ECM: Master Regulator of Cell Behavior & Disease

Lucas, Schneider^*
*Correspondence: Lucas, Schneider, Center for Tissue Bioengineering, Zurich Institute of Life Sciences, Zurich, Switzerland, Email:

Introduction

The extracellular matrix (ECM) is far more than inert scaffolding; it is a dynamic and interactive microenvironment that profoundly influences cellular behavior, tissue development, and disease progression. Understanding these intricate cell-matrix interactions is crucial for elucidating fundamental biological processes and developing novel therapeutic strategies. One significant area of investigation is mechanotransduction, the process by which cells sense and respond to mechanical cues from their surrounding ECM [1].

Specifically, this involves how mechanical properties, such as stiffness, trigger intracellular signaling pathways. This phenomenon is particularly critical in the development and progression of fibrosis, with studies actively exploring key signaling pathways involved and potential therapeutic strategies targeting these interactions to combat fibrotic diseases [1].

The ECM also serves as a dynamic niche that profoundly influences stem cell behavior [2].

This includes crucial aspects like self-renewal, differentiation, and tissue regeneration. Research delves into the molecular mechanisms by which the ECM regulates stem cell fate, highlighting the immense therapeutic potential of manipulating these interactions for various regenerative medicine applications [2].

In the context of disease, cell-matrix interactions play a critical role in driving the aggressive progression and metastasis of cancers, such as pancreatic cancer [3].

Investigations detail how altered ECM stiffness, composition, and specific signaling molecules contribute significantly to tumor growth, invasion, and resistance to therapy, offering vital insights into potential targets for intervention [3].

Similarly, mechanosensing in cancer examines how cancer cells perceive and respond to the physical properties of their ECM, including stiffness and topography [4].

These cell-ECM interactions are known to influence cancer initiation, progression, and metastasis, leading to emerging strategies that aim to disrupt these mechanical cues as novel therapeutic approaches [4].

The impact of ECM stiffness on a wide array of cell behaviors, including proliferation, differentiation, migration, and apoptosis, is a central theme in many studies [5].

These works summarize the biophysical mechanisms by which cells sense and transduce mechanical signals from their environment, underscoring the fundamental importance of ECM stiffness in both physiological processes and disease pathogenesis [5].

Furthermore, intricate cell-matrix interactions are pivotal in driving cardiovascular remodeling, a process central to many heart diseases [6].

Research in this area discusses how both mechanical and biochemical signals emanating from the ECM influence cardiomyocyte function, fibroblast activation, and immune cell responses, leading to either adaptive or maladaptive changes in cardiac tissue structure and function [6].

Integrin-mediated mechanotransduction represents a fundamental process where cells sense and respond to the mechanical properties at their extracellular matrix interface [7].

Integrins, functioning as key transmembrane receptors, form crucial links between the ECM and the cytoskeleton, initiating intracellular signaling cascades that regulate vital cellular processes like adhesion, migration, and differentiation, thereby profoundly impacting tissue development and disease [7].

The dynamic nature of the extracellular matrix is an extensive area of review, highlighting its crucial roles in tissue development, maintaining homeostasis, and contributing to various diseases [8].

It emphasizes that continuous remodeling of the ECM, driven by these cell-matrix interactions, is essential for proper tissue function, and how dysregulation of these dynamics invariably leads to pathological conditions such as fibrosis and cancer [8].

More broadly, the mechanobiology of the extracellular matrix details how the physical properties of the ECM, such as stiffness and topography, profoundly influence cell fate decisions, including proliferation, differentiation, and migration [9].

It discusses the molecular mechanisms by which cells sense and respond to these mechanical cues, thereby impacting tissue development, regeneration, and disease pathogenesis [9].

Finally, the multifaceted roles of glycosaminoglycans (GAGs) within the extracellular matrix and their critical interactions with cells are explored [10].

