Histatins are the major wound‐closure stimulating factors in human saliva as identified in a cell culture assay

Abstract

Wounds in the oral cavity heal much faster than skin lesions. Among other factors, saliva is generally assumed to be of relevance to this feature. Rodent saliva contains large amounts of growth factors such as epidermal growth factor (EGF) and nerve growth factor (NGF). In humans, however, the identity of the involved compounds has remained elusive, especially since EGF and NGF concentrations are approximately 100,000 times lower than those in rodent saliva. Using an in vitro model for wound closure, we examined the properties of human saliva and the fractions that were obtained from saliva by high-performance liquid chromotography (HPLC) separation. We identified histatin 1 (Hst1) and histatin 2 (Hst2) as major wound-closing factors in human saliva. In contrast, the d-enantiomer of Hst2 did not induce wound closure, indicating stereospecific activation. Furthermore, histatins were actively internalized by epithelial cells and specifically used the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway, thereby enhancing epithelial migration. This study demonstrates that members of the histatin family, which up to now were implicated in the antifungal weaponry of saliva, exert a novel function that likely is relevant for oral wound healing.

Cell-derived vesicles exposing coagulant tissue factor in saliva

“…This reflex has previously been explained by the presence of antimicrobial and wound-healing compounds, such as histatin, in saliva. 21 We hypothesized that there may be an alternative explanation for this reflex. For more than 70 years, human saliva has been known to contain a compound that efficiently triggers coagulation.…”

Salivary tissue factor induces thrombin generation in a diurnal rhythm

“…Saliva contains growth factors and histatin, which promote wound healing13, 14 and provide antimicrobial activity 15. In addition, saliva can serve as an additional source of extravascular TF to promote hemostasis.…”

Cationic Peptide Interactions with Biological Macromolecules

“…Histatins, a family of histidine-rich AMPs found in human saliva enter the cell in a receptor-mediated manner and target the mitochondria [74]. The histatin family consists of AMPs that have potent activity against fungi and constitutes an important aspect of antifungal and wound healing activity in the oral cavity [74,75]. It was found that histatin 5 kills intact Candida albicans without causing lysis and that spheroplasts (fragile with fragments of the cell wall) were 14-fold less susceptible compared to the intact cells.…”

“…It is generally noticeable that wounds in the oral cavity heal faster than skin lesions for example but it has emerged recently that this may be attributable to the histatin family, at least in part. At least two histatins have been identified as the major wound healing factors in human saliva [75]. Moreover this property was associated with active uptake of histatin by epithelial cells and the activation of an extracellular signal-regulated kinases ½ signalling pathway suggesting a mechanism by which these peptides effect their non-AMP role.…”