Topic 2: Cell Mechanobiology
Topic 2: Cell Mechanobiology (BME 3303 - Cellular Systems Engineering)
Aim:
Introduce the cytoskeleton and its role in cellular mechanotransduction.
Discuss how cells can "feel" their micro-environment.
Introduce the role of focal adhesions in cellular mechano-sensing.
Cell Mechanobiology Overview
Mechanobiology studies how cells respond to mechanical stimuli.
It explores how cells maintain structure and function
Key Focus:
The cytoskeleton provides necessary support for cellular interaction with environments.
Cytoskeleton
Definition: The cytoskeleton, often referred to as the "cell skeleton," is a complex and dynamic structure.
General Functions:
Serves as structural and mechanical scaffolding for cells.
Organizes shape and locations of cell compartments.
Facilitates formation and transport of organelles and vesicles.
Involves in mitosis and cytokinesis.
Specialized Functions:
Cell polarization.
Cell motility and translocation.
Contraction to maintain structural integrity.
Cytoskeleton Dynamics
Composed of a highly dynamic network of filamentous proteins that links all cell regions.
Functions:
Provides structural support.
Serves as a framework for active transport mechanisms.
Generates and transduces mechanical forces.
Plays a significant role in maintaining cellular organization, mediating communication across cells and impacting cellular functions.
Acts as a load-bearing network to transduce mechanical signals efficiently between the extracellular environment and cell interior.
Types of Cytoskeletal Filaments
Components:
Microfilaments (Actin Filaments):
Diameter: ~7nm; bear tension.
Most abundant protein in eukaryotic cells, constituting ~10% in muscle cells and ~1-5% in non-muscle cells.
Present as monomeric (G-actin) or polymeric (F-actin).
Intermediate Filaments:
Provide mechanical strength; cell-specific types (e.g., keratins in epithelial cells).
Microtubules:
Hollow, cylindrical structures resistant to compression; involved in kickstarting processes like mitosis.
Actin Filaments
Actin filaments are prevalent across cell structures, performing various roles:
Growth and Polymerization:
Actin responds to mechanical stimuli, polymerizing to form structures like lamellipodia and filopodia, directing cell motility.
Green and blue filaments indicate different actin organizations.
Mechanotransduction Indicators:
Key signaling molecules include Rho GTPases (RhoA, Rac, CDC42A) that regulate actin polymerization in response to mechanical stimuli.
Stress fibers' formation arises from various mechanical cues and is context-dependent, changing according to fluid flow.
Intermediate Filaments
Major function includes providing mechanical strength and stability to cells.
Several variants depending on tissue-specific demands (e.g., vimentin in mesenchymal cells).
Influence in cell dynamics (shape and movement) during states such as epithelial-mesenchymal transition (EMT).
Microtubules
Properties:
Stiffest of the cytoskeletal elements; important in intracellular transport.
Experiences buckling under stress.
Plays a role in cell division (mitosis) through dynamic assembly.
Mechanobiology of the Cell
Main Concepts:
All living cells respond to mechanical stimuli, shaping structure and function.
Mechanical environment necessitates a cellular response, vital for tissue homeostasis.
Aberrant mechanosensation can be linked to various diseases (e.g., cancer, heart disease).
Cellular Response Mechanism:
Mechanotransduction through integrin-based adhesion ("outside-in" and "inside-out").
Feedback loop involving gene transcription, ECM remodeling, and modifications in cell shape and activity.
Mechanotransduction Process
Illustrated as a feedback loop involving:
Sensing mechanical changes
Translocating signals to the nucleus
Intracellular signaling
ECM remodeling (MMPs, TIMPs)
Important:
Mechanical forces reach the nucleus quickly compared to chemical signals which take longer for response initiation.
Mechanisms of Signal Propagation:
Mechanical signals are transmitted along cytoskeletal filaments (1000 times faster than chemical signal propagation).
Focal Adhesions
Essential cellular structures linking microfilaments to the extracellular matrix.
Components:
Integrins, vinculin, talin, among over 100 different proteins.
Function as biomechanical sensors, allowing cells to autocomplete cellular functions in response to the environment.
Behavior:
Comparable to dynamic structures that can rapidly disassemble and reassemble during cell migration.
Lamellipodia and Filopodia
Definitions:
Lamellipodia: Broad, flat protrusions facilitating migration through actin polymerization force.
Filopodia: Thin projections acting as sensory antennas for the environment.
Actin binding proteins (e.g., fascin in filopodia) stabilize and organize these structures for effective motion.