This work elaborates on how different types of GAGs, through their diverse structures and charge densities, modulate essential cellular functions like adhesion, migration, and signaling, consequently influencing various physiological processes and contributing to the pathology of numerous diseases [10].

This collective body of research underscores the ECM's indispensable role as a critical regulator of cellular function and tissue fate, presenting vast opportunities for future biological and medical interventions.

Description

The extracellular matrix (ECM) plays a crucial, multifaceted role in regulating cell behavior and tissue physiology, extending far beyond providing mere structural support. Its dynamic nature and interactive properties are fundamental to understanding both normal biological processes and the pathogenesis of various diseases. A significant focus of current research is mechanotransduction, the intricate process by which cells perceive and respond to mechanical cues from their surrounding ECM [1, 7]. This cellular sensing mechanism is vital across numerous biological contexts. For instance, in the realm of fibrosis, cells actively sense and respond to mechanical signals from the ECM, particularly its stiffness, influencing the progression of the disease [1]. Understanding the specific signaling pathways involved in this process is critical for developing targeted therapeutic strategies to combat fibrotic conditions [1]. Similarly, integrin-mediated mechanotransduction, where integrins serve as key transmembrane receptors, forms a direct link between the ECM and the cellular cytoskeleton, initiating intracellular signaling cascades that regulate essential functions like cell adhesion, migration, and differentiation, profoundly impacting both tissue development and disease [7].

Beyond disease contexts, the ECM acts as a pivotal niche for stem cells, profoundly influencing their behavior, including self-renewal, differentiation, and tissue regeneration [2]. The molecular mechanisms governing how the ECM dictates stem cell fate are a rich area of study, with significant implications for regenerative medicine, where manipulating these interactions holds considerable therapeutic potential [2]. The physical properties of the ECM, such as stiffness and topography, are not merely passive factors but active determinants that influence a wide array of cell fate decisions, including proliferation, differentiation, and migration [9]. These mechanical cues are sensed and responded to by cells through complex molecular mechanisms, which in turn impact tissue development, regeneration, and disease pathogenesis [9]. This highlights the ECM's role as an active participant in shaping cellular identity and function. The overall impact of ECM stiffness on cell behaviors like proliferation, differentiation, migration, and apoptosis is extensively reviewed, summarizing the biophysical mechanisms by which cells transduce mechanical signals, underscoring its importance in both health and disease [5].

In oncology, altered cell-matrix interactions are recognized as key drivers in cancer progression and metastasis. For example, in pancreatic cancer, modifications in ECM stiffness, composition, and specific signaling molecules contribute significantly to tumor growth, invasion, and resistance to therapeutic interventions [3]. These insights offer promising avenues for identifying potential targets for intervention [3]. Mechanosensing in cancer specifically investigates how cancer cells perceive and react to the physical characteristics of their ECM, such as stiffness and topography [4]. These cell-ECM interactions are instrumental in influencing the initiation, progression, and metastatic spread of cancer, prompting the exploration of emerging strategies to disrupt these mechanical cues as innovative therapeutic approaches [4]. This emphasizes the ECM as a critical component of the tumor microenvironment, actively shaping cancer cell behavior and resistance.

The ECM's dynamic nature extends to its continuous remodeling, a process essential for maintaining tissue homeostasis and proper function, but whose dysregulation can lead to numerous pathological conditions [8]. This continuous remodeling, driven by intricate cell-matrix interactions, is critical for various physiological processes, including cardiovascular remodeling [6, 8]. In cardiovascular disease, the complex interplay of mechanical and biochemical signals from the ECM influences cardiomyocyte function, fibroblast activation, and immune cell responses, leading to either adaptive or maladaptive structural and functional changes in cardiac tissue [6]. Furthermore, specific components of the ECM, such as glycosaminoglycans (GAGs), play multifaceted roles in mediating crucial interactions with cells [10]. Different types of GAGs, with their varied structures and charge densities, modulate fundamental cell behaviors like adhesion, migration, and signaling, thereby impacting diverse physiological processes and contributing significantly to the pathology of numerous diseases [10]. These collective findings underscore the ECM's integral and active role in orchestrating cell fate and tissue function in both health and disease.

