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Growth factors but not gap junctions play a role in injury-induced Ca²⁺ waves in epithelial cells

¹ Departments of Pathology,
² Cognetix, Inc., Ivoryton, CT 06442, USA
³ Ophthalmology and
⁴ Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA

*Author for correspondence (e-mail: vickery{at}med-biochem.bu.edu)

Accepted August 30, 2001

This paper characterizes the early responses of epithelial cells to injury. Ca²⁺ is an important early messenger that transiently increases in the cytoplasm of cells in response to external stimuli. Its elevation leads to the regulation of signaling pathways responsible for the downstream events important for wound repair, such as cell migration and proliferation. Live cell imaging in combination with confocal laser scanning microscopy of fluo-3 AM loaded cells was performed. We found that mechanical injury in a confluent region of cells creates an elevation in Ca²⁺ that is immediately initiated at the wound edge and travels as a wave to neighboring cells, with [Ca²⁺]_i returning to background levels within two minutes. Addition of epidermal growth factor (EGF), but not platelet-derived growth factor-BB, resulted in increased [Ca²⁺]_i, and EGF specifically enhanced the amplitude and duration of the injury-induced Ca²⁺ wave. Propagation of the Ca²⁺ wave was dependent on intracellular Ca²⁺ stores, as was demonstrated using both thapsigargin and Ca²⁺ chelators (EGTA and BAPTA/AM). Injury-induced Ca²⁺ waves were not mediated via gap junctions, as the gap-junction inhibitors 1-heptanol and 18-glycyrrhetinic acid did not alter wave propagation, nor did the cells recover in photobleaching experiments. Additional studies also demonstrated that the wave could propagate across an acellular region. The propagation of the injury-induced Ca²⁺ wave occurs via diffusion of an extracellular mediator, most probably via a nucleotide such as ATP or UTP, that is released upon cell damage.

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Key words: Ca²⁺ signaling, Corneal epithelium, EGF, Wound repair

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