Biomechanical forces enhance directed migration and activation of bone marrow-derived dendritic cells

Abstract

Mechanical forces are pervasive in the inflammatory site where dendritic cells (DCs) are activated to migrate into draining lymph nodes. For example, fluid shear stress modulates the movement patterns of DCs, including directness and forward migration indices (FMIs), without chemokine effects. However, little is known about the effects of biomechanical forces on the activation of DCs. Accordingly, here we fabricated a microfluidics system to assess how biomechanical forces affect the migration and activity of DCs during inflammation. Based on the structure of edema, we proposed and experimentally analyzed a novel concept for a microchip model that mimicked such vascular architecture. The intensity of shear stress generated in our engineered chip was found as 0.2–0.6 dyne/cm2 by computational simulation; this value corresponded to inflammation in tissues. In this platform, the directness and FMIs of DCs were significantly increased, whereas the migration velocity of DCs was not altered by shear stress, indicating that mechanical stimuli influenced DC migration. Moreover, DCs with shear stress showed increased expression of the DC activation markers MHC class I and CD86 compared with DCs under static conditions. Taken together, these data suggest that the biomechanical forces are important to regulate the migration and activity of DCs.

Mechanosensing in macrophages and dendritic cells in steady-state and disease

“…Cells are cultured within the lower main channel, while medium is injected into the upper channel. Cells get exposed to shear stress generated through the bridge channel (as described in ( Kang et al, 2021 )), and mechanical forces experienced by cells get calculated using computational simulation.…”

“…DCs originate in the bone marrow and migrate towards peripheral tissues through blood circulation ( Liu et al, 2009 ), and can further travel from peripheral tissues towards lymph nodes through the lymphatic system ( Liu et al, 2009 ). How biochemical cues can influence DC maturation and function has been extensively studied ( Jonuleit et al, 1997 ; Waskow et al, 2008 ; Schaupp et al, 2020 ), but recent studies have started to focus on the impact that biophysical stimuli have on DC activation ( Craig et al, 2008 ; Mennens et al, 2017 ; Kang et al, 2021 ), migration ( Mennens et al, 2017 ; Kang et al, 2021 ), function ( Lewis et al, 2013 ; Chakraborty et al, 2021 ), and metabolism ( Pearce and Everts, 2015 ; Chakraborty et al, 2021 ).…”

“…Similarly, immature human moDCs showed a significant increase in the expression of CD80, CD86, CD83, and MHC class II molecules when maintained at elevated pressures ( Craig et al, 2008 ). Using a microfluidic channel to mimic inflammatory edema, murine bone marrow-derived DCs (BMDCs) exposed to higher shear stress show increased expression of the activation markers MHC class I and CD86 compared with DCs under static conditions ( Kang et al, 2021 ). In terms of static substrate stiffness effects on DCs, murine BMDCs grown on the stiffer hydrogels display significantly increased expression of CD80 and CD86 compared to those grown on more pliant hydrogels, with a trending increase in MHC class II molecules ( Chakraborty et al, 2021 ).…”

“…Although there is an increase in the proportion of DCs that migrate at 2 kPa, migration velocity is comparable between moDCs conditioned on the lower and higher substrate stiffnesses ( Mennens et al, 2017 ). Similarly, murine BMDCs exposed to differing levels of shear stress ranging from 0.2–0.6 dyne/cm 2 did not significantly differ in their migration speed ( Kang et al, 2021 ). However, increased shear stress potentiated their migratory abilities, as the BMDCs under higher shear stress followed more straightforward trajectories and demonstrated improved directness ( Kang et al, 2021 ).…”

“…Similarly, murine BMDCs exposed to differing levels of shear stress ranging from 0.2–0.6 dyne/cm 2 did not significantly differ in their migration speed ( Kang et al, 2021 ). However, increased shear stress potentiated their migratory abilities, as the BMDCs under higher shear stress followed more straightforward trajectories and demonstrated improved directness ( Kang et al, 2021 ). Therefore, these findings suggest that biomechanical cues may not affect DC migration velocity, but can impact the ability of DCs to migrate effectively.…”