Macrophages and fibroblasts in foreign body reactions: How mechanical cues drive cell functions?

Abstract

Biomaterials, when implanted in the human body, can induce a series of cell- and cytokine-related reactions termed foreign body reactions (FBRs). In the progression of FBRs, macrophages regulate inflammation and healing by polarizing to either a pro-inflammatory or pro-healing phenotype and recruit fibroblasts by secreting cytokines. Stimulated by the biomaterials, fibrotic capsule is formed eventually. The implant, along with its newly formed capsule, introduces various mechanical cues that influence cellular functions. Mechanosensing proteins, such as integrins or ion channels, transduce extracellular mechanical signals into cytoplasm biochemical signals in response to mechanical stimuli. Consequently, the morphology, migration mode, function, and polarization state of the cells are affected. Modulated by different intracellular signaling pathways and their crosstalk, the expression of fibrotic genes increases with fibroblast activation and fibroblast to myofibroblast transition under stiff or force stimuli. However, summarized in most current studies, the outcomes of macrophage polarization in the effect of different mechanical cues are inconsistent. The underlying mechanisms should be investigated with more advanced technology and considering more interfering aspects. Further research is needed to determine how to modulate the progression of fibrotic capsule formation in FBR artificially.

Keywords: Biomaterials; Fibroblasts; Fibrosis; Foreign body reaction; Macrophages; Mechanical cues.

Graphical abstract

Fig. 1

Following cell junction and focal adhesion, compression and tension could exist between cells and the surrounding ECM. Shear of fluid exerts on the cell surface of a lumen space. Between the surface of ECM or biomaterial with a certain stiffness and the cells, an interaction force consisting of an external resistance and an intrinsic force is generated. Created with BioRender.com.

Fig. 2

a. After the extracellular part of Integrins is activated, the intracellular part is assembled with integrin-associated proteins such as talin and vinculin. Meanwhile, FAK/Src signaling is phosphorylated. FAK activates downstream signaling while also recruiting more integrins to form a denser arrangement. As the downstream, Rho and ROCK change actin polymerization by modulating myosin. Piezo1 and TRPV4 participate in mehcanosensing and coordinate with integrins.YAP's nuclear translocations is activated by Ca²⁺ influx and cytoskeleton change. b. Shear exerts on VEGFR2/3 in a VE-cadherin-dependent manner and activates downstream PI3K/Akt signaling. c. The structural change of the lipid bilayer cell membrane by extracellular force or traction on the N-terminus causes GPCR activation. Created with BioRender.com.

Fig. 3

An ECM-integrin-talin-actin clutch orchestrates cell morphology and mobility. a. When the stiffness of the ECM does not reach the required threshold, the extracellular part of integrins does not engage with the ECM. Myosin maintains the pulling on actin while talin folds. With the cytoskeleton contracting, the mobility of the cell is reduced. b. When the stiffness of the ECM reaches the threshold required for integrins engagement, talin unfolds and myosin discharges actin depending on RhoA/ROCK. With the engagement of integrins and ECM, a force aiding cell protrusion is generated by cell-ECM adhesion. The cell presents a spreading shape with increased mobility. Created with BioRender.com.

Fig. 4

A. Under the stimulation of mechanical cues in FBR, integrins are recruited and activated on the cell membrane. FAK is recruited to the integrin clustering and interacts with integrin-associated proteins. Integrin stimulates FAK phosphorylation and binds with Src to form a FAK/Src complex. FAK/Rho/ROCK signaling also regulates the cytoskeleton by phosphorylating MLC. FAK also activates PI3K/Akt signal pathway and regulates Akt-mediated gene transcription. Rac-1, as a downstream of PI3K, activate Elk-1 which also is regulated from Rho to ERK and regulates related transcription in nuclear after phosphorylation. Latent TGF-β1 is stored in the ECM bounding latency-associated peptide (LAP) non-covalently. Mechanical cues cause the activation of TGF-β1 by an integrin-mediated conformational change in the LAP-TGF-β1 straitjacket configuration. The TGF-β1/Smad2/3 signaling is activated. TGF-β1 also induced Rho activation that changes the cytoskeleton which further enhanced the Smad2-phosphorylation and nuclear translocation. The cytoskeleton alignment changes lead to YAP activation and accumulation in the nuclei for TEAD-dependent gene expression. Created with BioRender.com.