, safety, and efficacy data for engineered heart muscle allografts. Those findings provided the pivotal basis for approval of a first-in-human clinical trial on tissue-engineered heart repair. Nature later reported promising early outcomes in patients with treatment-refractory advanced heart failure with reduced left ventricular function. Separately, studies in nude rats reported notable macrophage infiltration and improved outcomes after implantation of engineered heart muscle.

Building More Human-Like Heart Models

Human pluripotent stem cells are widely used to study human heart pathophysiology, but the immaturity of their derivative cardiomyocytes has largely limited disease modeling to cardiac ion-channel disorders. Advances in tissue engineering and organoids have opened opportunities to study diseases beyond those channelopathies. One defined, serum-free protocol generates engineered human myocardium from pluripotent stem cells in multi-well plates, producing up to 48 constructs in parallel for drug screening and disease modeling. Tissue-engineered myocardium is also being developed to deliver stem cell-derived cardiomyocytes for remuscularization of the failing heart, although pharmacological challenges remain in clinical translation.

The Dynamic Duo: Fibroblasts as Architects, Cardiomyocytes as Regulators

Interwoven heart muscle cells (cardiomyocytes) and supporting cells (fibroblasts).

In the early stages of EHM formation, fibroblasts take center stage. They act as architects, compacting the surrounding collagen network, a key component of the ECM. This compaction process stiffens the tissue, providing a foundation for cardiomyocytes to organize and form a functional syncytium – a group of cells that act as a single unit.

However, cardiomyocytes play a critical role in regulating this stiffening process. They act as cellular antagonists, tempering the fibroblast-mediated tissue stiffening. This balance is essential for creating EHM that can contract effectively and generate force. Too much stiffness can hinder cardiomyocyte function, while too little can compromise tissue structure.

Here are some key points about their roles:
  • Fibroblasts:
    • Drive collagen compaction and tissue stiffening
    • Activate transcription profiles that support heart muscle development and ECM synthesis
  • Cardiomyocytes:
    • Attenuate fibroblast-mediated tissue stiffening
    • Enable the assembly of stably contracting, force-generating EHM
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Patches Designed for Integration

An induced pluripotent stem cell-derived heart muscle allograft, also called engineered heart muscle, is described as a bioengineered myocardial construct. It contains cardiomyocytes and stromal cells derived from induced pluripotent stem cells embedded in a collagen hydrogel. The construct is designed to integrate with host myocardium and enhance cardiac function, with the aim of stabilizing and strengthening a failing heart. A separate 2026 research highlight describes early clinical outcomes as supporting further study of engineered heart muscle in advanced heart failure.

When Fibroblasts Add Risk

A study of a melt electrowriting-based composite system found that including cardiac fibroblasts did not improve tissue organization. Instead, fibroblast inclusion impaired the electrophysiological properties of myocardial constructs. Computational simulations calibrated with experimental electrophysiological data showed increased susceptibility to arrhythmias. This result demonstrates that adding a stromal cell type does not automatically improve engineered cardiac tissue.

Three-Dimensional Tissue as a Platform

Three-dimensional human cardiac tissues of different kinds are now generated routinely in many laboratories. Advances in stem cell biology and engineering allow constructs to approach the complex structure of heart muscle. Their structural similarity may make them useful for industrial applications such as drug development. The cited review presents engineered cardiac tissues as a platform that can more closely recapitulate heart muscle than simpler experimental systems.

Researchers discovered that fibroblasts are highly sensitive to tissue compaction, quickly activating transcription profiles that promote heart muscle development and ECM synthesis. This highlights the importance of fibroblasts in creating a supportive environment for cardiomyocytes to thrive.

Looking Ahead: Optimizing EHM for Heart Repair and Disease Modeling

This research provides valuable insights into the complex interplay between fibroblasts and cardiomyocytes during EHM formation. By understanding how these cells interact to influence tissue stiffening and cell organization, scientists can fine-tune EHM development for various applications. This includes creating more effective heart repair therapies, developing better models for studying heart disease in vitro, and testing new drug candidates.

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Perfusion and Scalable Engineering

Future cardiac tissue engineering efforts are expected to focus on overcoming technological and biological challenges. Early engineered heart muscles combined stem cell-derived cardiomyocytes with non-myocytes in collagen scaffolds, and constructs containing both cell types showed comparable physiological properties in the cited review. These constructs also promoted capillary-like structures with blood perfusion. Another review emphasizes the need for engineered cardiac tissue with functional blood vessels and anastomoses to the host heart for immediate perfusion and tissue retention.

Translation Requires Biomimetic Design

Reviews of tissue-engineered heart valves identify clinical translation as a central challenge. They call for integrated and biomimetically informed design approaches. The stated goal is to accelerate the development of durable, regenerative, and clinically translatable heart-valve tissues. These principles frame translation as a design problem involving durability, regeneration, and clinical usability together.

