title: Fusion of Human Fetal Mesenchymal Stem Cells with "Degenerating" Cerebellar Neurons in Spinocerebellar Ataxia Type 1 Model Mice.
abstract: Mesenchymal stem cells (MSCs) migrate to damaged tissues, where they participate in tissue repair. Human fetal MSCs (hfMSCs), compared with adult MSCs, have higher proliferation rates, a greater differentiation capacity and longer telomeres with reduced senescence. Therefore, transplantation of quality controlled hfMSCs is a promising therapeutic intervention. Previous studies have shown that intravenous or intracortical injections of MSCs result in the emergence of binucleated cerebellar Purkinje cells (PCs) containing an MSC-derived marker protein in mice, thus suggesting a fusion event. However, transdifferentiation of MSCs into PCs or transfer of a marker protein from an MSC to a PC cannot be ruled out. In this study, we unequivocally demonstrated the fusion of hfMSCs with murine PCs through a tetracycline-regulated (Tet-off) system with or without a Cre-dependent genetic inversion switch (flip-excision; FLEx). In the FLEx-Tet system, we performed intra-cerebellar injection of viral vectors expressing tetracycline transactivator (tTA) and Cre recombinase into either non-symptomatic (4-week-old) or clearly symptomatic (6-8-month-old) spinocerebellar ataxia type 1 (SCA1) mice. Then, the mice received an injection of 50,000 genetically engineered hfMSCs that expressed GFP only in the presence of Cre recombinase and tTA. We observed a significant emergence of GFP-expressing PCs and interneurons in symptomatic, but not non-symptomatic, SCA1 mice 2 weeks after the MSC injection. These results, together with the results obtained using age-matched wild-type mice, led us to conclude that hfMSCs have the potential to preferentially fuse with degenerating PCs and interneurons but not with healthy neurons.
authors: Department of Neurophysiology & Neural Repair, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.|Physiology Division, Department of Anatomy Physiology and Cell Biology, Faculty of Medicine Universitas Padjadjaran, Bandung, 40161, Indonesia.
authors: Fathul
authors: http://orcid.org/0000-0002-4818-1862
authors: F
authors: Huda
authors: Department of Reproductive Medicine, KK Women's and Children's Hospital, 229899, Singapore.|Experimental Fetal Medicine Group, Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University Health System, 119228, Singapore.
authors: Yiping
authors: Y
authors: Fan
authors: Department of Neurophysiology & Neural Repair, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors: Mamiko
authors: M
authors: Suzuki
authors: Department of Neurophysiology & Neural Repair, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors: Ayumu
authors: A
authors: Konno
authors: Department of Neurophysiology & Neural Repair, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors: Yasunori
authors: Y
authors: Matsuzaki
authors: Department of Neurophysiology & Neural Repair, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors: Nobutaka
authors: N
authors: Takahashi
authors: Department of Reproductive Medicine, KK Women's and Children's Hospital, 229899, Singapore.|Experimental Fetal Medicine Group, Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University Health System, 119228, Singapore.|Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 169857, Singapore.
authors: Jerry K Y
authors: JK
authors: Chan
authors: Department of Neurophysiology & Neural Repair, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors: Hirokazu
authors: H
authors: Hirai
mesh_terms: D000818:Animals; D000067696:Ataxin-1 / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D054338:Cell Transdifferentiation / Q000502:physiology; D002531:Cerebellum / Q000166:cytology* / Q000378:metabolism; D004195:Disease Models, Animal; D053686:Fetal Stem Cells / Q000166:cytology / Q000378:metabolism; D005333:Fetus / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D011689:Purkinje Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D000067696:Ataxin-1; C000593750:Atxn1 protein, mouse