Abstract
Distinct anti-inflammatory macrophage (M2) subtypes, namely M2a and M2c, are reported to modulate the tissue repair process tightly and chronologically by modulating fibroblast differentiation state and functions. To establish a well-defined three-dimensional (3D) cell culture model to mimic the tissue repair process, we utilized THP-1 human monocytic cells and a 3D collagen matrix as a biomimetic tissue model. THP-1 cells were differentiated into macrophages, and activated using IL-4/IL-13 (MIL-4/IL-13) and IL-10 (MIL-10). Both activated macrophages were characterized by both their cell surface marker expression and cytokine secretion profile. Our cell characterization suggested that MIL-4/IL-13 and MIL-10 demonstrate M2a- and M2c-like subtypes, respectively. To mimic the initial and resolution phases during the tissue repair, both activated macrophages were co-cultured with fibroblasts and myofibroblasts. We showed that MIL-4/IL-13 were able to promote matrix synthesis and remodeling by induction of myofibroblast differentiation via transforming growth factor beta-1 (TGF-β1). On the contrary, MIL-10 demonstrated the ability to resolve the tissue repair process by dedifferentiation of myofibroblast via IL-10 secretion. Overall, our study demonstrated the importance and the exact roles of M2a and M2c-like macrophage subtypes in coordinating tissue repair in a biomimetic model. The established model can be applied for high-throughput platforms for improving tissue healing and anti-fibrotic drugs testing, as well as other biomedical studies.
Highlights
Wound healing is a complex and dynamic process facilitated by four overlapping, continuous phases namely homeostasis, inflammation, proliferation, and tissue remodeling[1,2]
We found a higher expression of HLA-DR in MIL-4/IL-13 when compared to MIL-10 macrophages, suggesting a higher proinflammatory activity of MIL-4/IL-13
We used THP-1, a human monocytic cell line widely used as an established macrophages model in many biomedical studies such as wound repair, infection models, and immuno-oncology[80]
Summary
Wound healing is a complex and dynamic process facilitated by four overlapping, continuous phases namely homeostasis, inflammation, proliferation, and tissue remodeling[1,2] This entire process is tightly modulated and orchestrated by biochemical signals, such as growth factors and cytokines, and biophysical stimuli including cell–cell interactions and cell–extracellular matrix (ECM) interactions[3]. Myofibroblasts are characterized by pronounced actin stress fibers and the expression of alpha smooth-muscle actin (αSMA), as well as an extensive production and deposition of ECM proteins, e.g. type I collagen (Coll I) and fibronectin containing extra domain-A (EDA-FN)[8,14,15]. If the tissue repair is prolonged and myofibroblasts remain to produce excessive ECM components and steady remodel the tissue, it will result in scarring or fibrosis[20,21]
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