Activation of 5-HT4 receptors facilitates neurogenesis from transplanted neural stem cells in the anastomotic ileum.
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 × 10(5) 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.
Department of Molecular Pathology, Nara Medical University, School of Medicine, Kashihara, Nara, Japan.
Kei
K
Goto
Department of Molecular Pathology, Nara Medical University, School of Medicine, Kashihara, Nara, Japan.
Isao
I
Kawahara
Division of Homeostatic Development, Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, Aichi, Japan.
Hiroyuki
H
Inada
Department of Physiology II, Nara Medical University, School of Medicine, Kashihara, Nara, Japan.
Hiromi
H
Misawa
Department of Molecular Pathology, Nara Medical University, School of Medicine, Kashihara, Nara, Japan.
Hiroki
H
Kuniyasu
Division of Homeostatic Development, Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, Aichi, Japan.
Junich
J
Nabekura
Department of Physiology II, Nara Medical University, School of Medicine, Kashihara, Nara, Japan. mtakaki@naramed-u.ac.jp.|Department of Molecular Pathology, Nara Medical University, School of Medicine, Kashihara, Nara, Japan. mtakaki@naramed-u.ac.jp.|Department of Orthopedic Surgery, Nara Medical University, School of Medicine, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan. mtakaki@naramed-u.ac.jp.
Miyako
M
Takaki
D000714:Anastomosis, Surgical; D000818:Animals; D000906:Antibodies; D001549:Benzamides / Q000494:pharmacology*; D005456:Fluorescent Dyes; D007082:Ileum / Q000502:physiology* / Q000601:surgery; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology*; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology*; D009930:Organic Chemicals; D044422:Receptors, Serotonin, 5-HT4 / Q000235:genetics / Q000378:metabolism*; D058828:Serotonin 5-HT4 Receptor Agonists / Q000494:pharmacology*; D043222:Ubiquitin Thiolesterase / Q000276:immunology
D000906:Antibodies; D001549:Benzamides; D005456:Fluorescent Dyes; D009025:Morpholines; D009930:Organic Chemicals; C070080:PKH 26; D058828:Serotonin 5-HT4 Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4; D043222:Ubiquitin Thiolesterase; C496976:Uchl1 protein, mouse; C062720:mosapride
5-HT4 receptor; Granulation tissue; Myenteric neuron; Neural stem cells; YFP