Neurodegenerative diseases,including Parkinson＇s disease,Alzheimer＇s disease and Amyotrophic Lateral Sclerosis,are characterized by idiopathic neuron loss in different regions of the central nervous system,which con...Neurodegenerative diseases,including Parkinson＇s disease,Alzheimer＇s disease and Amyotrophic Lateral Sclerosis,are characterized by idiopathic neuron loss in different regions of the central nervous system,which contributes to the relevant dysfunctions in the patients.The application of cell replacement therapy using human embryonic stem（hES） cells,though having attracted much attention,has been hampered by the intrinsic ethical problems.It has been demonstrated that adult somatic cells can be reprogrammed into the embryonic state,called induced pluripotent stem（iPS） cells.It is soon realized that iPS cells may be an alternative source for cell replacement therapy,because it raises no ethical problems and using patient-specific iPS cells for autologous transplantation will not lead to immunological rejection.What＇s more,certain types of neurons derived from patient-specific iPS cells may display disease-relevant phenotypes.Thus,patientspecific iPS cells can provide a unique opportunity to directly investigate the pathological properties of relevant neural cells in individual patient,and to study the vulnerability of neural cells to pathogenic factors in vitro,which may help reveal the pathogenesis of many neurodegenerative diseases.In this review,the recent development in cellular treatment of neurodegenerative diseases using iPS cells was summarized,and the potential value of iPS cells in the modeling of neurodegenerative disease was discussed.展开更多
Glial cell derived neurotrophic factor （GDNF） holds promises for treating neurodegenerative diseases such as Parkinson＇s dis- ease. Human neural stem cells （hNSCs） have proved to be a suitable cell delivery vehic...Glial cell derived neurotrophic factor （GDNF） holds promises for treating neurodegenerative diseases such as Parkinson＇s dis- ease. Human neural stem cells （hNSCs） have proved to be a suitable cell delivery vehicle for the safe and efficient introduction of GDNF into the brain. In this study, we used hNSCs-infected with a lentivirus encoding GDNF and the hygromycin re- sistance gene as such vehicles. A modified tetracycline operator 7 （tetO7） was inserted into a region upstream of the EFI-α promoter to drive GDNF expression. After hygromycin selection, hNSCs were infected with a lentivirus encoding a KRAB-tetracycline repressor fusion protein （TTS）. TTS bound to tetO7 and suppressed the expression of GDNF in hNSCs. Upon administration of doxycycline （Dox） the TTS-tetO7 complex separated and the expression of GDNF resumed. The hNSCs infected with GDNF expressed the neural stem cell specific markers, nestin and sox2, and exhibited no significant change in proliferation rate. However, the rate of apoptosis in hNSCs expressing GDNF was lower compared with normal NSCs in response to actinomycin treatment. Furthermore, a higher percentage of Tuj-I positive cells were obtained from GDNF-producing NSCs under conditions that induced differentiation compared to control NSCs. The inducible expression of GDNF in hNSCs may provide a system for the controllable delivery of GDNF in patients with neurodegenerative diseases.展开更多
基金supported by grants of the Key Project of Shanghai Science and Technology Committee(No. 08411951100,10ZR1425800)National Major Special Project of Science and Technology from the Ministry of Science and Technology,China (No. 2008ZX09312)
文摘Neurodegenerative diseases,including Parkinson＇s disease,Alzheimer＇s disease and Amyotrophic Lateral Sclerosis,are characterized by idiopathic neuron loss in different regions of the central nervous system,which contributes to the relevant dysfunctions in the patients.The application of cell replacement therapy using human embryonic stem（hES） cells,though having attracted much attention,has been hampered by the intrinsic ethical problems.It has been demonstrated that adult somatic cells can be reprogrammed into the embryonic state,called induced pluripotent stem（iPS） cells.It is soon realized that iPS cells may be an alternative source for cell replacement therapy,because it raises no ethical problems and using patient-specific iPS cells for autologous transplantation will not lead to immunological rejection.What＇s more,certain types of neurons derived from patient-specific iPS cells may display disease-relevant phenotypes.Thus,patientspecific iPS cells can provide a unique opportunity to directly investigate the pathological properties of relevant neural cells in individual patient,and to study the vulnerability of neural cells to pathogenic factors in vitro,which may help reveal the pathogenesis of many neurodegenerative diseases.In this review,the recent development in cellular treatment of neurodegenerative diseases using iPS cells was summarized,and the potential value of iPS cells in the modeling of neurodegenerative disease was discussed.
基金supported by the National Basic Research Program of China (2007CB947704)the High-level Technical Personnel Training of Health Plan of Beijing
文摘Glial cell derived neurotrophic factor （GDNF） holds promises for treating neurodegenerative diseases such as Parkinson＇s dis- ease. Human neural stem cells （hNSCs） have proved to be a suitable cell delivery vehicle for the safe and efficient introduction of GDNF into the brain. In this study, we used hNSCs-infected with a lentivirus encoding GDNF and the hygromycin re- sistance gene as such vehicles. A modified tetracycline operator 7 （tetO7） was inserted into a region upstream of the EFI-α promoter to drive GDNF expression. After hygromycin selection, hNSCs were infected with a lentivirus encoding a KRAB-tetracycline repressor fusion protein （TTS）. TTS bound to tetO7 and suppressed the expression of GDNF in hNSCs. Upon administration of doxycycline （Dox） the TTS-tetO7 complex separated and the expression of GDNF resumed. The hNSCs infected with GDNF expressed the neural stem cell specific markers, nestin and sox2, and exhibited no significant change in proliferation rate. However, the rate of apoptosis in hNSCs expressing GDNF was lower compared with normal NSCs in response to actinomycin treatment. Furthermore, a higher percentage of Tuj-I positive cells were obtained from GDNF-producing NSCs under conditions that induced differentiation compared to control NSCs. The inducible expression of GDNF in hNSCs may provide a system for the controllable delivery of GDNF in patients with neurodegenerative diseases.
