title: Delivery of enteric neural progenitors with 5-HT4 agonist-loaded nanoparticles and thermosensitive hydrogel enhances cell proliferation and differentiation following transplantation in vivo.
abstract: Cell therapy offers an innovative approach for treating enteric neuropathies. Postnatal gut-derived enteric neural stem/progenitor cells (ENSCs) represent a potential autologous source, but have a limited capacity for proliferation and neuronal differentiation. Since serotonin (5-HT) promotes enteric neuronal growth during embryonic development, we hypothesized that serotonin receptor agonism would augment growth of neurons from transplanted ENSCs. Postnatal ENSCs were isolated from 2 to 4 week-old mouse colon and cultured with 5-HT4 receptor agonist (RS67506)-loaded liposomal nanoparticles. ENSCs were co-cultured with mouse colon explants in the presence of RS67506-loaded (n = 3) or empty nanoparticles (n = 3). ENSCs were also transplanted into mouse rectum in vivo with RS67506-loaded (n = 8) or blank nanoparticles (n = 4) confined in a thermosensitive hydrogel, Pluronic F-127. Neuronal density and proliferation were analyzed immunohistochemically. Cultured ENSCs gave rise to significantly more neurons in the presence of RS67506-loaded nanoparticles. Similarly, colon explants had significantly increased neuronal density when RS67506-loaded nanoparticles were present. Finally, following in vivo cell delivery, co-transplantation of ENSCs with 5-HT4 receptor agonist-loaded nanoparticles led to significantly increased neuronal density and proliferation. We conclude that optimization of postnatal ENSCs can support their use in cell-based therapies for neurointestinal diseases.
authors.affiliation: Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Ryo
authors.initials: R
authors.lastname: Hotta
authors.affiliation: Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.|Department of Surgery, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Lily
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Hannah K
authors.initials: HK
authors.lastname: Graham
authors.affiliation: Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.|Department of Human Morphology and Developmental Biology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Nandor
authors.initials: N
authors.lastname: Nagy
authors.affiliation: Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Belkind-Gerson
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, MA, USA.
authors.forename: George
authors.initials: G
authors.lastname: Mattheolabakis
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, MA, USA.
authors.forename: Mansoor M
authors.initials: MM
authors.lastname: Amiji
authors.affiliation: Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Allan M
authors.initials: AM
authors.lastname: Goldstein
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003692:Delayed-Action Preparations / Q000737:chemistry*; D017615:Enteric Nervous System / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D041981:Gastrointestinal Tract / Q000294:innervation; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000637:transplantation*; D055495:Neurogenesis / Q000187:drug effects*; D010523:Peripheral Nervous System Diseases / Q000628:therapy; D020442:Poloxamer / Q000737:chemistry*; D058828:Serotonin 5-HT4 Receptor Agonists / Q000008:administration & dosage* / Q000494:pharmacology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D013696:Temperature
chemical_list: D003692:Delayed-Action Preparations; D008081:Liposomes; D058828:Serotonin 5-HT4 Receptor Agonists; D013449:Sulfonamides; D020442:Poloxamer; C107556:RS 67506; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate
keywords: 5-HT(4) receptor agonist; Cell therapy; Enteric neuropathies; Liposomal nanoparticles; Serotonin; Thermosensitive hydrogel