title: Use of a Human Artificial Chromosome for Delivering Trophic Factors in a Rodent Model of Amyotrophic Lateral Sclerosis.
abstract: A human artificial chromosome (HAC) is maintained as an episome within a cell and avoids random integration into the host genome. It can transfer multiple and/or large transgenes along with their regulatory elements thereby resembling native chromosomes. Using this HAC system, we established mesenchymal stem cells (MSCs) that simultaneously expressed hepatocyte growth factor, glial cell line-derived neurotrophic factor, and insulin-like growth factor 1, termed HAC-MSCs. This cell line provides an opportunity for stable transplantation and thorough analyses. We then introduced the cells for the treatment of a neurodegenerative disorder, amyotrophic lateral sclerosis. The HAC-MSCs were transplanted via the fourth cerebral ventricle (CV) or intravenous (i.v.) infusion at various ages of recipient mice. Littermate- and sex-matched mice underwent a sham procedure. Compared to the controls, there was an encouraging trend of increased life span via CV transplantation and delayed onset in i.v. infusion 60 days after transplantation. Further, we confirmed a statistically significant increase in life span via CV transplantation at 100 days. This effect was not seen in mice transplanted with MSCs lacking the HAC. We successfully enhanced the trophic potential of the MSCs using the HAC. This strategy could be a promising direction for the treatment of neurodegenerative disorders.
authors.affiliation: Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, Japan.|Chromosome Engineering Research Center, Tottori University, Yonago, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kazuki
authors.affiliation: Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, Japan.|Chromosome Engineering Research Center, Tottori University, Yonago, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Kazuki
authors.affiliation: Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan.
authors.forename: Mitsutaka
authors.initials: M
authors.lastname: Ebiki
authors.affiliation: Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan.
authors.forename: Mami
authors.initials: M
authors.lastname: Nakanishi
authors.affiliation: Division of Laboratory Animal Science, Research Center for Bioscience and Technology, Tottori University, Yonago, Japan.
authors.forename: Kazuomi
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Yoshida Yamakawa
authors.affiliation: Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hosokawa
authors.affiliation: Division of Laboratory Animal Science, Research Center for Bioscience and Technology, Tottori University, Yonago, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ohbayashi
authors.affiliation: Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, Japan.|Chromosome Engineering Research Center, Tottori University, Yonago, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Oshimura
authors.affiliation: Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakashima