New Therapeutic Strategies for Amyotrophic Lateral Sclerosis Treatment

Amyotrophic lateral sclerosis (ALS) is characterized by progressive dysfunction and degeneration of motor neurons in cerebral cortex, brain stem and spinal cord. Degeneration of motor neurons causes muscle weakness and respiratory paralysis, leading to decease of ALS patients. Approximately 10% of the cases are familial and 20% of those are dominantly inherited mutations in superoxide dismutase 1 (SOD1). The transgenic animal model of ALS was the G93A mouse that expresses a mutant form of human SOD1 carrying the Gly93 → Ala and develops motor neuron disease similar to familial ALS. With the lack of effective drug treatments for ALS and compelling preclinical data, new therapeutic strategies have highlighted this disease as a candidate for stem cell treatment. Here we investigated whether neural induction enhances therapeutic potentials of mesenchymal stem cells (MSCs). We induced neural induction of MSCs by overexpressing Neurogenin1, a proneural transcription factor. Depending on transplantation time, systemic transplantation of Ngn1-expressing MSCs (MSCs-Ngn1) delayed the onset of neurobehavioral degeneration or dramatically improved motor functions compared to parental MSCs in mice carrying a high copy number of a human mutant SOD1(G93A) transgene. We found that compared to MSCs, more MSCs-Ngn1 were found in hippocampus, brainstem, and the spinal cord, where most of them remained undifferentiated. We also found that more motor neurons were preserved in the spinal cord of animals with MSCs-Ngn1, suggesting that MSCs-Ngn1 migrate to the central nervous system and exert beneficial effects on host neural cells through paracrine signaling for extended period of time. Our findings strongly suggest potential benefits of neural induction of MSCs to develop successful stem cell therapy for the treatment of ALS. Glial cell line-derived neurotrophic factor (GDNF), which has been demonstrated to be the most potent neurotrophic factor for the proliferation, differentiation, and survival of spinal motor neurons, exhibits very good therapeutic potential for ALS. MSCs were infected with recombinant adenovirus GDNF (MSCs-GDNF). The MSCs-GDNF were transplanted into tail vein of ALS mice (13, 15 weeks of age), and the animals were evaluated on health and behavioral measures. Transplantation of the MSC-GDNF into tail vein delayed the onset of motor behavioral symptoms, and prolongs the life span. The incidence of ALS is higher in men than women, but the female advantage disappears with increased age. Here, we report evidence that the female advantage is due to the protective role of estrogen. In an ALS mouse model carrying the human Cu/Zn superoxide dismutase (hSOD1) G93A transgene, ovariectomy did not alter the onset age of the disease while reducing the female lifespan by 7 days and making it comparable to that of the male transgenic mice. Treatment of ovariectomized females with 17β-estradiol (E2) did not delay the onset of disease, but prevented progression of ALS motor dysfunctions as shown by extension reflex test for a limited time window. Importantly, E2 treatment rescued the lifespans in overiectomized females. These findings will provide important new insights to strategy of ALS treatment.

Author dc:creator

• 최, 찬일

Contributors dc:contributor

• 서, 해영
• 대학원 의학과
• 200524491

• Mesenchymal Stem Cells (MSCs)
• Amyotrophic Lateral Sclerosis (ALS)
• SOD1G93A mouse
• Neurogenin1 (Ngn1)
• Glial cell line-Derived Neurotrophic Factor (GDNF)
• estrogen

Language dc:language

en

Identifier

http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000010520
000000010520

OAI identifier oai:identifier

oai:repository.ajou.ac.kr:201003/1296