A Patch Measured in Cells

A January 29, 2025 report describes engineered heart patches used in an early heart-failure study. Each patch contained about 200 million cells embedded in a collagen hydrogel. The study found that the patches built new muscle cells and improved the heart's pumping function. These findings connect the engineered-tissue approach to a measurable outcome in people with heart failure.

Co-culture force compared with cardiomyocytes alone

  • 1000At 1000 ms and 800 ms stimulation, the comparison found no force differences; those results were not statistically significant.[1]Caveat: No differences were observed; P > 0.05.

How related models frame co-culture

In the co-culture comparison, alignment scores were higher than in CM-only EHTs across both hiPSC lines, adding a structural comparison to the force measurements.[1]

Other engineered cardiac models reported sarcomere lengths in a similar range, while work on hiPSC-derived cardiomyocytes notes that functional and structural immaturity remains a constraint on disease modeling.[2] [3]

Fibroblast effects are not uniform across engineered systems: a separate comparison found that higher fibroblast proportions reduced the ability of tissues to follow stimulation at 1 Hz, a rate used there to represent average resting heart rate.[4]

Fibroblasts can also contribute through deposited matrix, soluble signaling factors, and gap-junction-mediated electrical signaling. Their transition toward a myofibroblast state can occur in vitro, where stiff culture conditions may promote that change, so the culture environment is part of how co-culture results should be interpreted.[3] [5]

What remains unresolved about fibroblast effects

  • How much of the force and alignment advantage reflects matrix organization, soluble signaling, or electrical coupling between cell types? The sources describe several possible fibroblast roles, while the extent of such coupling in native myocardium remains contested.[1] [5] [6]
  • Which fibroblast proportions and activation states support tissue performance without impairing pacing response, given that effects differ across engineered models?[3] [4]

Sources

  1. Co-culturing hiPSC-cardiomyocytes and cardiac fibroblasts enhances engineered heart tissue structure and function (pmc.ncbi.nlm.nih.gov)
  2. hiPSC-derived cardiac fibroblasts dynamically enhance the mechanical function of hiPSC-derived cardiomyocytes on an engineered substrate (pmc.ncbi.nlm.nih.gov)
  3. Generation of a human iPSC-derived cardiomyocyte/fibroblast engineered heart tissue model (pmc.ncbi.nlm.nih.gov)
  4. Human Cardiac Fibroblast Number and Activation State Modulate Electromechanical Function of hiPSC-Cardiomyocytes in Engineered Myocardium (pmc.ncbi.nlm.nih.gov)
  5. Multicellular Interactions in 3D Engineered Myocardial Tissue (www.frontiersin.org)
  6. Fibroblast–myocyte electrotonic coupling: Does it occur in native cardiac tissue?☆ (pmc.ncbi.nlm.nih.gov)

About this Article -

Written with AI assistance from published research, and reviewed by the Mystum team. See our About page for more information.

Everything You Need To Know

1

What is engineered heart muscle, and why is it important?

Engineered heart muscle (EHM) refers to functional heart tissue that's constructed from cells and supportive materials in a laboratory setting. This approach aims to replicate the structure and function of natural heart tissue. The significance lies in its potential to revolutionize heart disease treatment, offering possibilities for heart repair therapies, disease modeling, and drug testing.

2

What are cardiomyocytes, and what role do they play in engineered heart muscle?

Cardiomyocytes are the heart muscle cells responsible for the heart's ability to contract and generate force. They are essential for the EHM's ability to function like natural heart tissue. Their role extends to regulating tissue stiffening, acting as antagonists to fibroblast-mediated stiffening. The implications are that functional EHM relies on healthy, well-functioning cardiomyocytes.

3

What are fibroblasts, and what is their role in the context of heart tissue engineering?

Fibroblasts are cells that provide structural support within the heart tissue. They produce the extracellular matrix (ECM), a scaffolding that holds cells together. Fibroblasts drive collagen compaction and tissue stiffening, activating transcription profiles that support heart muscle development and ECM synthesis. This makes them crucial in the early stages of EHM formation, creating a supportive environment for cardiomyocytes.

4

What is the extracellular matrix, and why is it important for creating heart tissue?

The extracellular matrix (ECM) is the scaffolding that holds cells together within heart tissue. In EHM, the ECM is crucial because it provides the structural support necessary for cells to organize and function properly. Fibroblasts play a key role in producing and maintaining the ECM. Without a functional ECM, the EHM would lack the necessary framework for cardiomyocytes to effectively contract and generate force.

5

How do fibroblasts and cardiomyocytes work together in engineered heart muscle, and why is their interaction so important?

In the creation of EHM, fibroblasts and cardiomyocytes interact in a complex way. Fibroblasts initially compact the collagen network, stiffening the tissue, while cardiomyocytes regulate this stiffening process. This balance is essential; too much stiffness hinders cardiomyocyte function, while too little compromises tissue structure. This interplay highlights the need to understand and control these interactions for successful EHM development. The interaction and ratios between the two cells is an on going area of research.

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