Amoeboid Cells Exhibit Durotaxis Behavior Driven by Polarized Non-Muscle Myosin IIA

Core Concepts

Amoeboid cells, such as T cells and neutrophils, can sense and migrate along substrate stiffness gradients (durotaxis) through a mechanism involving polarized localization of non-muscle myosin IIA, rather than differential actin flow.

Abstract

The study demonstrates that amoeboid cells, which lack stable focal adhesions, can undergo durotaxis - directional migration along substrate stiffness gradients. Using an imaging-based cell migration device with stiffness gradients, the authors observed that T cells, neutrophils, and the amoeboid protist Dictyostelium all exhibited durotactic behavior, preferentially migrating towards stiffer regions of the substrate.

The underlying mechanism was found to involve the polarized localization of non-muscle myosin IIA (NMIIA) towards the softer end of the stiffness gradient, rather than differential actin flow as seen in mesenchymal cell durotaxis. Inhibition of NMIIA activity abolished the durotactic behavior, while enhancing myosin contractility increased durotaxis.

Computational modeling of the amoeboid cell as an active gel droplet captured the experimental observations, suggesting that the diffusion rate of NMIIA, which is sensitive to substrate stiffness, drives its polarized distribution and enables durotaxis. The authors further demonstrated that the initial local stiffness sensed by the cell can modulate the durotactic response, with cells on softer regions of the gradient exhibiting stronger durotaxis.

These findings reveal that amoeboid cells, despite their lack of stable adhesions, can sense and respond to mechanical cues in their microenvironment, which may have important implications for immune cell migration, wound healing, and cancer metastasis.

Stats

Cell migration velocity is around 16.21 μm/min for CD4+ Naïve T cells.
The stiffness gradient used in the experiments is 20.77 kPa/mm.

Quotes

"Amoeboid cells, such as T cells and neutrophils, can sense and migrate along substrate stiffness gradients (durotaxis) through a mechanism involving polarized localization of non-muscle myosin IIA, rather than differential actin flow."
"Computational modeling of the amoeboid cell as an active gel droplet captured the experimental observations, suggesting that the diffusion rate of NMIIA, which is sensitive to substrate stiffness, drives its polarized distribution and enables durotaxis."

Key Insights Distilled From

Amoeboid cells undergo durotaxis with soft end polarized NMIIA

by Yi,X., Chen,... at www.biorxiv.org 04-13-2023

https://www.biorxiv.org/content/10.1101/2023.04.13.536664v2

Deeper Inquiries

How might the findings on amoeboid cell durotaxis inform our understanding of immune cell migration and surveillance within the mechanically heterogeneous tumor microenvironment or inflamed tissues

The findings on amoeboid cell durotaxis shed light on the mechanisms underlying immune cell migration and surveillance within the mechanically heterogeneous tumor microenvironment or inflamed tissues. In the context of cancer, immune cells play a crucial role in tumor progression and response to therapy. Understanding how amoeboid cells can sense and respond to mechanical cues, such as substrate stiffness, provides insights into how immune cells navigate through the complex tumor microenvironment. The ability of immune cells to undergo durotaxis towards stiffer regions may influence their recruitment to specific areas within the tumor where stiffness is higher, potentially impacting immune surveillance and anti-tumor immune responses. Moreover, in inflamed tissues where stiffness gradients are present, the durotactic behavior of immune cells could regulate their migration towards sites of inflammation, contributing to the immune response. Overall, these findings enhance our understanding of how immune cells interact with their mechanical surroundings in pathological conditions, offering new perspectives on immune cell behavior in complex tissue environments.

Could the polarized distribution of NMIIA observed in this study be leveraged to develop new strategies for modulating amoeboid cell migration, such as in the context of cancer metastasis or immune therapies

The polarized distribution of NMIIA observed in this study presents an intriguing opportunity to develop new strategies for modulating amoeboid cell migration, particularly in the context of cancer metastasis or immune therapies. NMIIA plays a critical role in driving the durotactic response of amoeboid cells towards softer regions, as demonstrated in the study. Leveraging the polarized distribution of NMIIA could be a promising approach to manipulate amoeboid cell migration in various pathological conditions. For instance, targeting the localization or activity of NMIIA could potentially disrupt the durotactic behavior of immune cells, inhibiting their migration towards specific regions within the tumor microenvironment. This could have implications for designing novel therapeutic interventions aimed at modulating immune cell behavior in cancer or inflammatory diseases. By understanding and manipulating the mechanisms underlying NMIIA polarization, new strategies for controlling amoeboid cell migration may be developed, offering opportunities for therapeutic interventions in cancer metastasis and immune-related disorders.

What other mechanosensitive cellular components or signaling pathways, beyond NMIIA, might be involved in the durotactic response of amoeboid cells, and how could further elucidation of these mechanisms lead to new biological insights or therapeutic opportunities

Beyond NMIIA, several other mechanosensitive cellular components or signaling pathways may be involved in the durotactic response of amoeboid cells. One potential candidate is the Rho GTPase signaling pathway, which regulates actomyosin contractility and cell migration in response to mechanical cues. Activation of Rho GTPases, such as RhoA, Rac1, and Cdc42, can modulate cytoskeletal dynamics and cell polarity, influencing cell migration in a mechanosensitive manner. Additionally, integrins and focal adhesion proteins may also play a role in sensing and responding to substrate stiffness gradients, impacting cell migration and durotaxis. Further elucidation of these mechanosensitive components and signaling pathways could provide new insights into the molecular mechanisms governing amoeboid cell migration and durotaxis. Understanding how these pathways interact and coordinate in response to mechanical cues could lead to novel biological insights and therapeutic opportunities for targeting immune cell behavior in cancer, inflammation, and other pathological conditions.