Neurotrophin-Induced Migration and Neuronal Differentiation of Multipotent Astrocytic Stem Cells In Vitro

Abstract

Hypoxic ischemic encephalopathy (HIE) affects 2–3 per 1000 full-term neonates. Up to 75% of newborns with severe HIE die or have severe neurological handicaps. Stem cell therapy offers the potential to replace HIE-damaged cells and enhances the autoregeneration process. Our laboratory implanted Multipotent Astrocytic Stem Cells (MASCs) into a neonatal rat model of hypoxia-ischemia (HI) and demonstrated that MASCs move to areas of injury in the cortex and hippocampus. However, only a small proportion of the implanted MASCs differentiated into neurons. MASCs injected into control pups did not move into the cortex or differentiate into neurons. We do not know the mechanism by which the MASCs moved from the site of injection to the injured cortex. We found neurotrophins present after the hypoxic-ischemic milieu and hypothesized that neurotrophins could enhance the migration and differentiation of MASCs. Using a Boyden chamber device, we demonstrated that neurotrophins potentiate the in vitro migration of stem cells. NGF, GDNF, BDNF and NT-3 increased stem cell migration when compared to a chemokinesis control. Also, MASCs had increased differentiation toward neuronal phenotypes when these neurotrophins were added to MASC culture tissue. Due to this finding, we believed neurotrophins could guide migration and differentiation of stem cell transplants after brain injury.

Sexual dimorphism in BDNF signaling after neonatal hypoxia–ischemia and treatment with necrostatin-1

“…BDNF is a therapeutic target in neonatal brain injury because of its putative role in brain plasticity, enhancing neuronal survival, migration and differentiation, supporting neurogenesis and improving outcomes in adult ischemic and neonatal HI models (Marini et al, 2007, Yasuhara et al, 2010, Douglas-Escobar et al, 2012, Han et al, 2012, Rosenkranz et al, 2012). However, early BDNF exposure after oxidative stress and oxygen-glucose deprivation injury may also exacerbate neuronal death (Gwag et al, 1995, Koh et al, 1995, Kim et al, 2003).…”

Brain-region specific responses of astrocytes to an in vitro injury and neurotrophins

“…While NGF promoted the repopulation of the wound in astrocytes from all brain areas, BDNF only stimulated the striatal astrocytes. An effect of NGF and BDNF on migration of multipotent astrocytic stem cells has been reported earlier (Douglas-escobar et al, 2012). Although they used higher concentrations of NGF, ranging from 200 to 400 ng/mL to induce the wound closure.…”

Advances in Neo-Innervation of the Gut

“…Studies on ENS development during embryogenesis have exposed a number of factors that promote enteric neural migration, including GDNF. In the central nervous system (CNS), neurotrophic factors have been identified to induce migration of progenitor cells including, NGF, GDNF, BDNF, and NT-3 [48]. Additionally, over-expression of the neurotrophin receptor tyrosine kinase C (TrkC) similarly increased migration of neural progenitor cells in the spinal cord [49].…”