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Growth factor-expressing human neural progenitor cell grafts protect motor neurons but do not ameliorate motor performance and survival in ALS mice

Authors
 Sungju Park  ;  Hyoung-Tae Kim  ;  Seokhwan Yun  ;  Il-Sun Kim  ;  Jiyoon Lee  ;  Il-Shin Lee  ;  Kook In Park 
Citation
 Experimental and Molecular Medicine, Vol.41(7) : 487-500, 2009 
Journal Title
 Experimental and Molecular Medicine 
ISSN
 1226-3613 
Issue Date
2009
MeSH
Adenoviridae/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Amyotrophic Lateral Sclerosis/mortality ; Amyotrophic Lateral Sclerosis/therapy* ; Animals ; Astrocytes/metabolism ; Brain/embryology* ; Cell Differentiation ; Disease Models, Animal ; Excitatory Amino Acid Transporter 2/metabolism ; Female ; Fetal Stem Cells/metabolism* ; Genetic Vectors ; Humans ; Immunoenzyme Techniques ; Male ; Mice ; Mice, Transgenic ; Motor Neurons/physiology* ; Nerve Growth Factors/metabolism* ; Stem Cell Transplantation* ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Transfection ; Vascular Endothelial Growth Factor A/genetics ; Vascular Endothelial Growth Factor A/metabolism
Keywords
amyotrophic lateral sclerosis ; cell differentiation ; glial cell line-derived neurotrophic factor ; nerve growth factors ; stem cell transplantation ; stem cells
Abstract
Neural progenitor cells (NPs) have shown several promising benefits for the treatment of neurological disorders. To evaluate the therapeutic potential of human neural progenitor cells (hNPs) in amyotrophic lateral sclerosis (ALS), we transplanted hNPs or growth factor (GF)-expressing hNPs into the central nervous system (CNS) of mutant Cu/Zn superoxide dismutase (SOD1(G93A)) transgenic mice. The hNPs were engineered to express brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), VEGF, neurotrophin-3 (NT-3), or glial cell-derived neurotrophic factor (GDNF), respectively, by adenoviral vector and GDNF by lentiviral vector before transplantation. Donor-derived cells engrafted and migrated into the spinal cord or brain of ALS mice and differentiated into neurons, oligodendrocytes, or glutamate transporter-1 (GLT1)-expressing astrocytes while some cells retained immature markers. Transplantation of GDNF- or IGF-1-expressing hNPs attenuated the loss of motor neurons and induced trophic changes in motor neurons of the spinal cord. However, improvement in motor performance and extension of lifespan were not observed in all hNP transplantation groups compared to vehicle-injected controls. Moreover, the lifespan of GDNF-expressing hNP recipient mice by lentiviral vector was shortened compared to controls, which was largely due to the decreased survival times of female animals. These results imply that although implanted hNPs differentiate into GLT1-expressing astrocytes and secrete GFs, which maintain dying motor neurons, inadequate trophic support could be harmful and there is sexual dimorphism in response to GDNF delivery in ALS mice. Therefore, additional therapeutic approaches may be required for full functional recovery.
Files in This Item:
T200902965.pdf Download
DOI
10.3858/emm.2009.41.7.054
Appears in Collections:
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아청소년과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Medical Research Center (임상의학연구센터) > 1. Journal Papers
Yonsei Authors
Kim, Il-Sun(김일선) ORCID logo https://orcid.org/0000-0003-4033-4323
Kim, Hyoung Tae(김형태)
Park, Kook In(박국인) ORCID logo https://orcid.org/0000-0001-8499-9293
Park, Sung Joo(박성주)
Yun, Seok Hwan(윤석환)
Lee, Il Shin(이일신)
Lee, Ji Yoon(이지윤)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/104521
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