Growth factor-expressing human neural progenitor cell grafts protect motor neurons but do not ameliorate motor performance and survival in ALS mice.
10.3858/emm.2009.41.7.054
- Author:
Sungju PARK
1
;
Hyoung Tae KIM
;
Seokhwan YUN
;
Il Sun KIM
;
Jiyoon LEE
;
Il Shin LEE
;
Kook In PARK
Author Information
1. Department of Pediatrics, Yonsei University College of Medicine, Seoul 120-752, Korea. kipark@yuhs.ac
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
amyotrophic lateral sclerosis;
cell differentiation;
glial cell line-derived neurotrophic factor;
nerve growth factors;
stem cell transplantation;
stem cells
- MeSH:
Adenoviridae/genetics;
Amyotrophic Lateral Sclerosis/metabolism/mortality/*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;
Transfection;
Vascular Endothelial Growth Factor A/genetics/metabolism
- From:Experimental & Molecular Medicine
2009;41(7):487-500
- CountryRepublic of Korea
- Language:English
-
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 (SOD(1G93A)) 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.
