Effect of Electromagnetic Field on Proliferation and Migration of Fibroblasts and Keratinocytes: Implications in Wound Healing and Regeneration

Abstract

Proliferation and migration of fibroblasts, keratinocytes, and endothelial cells are key events in the physiological process of wound healing. This process includes different but overlapping stages: hemostasis, inflammatory phase, the proliferative phase, and the remodeling phase. Traumatic brain injury (TBI) is defined as a mechanical insult to the brain from external mechanical force (primary injury), usually followed by the secondary injury including edema, inflammation, excitotoxicity, oxidative stress, or mitochondrial dysfunction. The process of tissue repair following TBI is based on the neuronal-glial interactions, where phagocytosis by microglia plays a crucial role. Low-frequency electromagnetic field (LF-EMF) has been shown to enhance tissue repair after TBI, however, there are limited studies investigating the effects of LF-EMF on the proliferation and migration of keratinocytes, fibroblasts, VSMCs, and endothelial cells in the context of wound healing and on neuronal cells and microglia in relation to healing after TBI. Better understanding of the effects of LF-EMF on the proliferation, migration, and differentiation of these cells is important to enhance tissue healing after injury. This review article comprehensively discussed the effect of EMF/LF-EMF on these cells. Results published by different authors are hardly comparable due to different methodological approach and experimental settings. EMF promotes migration and proliferation of fibroblasts, keratinocytes and endothelial cells (EC), and thus could improve wound healing. The pilot study preformed on a large animal model of TBI suggests anti-inflammatory effects of EMF stimulation following TBI. Therefore, EMF is recognized as a potential therapeutic option to accelerate the wound healing and improve cellular recovery and function after TBI. Nonetheless, future studies are needed to define the optimal parameters of EMF stimulation in terms of frequency or duration of exposure.

Keywords: Cell Migration; Cell Proliferation; Electromagnetic field; Fibroblasts; Keratinocytes; Microglia; Neurons; Traumatic Brain Injury; Wound healing.

Figure 1:

Physiology of wound healing process. Wound healing dynamics typically includes four continuous and overlapping phases: hemostasis, inflammatory phase, proliferation phase and remodeling phase. Immediately after a tissue injury in the hemostasis phase activated platelets start the reparation process by growth factors production. Inflammatory phase is divided into early (predominant neutrophil action) and late phase (predominant macrophage action) aimed to protect the tissue from foreign particles. Extracellular matrix deposition and angiogenesis contribute to granulation tissue formation in the proliferative phase. Definitive healing of the wound occurs in the remodeling phase, through complete epithelization and scar formation.

Figure 2:

Microglia in response to traumatic brain injury (TBI). After TBI, in the interplay between damaged neurons and resting microglia, potentially two types of activated microglia, so-called M1-like microglia and M2-like microglia, could be differentiated. Polarization depends on local mediators and microenvironment. In response to LPS and IFN-γ, the M1-like phenotype arises, which produces proinflammatory cytokines and mediates neural dysfunction. M2-like phenotype is associated with tissue repair by producing anti-inflammatory cytokines and phagocytosis.

Figure 3:

EMF effects on different cell types in terms of wound healing and TBI. Increased migration and proliferation of fibroblasts and keratinocytes indicate improved wound healing through the processes of ECM formation and epithelialization. Tubulization and elongation of endothelial cells in response to EMF speaks in favor of angiogenesis, promoting wound healing. In response to EMF neuronal stem cells proliferate, while microglia exert proinflammatory or anti-inflammatory response, depending on the study.