Abstract
To explore a potential methodology for treating aganglionic megacolon, neural stem cells (NSCs) expressing engineered endothelin receptor type B (EDNRB) and glial cell-derived neurotrophic factor (GDNF) genes were transplanted into the aganglionic megacolon mice. After transplantation, the regeneration of neurons in the colon tissue was observed, and expression levels of differentiation-related genes were determined. Primary culture of NSCs was obtained from the cortex of postnatal mouse brain and infected with recombinant adenovirus expressing EDNRB and GDNF genes. The mouse model of aganglionic megacolon was developed by treating the colon tissue with 0.5 % benzalkonium chloride (BAC) to selectively remove the myenteric nerve plexus that resembles the pathological changes in the human congenital megacolon. The NSCs stably expressing the EDNRB and GDNF genes were transplanted into the benzalkonium chloride-induced mouse aganglionic colon. Survival and differentiation of the implanted stem cells were assessed after transplantation. Results showed that the EDNRB and GDNF genes were able to be expressed in primary culture of NSCs by adenovirus infection. One week after implantation, grafted NSCs survived and differentiated into neurons. Compared to the controls, elevated expression of EDNRB and GDNF was determined in BAC-induced aganglionic megacolon mice with partially improved intestinal function. Those founding indicated that the genes transfected into NSCs were expressed in vivo after transplantation. Also, this study provided favorable support for the therapeutic potential of multiple gene-modified NSC transplantation to treat Hirschsprung’s disease, a congenital disorder of the colon in which ganglion cells are absent.
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References
Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–1710
Grundy D, Schemann M (2007) Enteric nervous system. Curr Opin Gastroenterol 23:121–126
Temple S (2001) The development of neural stem cells. Nature 1414:112–117
Amar AP, Zlokovic BV, Apuzzo ML (2003) Endovascular restorative neurosurgery: A novel concept for molecular and cellular therapy of the nervous system. Neurosurgery 52:402–412
Modo M, Rezaie P, Heuschling P et al (2002) Transplantation of neural stem cells in a rat model of stroke: Assessment of short-term graft survival and acute host immunological response. Brain Res 958:70–82
Gonzalez-Gomez P, Sanchez P, Mira H (2011) MicroRNAs regulators of neural stem cell-related pathways in glioblastoma multiforme. Mol Neurobiol 44:235–249
Rauch U, Hänsgen A, Hagl C et al (2006) Isolation and cultivation of neuronal precursor cells from the developing human enteric nervous system as a tool for cell therapy in dysganglionosis. Int J Colorectal Dis 21:554–559
Lindley RM, Hawcutt DB, Connell MG et al (2008) Human and mouse enteric nervous system neurosphere transplants regulate the function of aganglionic embryonic distal colon. Gastroenterology 135:205–216
Micci MA, Kahrig KM, Simmons RS et al (2005) Neural stem cell transplantation in the stomach rescues gastric function in neuronal nitric oxide synthase-deficient mice. Gastroenterology 129:1817–1824
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Shu, X., Meng, Q., Jin, H. et al. Treatment of Aganglionic Megacolon Mice via Neural Stem Cell Transplantation. Mol Neurobiol 48, 429–437 (2013). https://doi.org/10.1007/s12035-013-8430-x
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DOI: https://doi.org/10.1007/s12035-013-8430-x