Efficient and rapid conversion of human astrocytes and ALS mouse model spinal cord astrocytes into motor neuron-like cells by defined small molecules
Abstract Background Motor neuron degeneration or loss in the spinal cord is the characteristic phenotype of motor neuron diseases or spinal cord injuries. Being proliferative and located near neurons, astrocytes are considered ideal cell sources for regenerating neurons. Methods We selected and test...
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| Format: | Article |
| Language: | English |
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BMC
2020-09-01
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| Series: | Military Medical Research |
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| Online Access: | http://link.springer.com/article/10.1186/s40779-020-00271-7 |
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| author | An-Dong Zhao Hua Qin Meng-Li Sun Kui Ma Xiao-Bing Fu |
| author_facet | An-Dong Zhao Hua Qin Meng-Li Sun Kui Ma Xiao-Bing Fu |
| author_sort | An-Dong Zhao |
| collection | DOAJ |
| description | Abstract Background Motor neuron degeneration or loss in the spinal cord is the characteristic phenotype of motor neuron diseases or spinal cord injuries. Being proliferative and located near neurons, astrocytes are considered ideal cell sources for regenerating neurons. Methods We selected and tested different combinations of the small molecules for inducing the conversion of human and mouse astrocytes into neurons. Microscopic imaging and immunocytochemistry analyses were used to characterize the morphology and phenotype of the induced neurons while RT-qPCR was utilized to analyze changes in gene expression. In addition, whole-cell patch-clamp recordings were measured to examine the electrophysiological properties of induced neurons. Results The results showed that human astrocytes could be rapidly and efficiently converted into motor neuron-like cells by treatment with defined small molecules, with a yield of over 85% motor neuron-like cells attained. The induced motor neuron-like cells expressed the pan-neuronal markers TUJ1, MAP2, NeuN, and Synapsin 1 and motor neuron markers HB9, ISL1, CHAT, and VAChT. During the conversion process, the cells did not pass through a proliferative neural progenitor cell intermediate. The induced motor neurons were functional, showing the electrophysiological properties of neurons. The same chemical cocktail could induce spinal cord astrocytes from an amyotrophic lateral sclerosis mouse model carrying a SOD1 mutation to become motor neuron-like cells that exhibited a decrease in cell survival and an increase in oxidative stress compared to that observed in wild-type MNs derived from healthy mice. Moreover, the chemical induction reduced oxidative stress in the mutant astrocytes. Conclusion The results of the present study demonstrated the feasibility of chemically converting human and mouse astrocytes into motor neuron-like cells that are useful for neurodegenerative disease modeling and regenerative medicine. |
| first_indexed | 2024-12-11T21:26:30Z |
| format | Article |
| id | doaj.art-23727edac69143f49ab5e0168b820360 |
| institution | Directory Open Access Journal |
| issn | 2054-9369 |
| language | English |
| last_indexed | 2024-12-11T21:26:30Z |
| publishDate | 2020-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Military Medical Research |
| spelling | doaj.art-23727edac69143f49ab5e0168b8203602022-12-22T00:50:19ZengBMCMilitary Medical Research2054-93692020-09-017111710.1186/s40779-020-00271-7Efficient and rapid conversion of human astrocytes and ALS mouse model spinal cord astrocytes into motor neuron-like cells by defined small moleculesAn-Dong Zhao0Hua Qin1Meng-Li Sun2Kui Ma3Xiao-Bing Fu4Tianjin Medical UniversityResearch Center for Tissue Repair and Regeneration affiliated to the Medical Innovation Research Division and 4th Medical Center, PLA General Hospital and PLA Medical CollegeResearch Center for Tissue Repair and Regeneration affiliated to the Medical Innovation Research Division and 4th Medical Center, PLA General Hospital and PLA Medical CollegeResearch Center for Tissue Repair and Regeneration affiliated to the Medical Innovation Research Division and 4th Medical Center, PLA General Hospital and PLA Medical CollegeResearch Center for Tissue Repair and Regeneration affiliated to the Medical Innovation Research Division and 4th Medical Center, PLA General Hospital and PLA Medical CollegeAbstract Background Motor neuron degeneration or loss in the spinal cord is the characteristic phenotype of motor neuron diseases or spinal cord injuries. Being proliferative and located near neurons, astrocytes are considered ideal cell sources for regenerating neurons. Methods We selected and tested different combinations of the small molecules for inducing the conversion of human and mouse astrocytes into neurons. Microscopic imaging and immunocytochemistry analyses were used to characterize the morphology and phenotype of the induced neurons while RT-qPCR was utilized to analyze changes in gene expression. In addition, whole-cell patch-clamp recordings were measured to examine the electrophysiological properties of induced neurons. Results The results showed that human astrocytes could be rapidly and efficiently converted into motor neuron-like cells by treatment with defined small molecules, with a yield of over 85% motor neuron-like cells attained. The induced motor neuron-like cells expressed the pan-neuronal markers TUJ1, MAP2, NeuN, and Synapsin 1 and motor neuron markers HB9, ISL1, CHAT, and VAChT. During the conversion process, the cells did not pass through a proliferative neural progenitor cell intermediate. The induced motor neurons were functional, showing the electrophysiological properties of neurons. The same chemical cocktail could induce spinal cord astrocytes from an amyotrophic lateral sclerosis mouse model carrying a SOD1 mutation to become motor neuron-like cells that exhibited a decrease in cell survival and an increase in oxidative stress compared to that observed in wild-type MNs derived from healthy mice. Moreover, the chemical induction reduced oxidative stress in the mutant astrocytes. Conclusion The results of the present study demonstrated the feasibility of chemically converting human and mouse astrocytes into motor neuron-like cells that are useful for neurodegenerative disease modeling and regenerative medicine.http://link.springer.com/article/10.1186/s40779-020-00271-7Human astrocyteMotor neuronReprogrammingTransdifferentiationConversionRegeneration |
| spellingShingle | An-Dong Zhao Hua Qin Meng-Li Sun Kui Ma Xiao-Bing Fu Efficient and rapid conversion of human astrocytes and ALS mouse model spinal cord astrocytes into motor neuron-like cells by defined small molecules Military Medical Research Human astrocyte Motor neuron Reprogramming Transdifferentiation Conversion Regeneration |
| title | Efficient and rapid conversion of human astrocytes and ALS mouse model spinal cord astrocytes into motor neuron-like cells by defined small molecules |
| title_full | Efficient and rapid conversion of human astrocytes and ALS mouse model spinal cord astrocytes into motor neuron-like cells by defined small molecules |
| title_fullStr | Efficient and rapid conversion of human astrocytes and ALS mouse model spinal cord astrocytes into motor neuron-like cells by defined small molecules |
| title_full_unstemmed | Efficient and rapid conversion of human astrocytes and ALS mouse model spinal cord astrocytes into motor neuron-like cells by defined small molecules |
| title_short | Efficient and rapid conversion of human astrocytes and ALS mouse model spinal cord astrocytes into motor neuron-like cells by defined small molecules |
| title_sort | efficient and rapid conversion of human astrocytes and als mouse model spinal cord astrocytes into motor neuron like cells by defined small molecules |
| topic | Human astrocyte Motor neuron Reprogramming Transdifferentiation Conversion Regeneration |
| url | http://link.springer.com/article/10.1186/s40779-020-00271-7 |
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