High pressure 3D migration of cardiac fibroblasts through crosslinked matrices

Project: Research

Investigators

  • Pragati Chengappa (PI)

Description

3D fibroblast migration is important for post-myocardial infarction wound healing. For this reason, is critical to understand the mechanisms that drive 3D migration in cardiac fibroblasts through complex 3D extracellular matrix and epithelial cell layers. This knowledge could help us promote post-MI wound healing and increase the likelihood of recovery. Unlike 2D substrates where the cell can migrate unimpeded, dense 3D matrices present a unique challenge to migration by hindering movement of the nucleus. Since the nucleus is rigid and bulky, translocating the nucleus through a crosslinked matrix is the rate-limiting step of 3D migration. Excitingly, our preliminary data show that cardiac fibroblasts can overcome these physical constraints to 3D movement in cell-derived matrix by using forces generated by myosin II to pull the nucleus through the narrow openings between adjacent fibers. By pulling the nucleus forward, myosin II activity generates high-pressure protrusions called lobopodia. However, it is unclear how the pulling force of myosin II is physically connected to the nucleus to facilitate its translocation through the CDM. Additionally, classical markers of polarity, which dictate where cellular protrusions form in migrating cells to sustain directional migration, are nonpolarized in lobopodial fibroblasts. This is remarkable since lobopodial fibroblasts can directionally migrate in 3D matrices over long distances. This proposal will investigate how cardiac fibroblasts move efficiently through tissues by focusing on two specific aims:Aim 1: Establish how force is transmitted from actomyosin filaments in the front of cardiac fibroblasts to the nucleus to pull the nucleus through narrow openings in 3D matrices.Aim 2: Determine the non-classical mechanisms that polarize high-pressure cardiac fibroblasts to drive directional 3D migration.
Award amount$62,032.00
Award date01/01/2020
Program typePredoctoral Fellowship
Award ID20PRE35170041
Effective start/end date01/01/202012/31/2021
StatusActive