4.4 Article

X-linked severe combined immunodeficiency (X-SCID) rats for xeno-transplantation and behavioral evaluation

期刊

JOURNAL OF NEUROSCIENCE METHODS
卷 243, 期 -, 页码 68-77

出版社

ELSEVIER SCIENCE BV
DOI: 10.1016/j.jneumeth.2015.01.027

关键词

Severe combined immunodeficiency rats; Xeno-transplantation; Parkinson's disease; Dopaminergic neurons; 6-Hydroxydopamine; Immune response

资金

  1. Highway Project for Realization of Regenerative Medicine from the Ministry of Education, Culture, Sports, Science and Technology (MEXT)
  2. Network Program for Realization of Regenerative Medicine from the Japan Science and Technology Agency (JST)
  3. Grants-in-Aid for Scientific Research [26290033] Funding Source: KAKEN

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Background: To evaluate the in vivo function of human dopaminergic (DA) neurons, Parkinson's disease (PD) model rats made by the hemi-lateral injection of 6-hydroxydopamine (6-OHDA) are widely used as host animals. In the case of such xeno-transplantation, however, immunosuppression is needed for good survival of the grafted cells. New methods: In order to determine whether human mature neurons can survive in X-linked severe combined immunodeficiency (X-SCID) rats without immunosuppression, we grafted human embryonic stem cell (ESC)-derived DA neurons into the striatum of X-SCID rats. We next treated the X-SCID rats with 6-OHDA and grafted mouse fetal DA neurons or human induced pluripotent stem cell (iPSC)-derived DA neurons to examine whether these rats can be used as PD model rats. Results: X-SCID rats did not elicit immune responses against human ESC-derived DA neurons and consequently resulted in good survival of the cells without immunosuppression. Furthermore, 6-OHDA-lesioned X-SCID rats exhibited rotational behavior, which was recovered by grafting mouse fetal DA neurons or human iPSC-derived DA neurons. Comparison with existing methods: Immunosuppression by drugs such as Cyclosporine A requires daily injection, which is stressful for rats and moreover may cause renal or hepatic failure. Furthermore, blood levels of the drug may not be stable, which weakens the reliability of the data. Conclusions: Our results provide a more accessible and reliable method to evaluate the in vivo function of human DA neurons, potentially offering a pre-clinical study for the application of pluripotent stem cells. (C) 2015 Elsevier B.V. All rights reserved.

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