Formation of stress fibers in fibrosis

Question 1

Stress fibers

Answer 1

Stress fibers are large and thick bundles of cross-linked actin filaments. There are three types of stress fibers, but not all 3 are present in each cell type. Stress fibers are mainly build from actin, and some other proteins like crosslinking proteins α-actinin and filamin, and motor protein myosin

Question 2

Dorsal stress fibers

Answer 2

These cannot contract due to lack of myosin motor proteins and transmit forces and link to Focal Adhesions.

Question 3

What are the functions of stress fibers?(6 functions)

Answer 3

Functions(o.a.):

• mechanotransduction
• cell contraction
• cell adhesion
• morphogenesis
• migraion
• cytokinesis
• endo/phagocytose

Question 4

How does mechenical stress cause stress fibers to grow?

Answer 4

A mechanical signal reaches the cell through 1 or more of the 4 proteins in the cell membrane: E-cadherin, Integrin, TNFR or LPA receptor. The signal is then passed through via Rho protein family GTPases (Rho, Rac, Cdc42). Rho and ROCK are relevant for stress fiber formation/destruction and are involved in fibrosis.

Question 5

How do stress fibers and focal adhesions involved in fibrosis?

Answer 5

Stress fibers and focal adhesions are involved in migration, adhesion and mechanotransduction, which are all mechanisms essential to an immune response and wound healing (and so relevant when looking at fibrosis). The force that is generated by stress fibers regulated many different pathways (biochemical or signaling) in the cell.

• Migration: stress fibers can constrict the ECM and deform the substrate by generating force. Depending on the environment: suited for migration or not?
• Adhesion: tension or contractility in stress fibers can convert mechanical signals into biochemical cues. So it has an important function in FA maturation and dynamics.
• Mechanotransduction: cell differentiation, cell fate determination and cell shape etc. can be regulated by stress fibers. The organization and prominence of stress fibers is controlled by substrate stiffness.

Question 6

Transverse stress fibers

Answer 6

These drive actin flow in migrating cells and transfer force to environment

Question 7

Ventral stress fibers

Answer 7

Play a role in cell migration, changing cell shape and give structure to the cell (cell border)

Question 8

What mechanisms can stress fibers use to forfill their functions?(2 mechanisms)

Answer 8

1. Rapid (de-)polymerization of actin filaments. One side of the filaments is degraded while the other side is build up -> treadmilling mechanism (+ side is preferred building end).
2. ATP-driven movement of the myosin II motor domains. 2 actin filament bundles move into each other due to myosin motor proteins. Dorsal stress fibers cannot do this (lack of myosin)

Both of these mechanisms lead to the generation of force.