Paracrine Loop of Keratinocyte Proliferation and Directed Neuritic Outgrowth in a Neuroepithelial Coculture

Abstract

In the absence of skin innervation, wound healing is delayed and chronic nonhealing wounds may occur. Keratinocytes produce neurotrophic factors, such as nerve growth factor (NGF), which has been suggested to attract primary cutaneous afferent axons and exert mitogenic effects on keratinocytes. The present study was performed to examine the interaction of primary human keratinocytes (hKTs) and rat cutaneous primary afferent dorsal root ganglion (DRG) neurons with regard to neuritic outgrowth and keratinocyte proliferation. Neuritic outgrowth was assessed with neurofilament immunostaining where cell bodies and fine neuritic processes were identified. Neuritic outgrowth of neurons alone in culture is spatially random and radial. Neurites in cocultures of DRG neurons insinuated between the hKTs and grew to "clumps" of hKTs within the cultures. Immunostaining with anti-NGF antibody indicates that hKTs expressed the neurotrophin NGF. Proliferation of keratinocytes was significantly enhanced in coculture with DRG and hKT, and NGF levels were increased as compared to DRG or hKT culture alone. These results indicate a dynamic interaction between DRG neurons and hKTs whereby the DRG neurons issue neurites in association with hKTs and the hKTs up-regulate NGF and increase their proliferation rate. These findings support the hypothesis that nerve-skin interactions play a significant role in wound healing.

Sensory nerve supports epithelial stem cell function in healing of corneal epithelium in mice: the role of trigeminal nerve transient receptor potential vanilloid 4

“…NGF and CGRP are both reportedly involved in acceleration of cell proliferation and wound healing in epidermis or corneal epithelium [60,61,68,69]. As described above, expression of CGRP was not affected by trigeminal denervation.…”

Characterization of NGF, trkANGFR, and p75NTRin Retina of Mice Lacking Reelin Glycoprotein

“…As reported, the loss of RGCs might be an outcome of the reduced crosstalk with the RBCs (synapses decline) [1]. NGF overexpression in RGCs or accessory/Müller cells might be also viewed as an attempt to stimulate RBC dendrites/arbors elongation, to (re)establish synaptic connections, or to provide a gradient for new dendrites [45–48]. As a support, p75 NTR binds both pro/mature forms of NGF and other neurotrophins (NTs, BDNF, NT3, and NT5), takes part in retrograde axonal transport of NTs (as survival or apoptotic factor), and works as a shuttle molecule for BDNF and NT4 (RBC survival NTs) [44, 49].…”

Epidermal expression of Lgr6 is dependent on nerve endings and Schwann cells

“…In the upper region, nerve endings dock to epidermal cells together with terminal Schwann cells, forming a specialized structure similar to the neuromuscular junction, enabling the hair follicle to sense the environment . The crosstalk between nerves and epidermal cells is important for morphogenesis and homeostasis .…”