1、神经退行性疾病干细胞移植治疗：目前研究现状与未来展望,Stem Cell Sources for Treatmentof Neurological Diseases (AD, PD, ALS, MS, Stroke, SCI),Fabin Han, et al, Journal of Neurorestoratology 2015:3 112,胎儿神经干细胞治疗帕金森氏病临床研究发展历程,Evans JR, Mason SL, Barker RA. Prog Brain Res. 2012;200:169-98,Lindvall O, et al，Nat Med. 2008 May;14(5)
2、:501-3,TH,Synuclein,Overlay,Transplanted fetal mesencephalic dopaminergic neurons (11-16 years) developed alpha-synuclein-positive Lewy bodies in grafted neurons,Synuclein-Host,Ubiquintin-Host,Synuclein-Grafted Neurons,Ubiquintin-Grafted Neurons,Grafted nigral neurons were found to have Lewy body-li
3、ke inclusions14 years after transplantation into the striatum of an individual with PD,Olanow CW. et al Nat Med. 2008May;14(5):504-6.,Transplanted dopamine neurons in people with PD do not contain Lewy bodies,Mendez, Isacson et al, , NATURE MEDICINE VOLUME 14 (5):507-509, 2008,Freed CR, J Nucl Med.
4、2010 Jan;51(1):7-15,- Long term Study - 33 of the original trial participants who were followed for 2 years after transplantation and 15 of these subjects who were followed for 2 additional years. - These results suggest that clinical benefit and graft viability are sustained up to 4 y after transpl
5、antation.,Freed CR, Neurotherapeutics (2011) 8:549 561,人体胚胎干细胞分化的多巴胺神经元移植 改善小鼠，大鼠和猴子帕金森氏病的运动障碍,22/29 DECEMBER 2011 | VOL 480 | NATURE | 547， Lorenz Studer，et al Memorial Sloan-Kettering Cancer Center,Improved Cell Therapy Protocol for Parkinsons Disease Based on Differentiation Efficiency and Safety
6、 of hESC-, Hipsc and Non-Human Primate iPSC-Derived DA Neurons,Isacson et al, , Stem Cells. 2013 ;31(8):1548-62.,Dopamine release from transplanted neural stem cells in Parkinsonian rat striatum in vivo.,Zhou z, et al, Proc Natl Acad Sci U S A.2014 Nov 4;111(44):15804-9,iPSC-Derived Dopamine Neurons
7、 function after Transplantation in a Non-Human Primate Model of Parkinsons Disease,Cell Stem Cell. 2015 Mar 5;16(3):269-74. Ole Isacson et al，Harvard Stem Cell Institute,Stem cell-based Clinical Trials for (ALS),Nuralstem, In c . the first Phase I clinical trial for a stem cell-based treatment of AL
8、S. Initiated in 2010 and completed in 2013, involved the transplan-tation of human spinal cord-derived NSCs into the spinal cord of 15 late to mid-stage ALS patients,Glass, Feldman, E.L., 2012. Lumbar intraspinal injection of neural stem cells in patients with amyotrophic lateral sclerosis: results
9、of a phase I trial in 12 patients. Stem Cells 30 (6), 1144 1151.Riley, J., Feldman, E.L., 2014. “Intraspinal stem cell transplantation in ALS: a phase I trial, cervical microinjection and final surgical safety outcomes”. Neurosurgery 74 (1), 77 87,RESULTS: Unilateral cervical (group D, n = 3) and ce
10、rvical plus thoracolumbar (group E, n = 3) microinjections to the ventral horn have been completed in ambulatory patients. One patient developed a postoperative kyphotic deformity prompting completion of a laminoplasty in subsequent patients. Another required reoperation for wound dehiscence and inf
11、ection. The solitary patient with bulbar amyotrophic lateral sclerosis required perioperative reintubation. CONCLUSION: Delivery of a cellular payload to the cervical or thoracolumbar spinal cord was well tolerated by the spinal cord in this vulnerable population. This encouraging finding supports c
12、onsideration of this delivery approach for neurodegenerative, oncologic, and traumatic spinal cord afflictions.,Intraspinal stem cell transplantation in ALS: a phase I trial, 2014,iPS Cells Were Generated from PD patients and Normal Controls,6-OHDA-induced Rat PD Model,Human iPS cells Integrated to
13、the Host Brain of 6-OHDA-induced Rat PD Model,Han F, Wang W, Chen C, Duan J, et al Cytotherapy 2015,分化的胎脑神经干细胞移植治疗PD,建立大鼠SCI损伤模型,A. 暴露和部分横切脊髓外科手术。 B. T7 横断损伤产生后肢瘫痪。 C. 无脊髓损伤的正常大鼠。,RT-PCR to Detect the MicroRNA Expression in Rat SCI Model,Real-Time RT-PCR to Detect the MicroRNA Expression in SCI,干细胞移
