title: Transplantation of insulin-secreting multicellular spheroids for the treatment of type 1 diabetes in mice.
abstract: The efficacy of cell-based therapy depends on the function and survival of transplanted cells, which have been suggested to be enhanced by spheroid formation. However, few attempts at spheroid generation from insulin-secreting cells, which may be used to treat type 1 diabetes, have been reported. We therefore developed spheroids from the mouse insulinoma cell line NIT-1 by using polydimethylsiloxane (PDMS)-based microwells with a coating of poly(N-isopropylacrylamide) (PNIPAAm). The prepared NIT-1 spheroids or dissociated NIT-1 cells were transplanted into the subrenal capsule in streptozotocin-induced diabetic mice. NIT-1 spheroids prepared using the PNIPAAm-coated PDMS-based microwells had a uniformly sized spherical structure with a diameter of 200-300μm. The PNIPAAm coating increased cell survival in the spheroids and the recovery of the spheroids from the microwells. In diabetic mice, the transplanted NIT-1 spheroids reduced blood glucose levels to normal values faster than dissociated NIT-1 cells did. Additionally, survival was higher among NIT-1 cells in spheroids than among dissociated NIT-1 cells 24h after transplantation. These results indicate that insulin-secreting NIT-1 spheroids prepared using PNIPAAm-coated PDMS-based microwells are more effective for the treatment of type 1 diabetes than dissociated cells in suspension.
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshidashimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kusamori
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshidashimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Institute for Innovative NanoBio Drug Discovery and Development, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-20 Yoshida-shimoadachi, Sakyo-ku, Kyoto 606-8501, Japan; Institute for Integrated Cell-Material Sciences, Kyoto University, Yoshida Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: makiya@pharm.kyoto-u.ac.jp.
authors.forename: Makiya
authors.initials: M
authors.lastname: Nishikawa
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshidashimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Narumi
authors.initials: N
authors.lastname: Mizuno
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshidashimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nishikawa
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshidashimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Masuzawa
authors.affiliation: Institute for Innovative NanoBio Drug Discovery and Development, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-20 Yoshida-shimoadachi, Sakyo-ku, Kyoto 606-8501, Japan; Ritsumeikan-Global Innovation Research Organization, Ritsumeikan University, Nojihigashi 1-1-1, Kusatsu, Shiga 525-8577, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Shimizu
authors.affiliation: Institute for Innovative NanoBio Drug Discovery and Development, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-20 Yoshida-shimoadachi, Sakyo-ku, Kyoto 606-8501, Japan; Ritsumeikan-Global Innovation Research Organization, Ritsumeikan University, Nojihigashi 1-1-1, Kusatsu, Shiga 525-8577, Japan; Department of Micro System Technology, Ritsumeikan University, 1-1-1 Noji-higashi, Kusatsu, Shiga 525-8577, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Konishi
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshidashimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Institute for Integrated Cell-Material Sciences, Kyoto University, Yoshida Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshidashimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Institute for Innovative NanoBio Drug Discovery and Development, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-20 Yoshida-shimoadachi, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Takakura
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry; D000818:Animals; D018929:Cell Culture Techniques / Q000379:methods; D002460:Cell Line; D002470:Cell Survival; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000601:surgery / Q000628:therapy; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000601:surgery* / Q000628:therapy; D004129:Dimethylpolysiloxanes / Q000737:chemistry; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018874:Spheroids, Cellular / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*
chemical_list: D000180:Acrylic Resins; D004129:Dimethylpolysiloxanes; D007328:Insulin; C052970:poly-N-isopropylacrylamide; C013830:baysilon; D005947:Glucose
keywords: Allogeneic cell; Cell viability; Diabetes; Multicellular spheroid; Silicone elastomer; Transplantation