Activation of 5-HT<sub>4</sub> receptors facilitates neurogenesis of injured enteric neurons at an anastomosis in the lower gut
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- Takaki Miyako
- Department of Physiology II, Nara Medical University, School of Medicine, Kashihara, Nara, Japan Department of Molecular Pathology, Nara Medical University, School of Medicine, Kashihara, Nara, Japan Department of Orthopedic Surgery, Nara Medical University, School of Medicine, Kashihara, Nara, Japan
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- Goto Kei
- Department of Molecular Pathology, Nara Medical University, School of Medicine, Kashihara, Nara, Japan
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- Kawahara Isao
- Department of Molecular Pathology, Nara Medical University, School of Medicine, Kashihara, Nara, Japan
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- Nabekura Junich
- Division of Homeostatic Development, Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, Aichi, Japan
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抄録
Two-photon microscopy (2PM) can enable high-resolution deep imaging of thick tissue by exciting a fluorescent dye and protein at anastomotic sites in the mouse small intestine in vivo. We performed gut surgery and transplanted neural stem cells (NSC) from the embryonic central nervous system after marking them with the fluorescent cell linker, PKH26. We found that neurons differentiated from transplanted NSC (PKH [+]) and newborn enteric neurons differentiated from mobilized (host) NSC (YFP [+]) could be localized within the granulation tissue of anastomoses. A 5-HT4-receptor agonist, mosapride citrate (MOS), significantly increased the number of PKH (+) and YFP (+) neurons by 2.5-fold (P<0.005). The distribution patterns of PKH (+) neurons were similar to those of YFP (+) neurons. On the other hand, the 5-HT4-receptor antagonist, SB-207266 abolished these effects of MOS. These results indicate that neurogenesis from transplanted NSC is facilitated by activation of 5-HT4-receptors. Thus, a combination of drug administration and cell transplantation could be more beneficial than exclusive cell transplantation in treating Hirschsprung’s disease and related disorders including post rectal cancer surgery. The underlying mechanisms for its action were explored using immunohistochemistry of the longitudinal mouse ileum and rat rectal preparations including an anastomosis. MOS significantly increased the number of new neurons, but not when co-administered with either of a protein tyrosine kinase receptor, c-RET two inhibitors. The c-RET signaling pathway contributes to enteric neurogenesis facilitated by MOS. In the future, we would perform functional studies of new neurons over the thick granulation tissue at anastomoses, using in vivo imaging with 2PM and double transgenic mice expressing a calcium indicator such as GCaMP6 and channelrhodopsin.<br>
収録刊行物
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- Ｊｏｕｒｎａｌ ｏｆ Ｓｍｏｏｔｈ Ｍｕｓｃｌｅ Ｒｅｓｅａｒｃｈ
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Ｊｏｕｒｎａｌ ｏｆ Ｓｍｏｏｔｈ Ｍｕｓｃｌｅ Ｒｅｓｅａｒｃｈ 51 (0), 82-94, 2015
日本平滑筋学会