Abstract
Re‐epithelialization is a critical step in wound healing and results from the collective migration of keratinocytes. Previous work demonstrated that immobilized, but not soluble, epidermal growth factor (EGF) resulted in leader cell‐specific activation of phospholipase C gamma 1 (PLCγ1) in HaCaT keratinocytes, and that this PLCγ1 activation was necessary to drive persistent cell migration. To determine the mechanism responsible for wound edge‐localized PLCγ1 activation, we examined differences in cell area, cell–cell interactions, and EGF receptor (EGFR) localization between wound edge and bulk cells treated with vehicle, soluble EGF, or immobilized EGF. Our results support a multistep mechanism where EGFR translocation from the lateral membrane to the basolateral/basal membrane allows clustering in response to immobilized EGF. This analysis of factors regulating PLCγ1 activation is a crucial step toward developing therapies or wound dressings capable of modulating this signal and, consequently, cell migration.
Highlights
Collective migration results from the coordinated movement of cells that are in physical contact
The pPLCγ1 intensity was comparable to background levels in control conditions, while pPLCγ1 intensity was significantly elevated by treatment with epidermal growth factor (EGF) and was further elevated when cells were exposed to immobilized rather than soluble EGF (Figure 1a, Supporting Information Figure 1)
Edge-specific activation of leader cells has been observed in response to chemotactic gradients[6]; all of the cells in the keratinocyte sheet in our experiments were exposed to a uniform concentration of immobilized EGF
Summary
Collective migration results from the coordinated movement of cells that are in physical contact. When a wound occurs in a confluent sheet of cells, the cells experience an intrinsic polarity based on the localization of cell–cell contacts at the trailing edge, which allows for cell protrusions to be extended into the open space to initiate migration.[2]. These “leader cells” pull the cells from the bulk along through coordinated cell–cell connections. Impairment of this process leads to the development of chronic wounds, such as those associated with diabetes.[3]
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