Activation of 5-HT4 receptors facilitates neurogenesis from transplanted neural stem cells in the anastomotic ileum.

Kei Goto,Hiroki Kuniyasu,Hiromi Misawa,Hiroyuki Inada,Miyako Takaki,Junich Nabekura,Isao Kawahara

doi:10.1007/s12576-015-0396-1

Abstract

An orally administered serotonin-4 (5-HT4) receptor agonist, mosapride citrate (MOS), promotes enteric neurogenesis in anastomoses after gut surgery. We performed gut surgery and transplanted 2 × 105 neural stem cells (NSCs) from the embryonic central nervous system after marking them with the cell linker, PKH26. We found that neurons differentiated from transplanted NSCs (PKH [+]) and newborn enteric neurons differentiated from mobilized (host) NSCs (YFP [+]) in the deep granulation tissue of the anastomotic ileum. MOS significantly increased the number of PKH (+) and YFP (+) neurons by 2.5-fold (P < 0.005) (n = 4). The distribution patterns of PKH (+) neurons and YFP (+) neurons were similar along the depth of the anastomosis. A 5-HT4 receptor antagonist, SB-207266, abolished these effects of MOS (n = 4). Our results indicate that neurogenesis from transplanted NSCs is potentiated by activation of 5-HT4 receptors. Thus, a combination of drug administration and cell transplantation could be more beneficial than cell transplantation alone in treating Hirschsprung’s disease and related disorders.

Highlights

We have previously shown that enteric neural 5-HT4 receptors activated by mosapride citrate (MOS) promote reconstruction of the impaired enteric neural circuit after transection and formation of an anastomosis
As the preliminary for cell transplantation, we examined the effects of MOS on neural stem cells (NSCs) in culture
We confirmed that enteric neurons were visible in vivo in the terminal ileum, which had a maximal thickness of 50 lm at the myenteric ganglion level in an intact Thy1-YFP mouse

Summary

Introduction

We have previously shown that enteric neural 5-HT4 receptors activated by mosapride citrate (MOS) promote reconstruction of the impaired enteric neural circuit after transection and formation of an anastomosis. This treatment promoted recovery of the ‘‘defecating reflex’’ [1, 2] in the rectum of guinea pigs [3]. This plasticity of enteric neurons is brought about by mobilized neural stem cells (NSCs) [3]. Liu et al [6] demonstrated that neuroprotection and/or neurogenesis in the adult mouse enteric nervous system (ENS) is mediated by 5-HT4 receptor

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Results

Conclusion