Transplanting enteric neural stem cells (ENSCs) is an innovative approach for replacing enteric neurons in Hirschsprung's disease (HSCR). However, posttransplantation cell survival and differentiation limit efficacy. We aimed to investigate whether transplantation of ENSCs engineered with insulin-like growth factor 1 (IGF-1) could improve survival and differentiation of the engrafted cells and promote functional recovery of the aganglionic colon. ENSCs were isolated from the intestine of neonatal mice and genetically modified to express IGF-1. After implantation into the mice aganglionic colon induced by benzalkonium chloride, survival and differentiation of engrafted cells were assessed by immunohistochemistry for GFP, neuronal, and glial cell markers. Colonic motility was quantified by colonic bead expulsion time and response to electrical field stimulation (EFS). Expression of the neural marker nNOS and the glial cell marker (glial fibrillary acidic protein [GFAP]) was increased in IGF-1-ENSCs. IGF-1 had also improved neuroglial differentiation of ENSCs following transplantation in vivo. Colonic motility was significantly improved after IGF-1-ENSC transplantation, as demonstrated by reduction of colonic bead expulsion time and recovery of EFS-induced relaxation. IGF-1 has enhanced neurogenesis and function of ENSCs upon transplantation for enteric nervous system replacement, which may provide a potential novel therapy for the treatment of HSCR.
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References
1.
BakshiA., ShimizuS., KeckC.A., ChoS., LeBoldD.G., MoralesD., et al. (2006). Neural progenitor cells engineered to secrete GDNF show enhanced survival, neuronal differentiation and improve cognitive function following traumatic brain injury. Eur J Neurosci, 23, 2119–2134.
2.
BeckerL., KulkarniS., TiwariG., MicciM.A., and PasrichaP.J. (2012). Divergent fate and origin of neurosphere-like bodies from different layers of the gut. Am J Physiol, 302, G958–965.
3.
BelangerM., and MagistrettiP.J. (2009). The role of astroglia in neuroprotection. Dialogues Clin Neurosci, 11, 281–295.
4.
BettolliM., De CarliC., Jolin-DahelK., BaileyK., KhanH.F., SweeneyB., et al. (2008). Colonic dysmotility in postsurgical patients with Hirschsprung's disease. Potential significance of abnormalities in the interstitial cells of Cajal and the enteric nervous system. J Pediatr Surg, 43, 1433–1438.
5.
ChengC.M., MervisR.F., NiuS.L., SalemN.Jr., WittersL.A., TsengV., et al. (2003). Insulin-like growth factor 1 is essential for normal dendritic growth. J Neurosci Res, 73, 1–9.
6.
CooperJ.E., McCannC.J., NatarajanD., ChoudhuryS., BoesmansW., DelalandeJ.M., et al. (2016). In vivo transplantation of enteric neural crest cells into mouse gut; engraftment, functional integration and long-term safety. PLoS One, 11, e0147989.
7.
DettmannH.M., ZhangY., WronnaN., KraushaarU., GuentherE., MohrR., et al. (2014). Isolation, expansion and transplantation of postnatal murine progenitor cells of the enteric nervous system. PLoS One, 9, e97792.
8.
FindlayQ., YapK.K., BergnerA.J., YoungH.M., and StampL.A. (2014). Enteric neural progenitors are more efficient than brain-derived progenitors at generating neurons in the colon. Am J Physiol Gastrointest Liver Physiol, 307, G741–748.
9.
HetzS., AcikgoezA., VossU., NieberK., HollandH., HegewaldC., et al. (2014). In vivo transplantation of neurosphere-like bodies derived from the human postnatal and adult enteric nervous system: a pilot study. PLoS One, 9, e93605.
10.
HottaR., ChengL.S., GrahamH.K., PanW., NagyN., Belkind-GersonJ., et al. (2016). Isogenic enteric neural progenitor cells can replace missing neurons and glia in mice with Hirschsprung disease. Neurogastroenterol Motil, 28, 498–512.
11.
HottaR., StampL.A., FoongJ.P., McConnellS.N., BergnerA.J., AndersonR.B., et al. (2013). Transplanted progenitors generate functional enteric neurons in the postnatal colon. J Clin Investig, 123, 1182–1191.
