Placenta Growth Factor is Induced in Human Keratinocytes during Wound Healing

Abstract

Placenta growth factor (PlGF) is a dimeric glycoprotein, structurally and functionally related to the vascular endothelial growth factor, a potent angiogenic/permeability factor known to play a role in the neoangiogenesis during wound repair. In this study we evaluated the expression of PlGF in human keratinocytes and investigated its possible role in wound healing. Northern blot analysis on cultured keratinocytes revealed a 1.7 kb mRNA transcript and reverse transcriptase-polymerase chain reaction allowed the detection of two PlGF isoforms generated by alternative RNA splicing. PlGF and vascular endothelial growth factor homodimers as well as vascular endothelial growth factor/PlGF heterodimers could be detected in keratinocyte conditioned medium. Increased expression of both PlGF mRNA and protein was observed upon treatment of keratinocytes with epidermal growth factor, transforming growth factor-alpha, transforming growth factor-beta, and interleukin-6, all cytokines present at the wound site during the early phase of repair. The analysis of human full-thickness healing wounds revealed appreciable levels of PlGF mRNA and protein in the migrating keratinocytes starting from day 3 after injury, and increasing at day 5. At day 7 PlGF mRNA was no longer detectable, while the protein was still expressed by migrating suprabasal keratinocytes. At day 13, when the wound had reepithelialized, PlGF immunostaining was completely negative. By in situ hybridization an intense signal for PlGF was also found on endothelial capillaries adjacent to the wound. These data demonstrate that keratinocytes are a source of PlGF during wound healing in vivo and indicate a role for this factor in the neoangiogenesis process associated with cutaneous wound repair.

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

“…PlGF recruits mesenchymal progenitors in endochondral ossification (Fiedler et al 2005), stimulates keratinocyte migration in wound healing (Failla et al 2000), and enhances chemotaxis of retinal pigment epithelial cells (Hollborn et al 2006). It also promotes survival of cortical neurons (Du et al 2010), promotes axon growth cone formation of dorsal root ganglion neurons , and stimulates proliferation and migration of Schwann cells (Chaballe et al 2011a).…”

“…In the skin, PlGF expression is up-regulated during wound healing (Failla et al 2000;Kagawa et al 2009), and PlGF-deficient mice show delayed wound closure (Carmeliet et al 2001). This finding is corroborated by results that PlGF gene or protein delivery in the skin stimulates angiogenesis, macrophage infiltration, granulation tissue formation, keratinocyte migration and healing of skin wounds in normal mice as well as in diabetic mice, which suffer impaired wound healing (Carmeliet et al 2001;Cianfarani et al 2006;Odorisio et al 2006).…”

The effect of Mindfulness-Based Stress Reduction on wound healing: a preliminary study

“…In addition to cytokines, growth factors such as vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are important for wound repair (Failla et al 2000;Johnson and Wilgus 2014). The role of VEGF in particular is well documented and considered important in stimulating the formation of new blood vessels (i.e.…”

Placenta Growth Factor in Diabetic Wound Healing

“…17,18 In adult skin, PlGF expression is barely detectable, and it is up-regulated in association with both physiological and pathological neoangiogenesis, such as in the hair follicle cycle, 19 during wound healing, 20 and in melanoma cells. 21,22 During the angiogenic phase of wound healing, PlGF is expressed by migrating keratinocytes and endothelial cells of small blood vessels, acting in a paracrine and autocrine way on VEGFR-1-expressing endothelium.…”

“…21,22 During the angiogenic phase of wound healing, PlGF is expressed by migrating keratinocytes and endothelial cells of small blood vessels, acting in a paracrine and autocrine way on VEGFR-1-expressing endothelium. 20 Moreover, lack of PlGF results in delayed wound closure, indicating that this factor is required for optimal skin repair. 4 By using streptozotocin-induced diabetic mice, a mouse model of type-1 diabetes, we investigated whether PlGF may be involved in the healing impairment of diabetic cutaneous wounds.…”