Conclusion

The extracellular matrix (ECM) plays a pivotal role in governing cell behavior and tissue dynamics, impacting both physiological processes and disease states. Extensive research highlights the ECM's function beyond mere structural support, emphasizing its role as a dynamic, interactive environment. A key aspect explored is mechanotransduction, where cells sense and respond to mechanical cues, particularly stiffness, from their surrounding ECM. This process, often mediated by integrins, is fundamental to cell adhesion, migration, differentiation, and overall fate. Dysregulation of mechanotransduction is critically implicated in pathologies like fibrosis, where understanding signaling pathways offers therapeutic avenues. The ECM's influence extends to stem cell behavior, acting as a crucial niche that regulates self-renewal, differentiation, and regenerative potential. Moreover, aberrant cell-matrix interactions are central to cancer progression, mechanosensing in tumors, and metastasis, notably in aggressive forms like pancreatic cancer. Altered ECM stiffness and composition contribute to tumor growth, invasion, and therapy resistance, suggesting strategies to disrupt these mechanical cues could be therapeutic. The continuous remodeling of the ECM is vital for maintaining tissue homeostasis, with dysregulation contributing to diseases such as cardiovascular remodeling and various cancers. Furthermore, specific ECM components like glycosaminoglycans significantly modulate cell adhesion, migration, and signaling, underscoring the complexity and therapeutic potential of targeting these intricate cell-matrix interactions across a spectrum of biological and pathological contexts.

Acknowledgement

None

Conflict of Interest

None

References

Xiaolei M, Ning T, Shuyi L. "Mechanotransduction in Fibrosis: From Signaling Pathways to Therapeutic Targets".Cell Mol Life Sci 80 (2023):11.

Indexed at, Google Scholar, Crossref

Adan SM, Nuri O, Hidenori K. "The Extracellular Matrix as a Niche for Stem Cells: Regulation and Therapeutic Potential".Adv Drug Deliv Rev 181 (2022):114099.

Indexed at, Google Scholar, Crossref

Hao C, Ruili S, Yujia W. "Cell-Matrix Interactions in Pancreatic Cancer Progression and Metastasis".Front Cell Dev Biol 9 (2021):746685.

Indexed at, Google Scholar, Crossref

Prasenjit KC, Stefan V, Rong L. "Mechanosensing in Cancer: The Role of Cell-Extracellular Matrix Interactions".Trends Cancer 7 (2021):457-469.

Indexed at, Google Scholar, Crossref

Qian W, Shaoying Z, Yue L. "Extracellular matrix stiffness and its impact on cell behavior: A review".J Biomech 120 (2021):110323.

Indexed at, Google Scholar, Crossref

Saif H, Farah S, Divya LV. "Cell-Matrix Interactions in Cardiovascular Remodeling".Annu Rev Physiol 84 (2022):119-140.

Indexed at, Google Scholar, Crossref

Mingmin S, Bingyi L, Shanshan C. "Integrin-mediated mechanotransduction at the cell-matrix interface".Mol Biol Cell 32 (2021):ra1.

Indexed at, Google Scholar, Crossref

Andreas DT, Stavros SS, Irinia G. "Extracellular matrix dynamics in tissue development, homeostasis, and disease".Matrix Biol 91 (2020):4-33.

Indexed at, Google Scholar, Crossref

Jay DH, Eric RD, Martin AS. "Mechanobiology of the Extracellular Matrix: Role in Cell Fate and Disease".Annu Rev Biomed Eng 21 (2019):171-193.

Indexed at, Google Scholar, Crossref

Dongliang X, Beom-Gyu K, Youngmi K. "Glycosaminoglycans in the extracellular matrix and their interactions with cells".Curr Opin Struct Biol 67 (2021):12-19.

Indexed at, Google Scholar, Crossref