12.
KrugerG.M., MosherJ.T., BixbyS., JosephN., IwashitaT., and MorrisonS.J. (2002). Neural crest stem cells persist in the adult gut but undergo changes in self-renewal, neuronal subtype potential, and factor responsiveness. Neuron, 35, 657–669.
13.
LakeJ.I., and HeuckerothR.O. (2013). Enteric nervous system development: migration, differentiation, and disease. Am J Physiol Gastrointest Liver Physiol, 305, G1–G24.
14.
LiuW., WuR., DongY., and GaoY. (2007). Neuroepithelial stem cells differentiate into neuronal phenotypes and improve intestinal motility recovery after transplantation in the aganglionic colon of the rat. Neurogastroent Motil, 19, 1001–1009.
15.
LiuW., YueW., and WuR. (2013). Overexpression of Bcl-2 promotes survival and differentiation of neuroepithelial stem cells after transplantation into rat aganglionic colon. Stem Cell Res Ther, 4, 7.
16.
LunnJ.S., PacutC., BackusC., HongY., JoheK., HefferanM., et al. (2010). The pleotrophic effects of insulin-like growth factor-I on human spinal cord neural progenitor cells. Stem Cells Dev, 19, 1983–1993.
17.
LunnJ.S., SakowskiS.A., McGinleyL.M., PacutC., HazelT.G., JoheK., et al. (2015). Autocrine production of IGF-I increases stem cell-mediated neuroprotection. Stem cells, 33, 1480–1489.
18.
MaJ., GuoC., GuoC., SunY., LiaoT., BeattieU., et al. (2015). Transplantation of human neural progenitor cells expressing IGF-1 enhances retinal ganglion cell survival. PLoS One, 10, e0125695.
19.
McGinleyL.M., SimsE., LunnJ.S., KashlanO.N., ChenK.S., BrunoE.S., et al. (2016). Human cortical neural stem cells expressing insulin like growth factor-I: a novel cellular Therapy for Alzheimer's disease. Stem Cells Transl Med, 5, 379–391.
20.
MetzgerM., BareissP.M., DankerT., WagnerS., HennenlotterJ., GuentherE., et al. (2009a). Expansion and differentiation of neural progenitors derived from the human adult enteric nervous system. Gastroenterology, 137, 2063–2073.e4.
21.
MetzgerM., CaldwellC., BarlowA.J., BurnsA.J., and ThaparN. (2009b). Enteric nervous system stem cells derived from human gut mucosa for the treatment of aganglionic gut disorders. Gastroenterology, 136, 2214–2225.e1–e3.
22.
NishikawaR., HottaR., ShimojimaN., ShibataS., NagoshiN., NakamuraM., et al. (2015). Migration and differentiation of transplanted enteric neural crest-derived cells in murine model of Hirschsprung's disease. Cytotechnology, 67, 661–670.
23.
NobleM., Fok-SeangJ., and CohenJ. (1984). Glia are a unique substrate for the in vitro growth of central nervous system neurons. J Neurosci, 4, 1892–1903.
24.
RintalaR,J, and PakarinenM.P. (2012). Long-term outcomes of Hirschsprung's disease. Semin Pediatr Surg, 21, 336–343.
25.
RiveraL.R., PooleD.P., ThackerM., and FurnessJ.B. (2011). The involvement of nitric oxide synthase neurons in enteric neuropathies. Neurogastroenterol Motil, 23, 980–988.
26.
ShuX., MengQ., JinH., ChenJ., XiaoY., JiJ., et al. (2013). Treatment of aganglionic megacolon mice via neural stem cell transplantation. Mol Neurobiol, 48, 429–437.
27.
SuzukiM., and SvendsenC.N. (2008). Combining growth factor and stem cell therapy for amyotrophic lateral sclerosis. Trends Neurosci, 31, 192–198.
28.
WaelE., and TracyG. (2014). Enteric nervous system cell replacement therapy for Hirschsprung disease: beyond tissue-engineered intestine. Eur J Pediatr Surg, 24, 214–218.
