Parasympathetic stimulation improves epithelial organ regeneration

Abstract

Parasympathetic nerves are a vital component of the progenitor cell niche during development, maintaining a pool of progenitors for organogenesis. Injured adult organs do not regenerate after parasympathectomy, and there are few treatments to improve organ regeneration, particularly after damage by therapeutic irradiation. Here we show that restoring parasympathetic function with the neurotrophic factor neurturin increases epithelial organ regeneration after damage. We use mouse salivary gland explant culture containing fluorescently-labeled progenitors, and injure the tissue with irradiation. The progenitors survive, parasympathetic function is diminished, and epithelial apoptosis reduces expression of neurturin, which increases neuronal apoptosis. Treatment with neurturin reduces neuronal apoptosis, restores parasympathetic function, and increases epithelial regeneration. Furthermore adult human salivary glands damaged by irradiation also have reduced parasympathetic innervation. We propose that neurturin will protect the parasympathetic nerves from damage and improve organ regeneration. This concept may be applicable for other organs where parasympathetic innervation influences their function.

Enhanced Neurogenic Biomarker Expression and Reinnervation in Human Acute Skin Wounds Treated by Electrical Stimulation

“…Several biomarkers for neural differentiation have been identified, including mitotic spindle components (7) and lipid membrane domains (8). Microtubule protein-Class III β-tubulin (TUBB3) has been classified as a neural-specific differentiation marker (9) of reinnervation in tissue regeneration (10), although at least one report suggests expression by non-neural cell types (11). Factor Induced Gene 4 (FIG4), a key plasma membrane protein with critical roles in phosphatidylinositol (3,4,5)-triphosphate (PI(3,4,5)P 3 or PIP 3 ) synthesis and neural differentiation (12), has also been established as a biomarker for reinnervation.…”

Rescue Effects and Underlying Mechanisms of IntraglandShhGene Delivery on Irradiation-Induced Hyposalivation

“…5 Hyposalivation exacerbates dental caries and periodontal disease and causes problems of mastication, swallowing, sleep, and speech, a burning sensation of the mouth, and dysgeusia, which severely impair the quality of life of patients. The irreversible hyposalivation is caused by the loss or impairment of saliva-producing acinar cells and their replacement by connective tissue and fibrosis, which has been attributed to the loss of functional glandular stem/progenitor cells 6 and the impairment of parasympathetic innervation 7 and microvessels. 8 Current treatments for IR-induced xerostomia, such as artificial saliva and saliva secretion stimulators, can only temporarily relieve these symptoms.…”

Roles of innervation in developing and regenerating orofacial tissues

“…In these patients parasympathetic innervation of salivary glands is strongly compromised; its restoration through the addition of specific neurotrophic factors resulted in salivary gland regeneration in vitro. [67]. Proper innervation is also needed to obtain fully functional organs.…”

“…Generally repulsive [1,67] Ephrins Eph Kinases [9] Contact repulsion [9] Extracellular Matrix (ECM) components (E.g. Laminin, Fibronectin)…”

“…Mainly integrins [67] Contact adhesion or repulsion [67] Cell Adhesion Molecules (CAMs) (IgSF-CAMs, Cadherins) Homophilic or heterophilic interactions within class [67] Contact adhesion or repulsion [67] Prototypic myelin inhibitors (Nogo-A, MAG, OMgp) NgR1, NgR2, Lingo1, p75NTR, TNFR, PirB, Integrins [11,12] Inhibitors of axonal growth and regeneration; restriction of axonal plasticity [11,12] …”