Podosomes and Invadopodia
Podosomes: Actin-rich structures that facilitate adhesion and localize to cell migration regions.
Invadopodia: Specialized structures with concentrated proteolytic activity enabling invasive behavior in cancer cells.
Form in response to various extracellular signals.
Summary of Key Concepts
Key Learnings:
Functions of the cytoskeleton in mechanotransduction.
How cells sense and respond to their microenvironment.
The role of mechanosensing structures like focal adhesions in cell behavior.
Relationships between endogenous and applied forces that affect cellular activities.
The aim of this course is to introduce the cytoskeleton and its role in cellular mechanotransduction, discussing how cells can "feel" their micro-environment and the role of focal adhesions in cellular mechano-sensing.
Mechanobiology studies how cells respond to mechanical stimuli, exploring how they maintain structure and function. A key focus is on the cytoskeleton, which provides the necessary support for cellular interaction with environments.
The cytoskeleton, often referred to as the "cell skeleton," is a complex and dynamic structure serving as structural and mechanical scaffolding for cells. It organizes the shape and locations of cell compartments, facilitates the formation and transport of organelles and vesicles, and plays a role in mitosis and cytokinesis. Additionally, it supports specialized functions such as cell polarization, motility, translocation, and contraction to maintain structural integrity.
Composed of a highly dynamic network of filamentous proteins, the cytoskeleton links all cell regions and provides structural support, serving as a framework for active transport mechanisms and generating and transducing mechanical forces. It significantly maintains cellular organization, mediates communication across cells, and impacts cellular functions, acting as a load-bearing network to efficiently transduce mechanical signals between the extracellular environment and cell interior.
The cytoskeletal filaments can be categorized into three main components. Microfilaments (actin filaments) have a diameter of approximately 7 nm and bear tension. Actin is the most abundant protein in eukaryotic cells, constituting about 10% in muscle cells and 1-5% in non-muscle cells, present as either monomeric (G-actin) or polymeric (F-actin). Intermediate filaments provide mechanical strength with cell-specific types, such as keratins in epithelial cells. Microtubules are hollow, cylindrical structures resistant to compression and crucial in processes like mitosis.
Actin filaments perform various roles across cell structures, responding to mechanical stimuli by polymerizing to form lamellipodia and filopodia, which direct cell motility. Key signaling molecules, including Rho GTPases, regulate actin polymerization in response to mechanical signals, leading to the formation of stress fibers, which depend on mechanical cues and are context-dependent.
Intermediate filaments mainly function to provide mechanical strength and stability to cells, with various variants depending on tissue-specific demands, influencing cell dynamics during transitions such as epithelial-mesenchymal transition (EMT). Microtubules are the stiffest cytoskeletal elements and are important for intracellular transport, experiencing buckling under stress and assisting in cell division through dynamic assembly.
In terms of mechanobiology, all living cells respond to mechanical stimuli, which shapes structure and function. The mechanical environment necessitates cellular responses vital for tissue homeostasis, with aberrant mechanosensation linked to various diseases such as cancer and heart disease. Mechanotransduction occurs through integrin-based adhesion and involves a feedback loop with gene transcription, ECM remodeling, and modifications in cell shape and activity.
The mechanotransduction process is illustrated as a feedback loop involving sensing mechanical changes, translocating signals to the nucleus, intracellular signaling, and ECM remodeling involving MMPs and TIMPs. Notably, mechanical forces reach the nucleus more quickly than chemical signals, which require a longer time for response initiation. Mechanical signals are transmitted along cytoskeletal filaments approximately 1000 times faster than chemical signals.
Focal adhesions, essential cellular structures, connect microfilaments to the extracellular matrix and comprise integrins, vinculin, and talin, among other proteins. They function as biomechanical sensors that enable cells to adapt their functions in response to the environment. These structures are dynamic, capable of rapid disassembly and reassembly during cell migration.
Lamellipodia are broad, flat protrusions that facilitate migration through actin polymerization, while filopodia are thin projections acting as sensory antennas for the environment. Actin-binding proteins, such as fascin, stabilize these structures for effective motion. Podosomes are actin-rich structures that facilitate adhesion and are localized in regions of cell migration, whereas invadopodia are specialized structures with concentrated proteolytic activity enabling invasive behavior in cancer cells, forming in response to various extracellular signals.
In summary, key concepts learned include the functions of the cytoskeleton in mechanotransduction, how cells sense and respond to their microenvironment, the role of mechanosensing structures like focal adhesions in cell behavior, and the relationships between endogenous and applied forces that affect cellular activities.