14、植修复脊髓神经损伤,移植神经干细胞分化的神经轴索与宿主脊髓神经细胞及其树突形成突触连接,Lu P et al，Cell. 2012 September 14; 150(6): 12641273,Bone Marrow Stromal Cell Intraspinal Transplants Fail to Improve Motor Outcomes in a Severe Model of SCI,Journal of Neurotrauma 2015， Tuszynski MH To determine whether local mechanisms mediate BMSC neuro
15、protective actions grafted allogeneic BMSCs to sites of severe, compressive spinal cord injury (SCI) in Sprague Dawley rats. Cells were administered 48 hours after the original injury. Additional animals received allogeneic MSCs that were genetically modified to secrete BDNF, to further determine wh
16、ether a locally administered neurotrophic factor provides or extends neuroprotection. two months post-injury in a clinically relevant model of severe SCI, BMSC grafts with or without BDNF secretion failed to improve motor outcomes. Thus, allogeneic grafts of BMSCs do not appear to act through local
17、mechanisms, and future clinical trials that acutely deliver BMSCs to actual sites of injury within days are unlikely to be beneficial.,Intraspinal Stem Cell Transplantation in Amyotrophic Lateral Sclerosis: A Phase I Safety Trial, Technical Note, and Lumbar Safety Outcomes NEUROSURGERY VOLUME 71 | N
18、UMBER 2 | AUGUST 2012Department of Neurosurgery, Emory University , Atlanta , Georgia ; Department of Neurology, Emory University, Atlanta, Georgia; Department of Neurology, University of Michigan, Ann Arbor, Michigan,神经干细胞移植方法,Each microinjection series comprised 5 injections (10mL/injection) separ
19、ated by 4 mm. Each injection :100 000 neural stem cells derived from a fetal spinal cord. Twelve patients were treated with either unilateral or bilateral injections.Patients are followed clinically and radiologically to assess potential toxicity of the procedure.,Lumbar Laminectomy,Microinjection p
20、latform application,Postoperative imaging progression,Riley, J., Feldman, E.L., 2014. “Intraspinal stem cell transplantation in ALS: a phase I trial, cervical microinjection and final surgical safety outcomes”. Neurosurgery 74 (1), 77 87,Clinical Trials using ESCs and iPSCs,There is also a report of
21、 one Japanese patient who received a transplant of a sheet of iPSC-derived RPE,Summary on Molecular Mechanism of Stem Cell Transplantation for Neurological Diseases,Transplanted cells survive，differentiate to neurons, astrocytes,oligodendrocyte precursors (hESC, hiPSC, NSC ) and release neurological
22、 transmittors such as dopamine,Ach. Release of neurotrophic factors (GDNF, GDNE,IGF,)to increase the functions of the endogenous neural stem cells Release of immuno-regulatory factors such as IL-2, 6,8,10 to play immuno-modulation and attenuation of the inflammatory process, such as MSC. The transpl
23、anted cells formed synapse with host cells. Others such as delaying the onset and prolonging survival of SOD1 rats Increasing host neurogenesis,今后干细胞治疗神经退行性疾病的临床研究 需要考虑的问题,1. Cell Sources： Neural projenitors， MSC， hES cells， iPS cells 2. SC grafting should be conducted to ensure 100,000 dopaminergic
24、 neurons （PD）survive per transplantation site. 3. SC grafts should exhibit regulated release of dopamine in line with that of endogenous dopaminergic neurons. 4. By reestablishing the striatal dopaminergic system, grafts should show the capacity to restore functional connectivity within the basal ga
25、nglia and at extra-striatal loci. 5. Long-lasting and significant symptom- relief must be achieved （over 2-3 years）. 6. Evaluation System （Symptoms, Dopamine release, Levodopa-response), Unified Parkinson s Disea se Ra ting Scal e (UPDRS)，Biomarkers 7. Adverse effects must be minimal. This include s
26、 the absence of tumor formation and GIDs （graf t-induced dyskinesia） throughout long-term follow-up periods. 8. Sample Size： over 50-100 patients。,致谢/Acknowledgements,北京大学生命科学研究中心康新江博士干细胞与再生医学实验室全体科研人员：王伟，张男，陈超，李森，卢现杰，段婧，吴士超，宋昊，宋娜，陈清法，刘延明,干细胞与再生医学实验室研究团队,Neural Differentiation of hUCB-MSC in Vitro,hUCB-MSC 细胞移植改善6-OHDA诱导PD大鼠不对称运动行为,Differentiation of UC-MSC cells into Neurons and Dopamine Neurons,
