Differentiated Parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats

被引:359
作者
Hargus, Gunnar [2 ,3 ]
Cooper, Oliver [2 ,3 ]
Deleidi, Michela [2 ,3 ]
Levy, Adam [2 ,3 ]
Lee, Kristen [2 ,3 ]
Marlow, Elizabeth [2 ,3 ]
Yow, Alyssa [2 ,3 ]
Soldner, Frank [1 ]
Hockemeyer, Dirk [1 ]
Hallett, Penelope J. [2 ,3 ]
Osborn, Teresia [2 ,3 ]
Jaenisch, Rudolf [1 ]
Isacson, Ole [2 ,3 ]
机构
[1] MIT, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA
[2] Harvard Univ, Sch Med, McLean Hosp, Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA 02478 USA
[3] Harvard Univ, Sch Med, McLean Hosp, Ctr Neuroregenerat Res, Belmont, MA 02478 USA
关键词
cell replacement therapy; dopaminergic neurons; Parkinson's disease; reprogramming; transplantation; DOPAMINERGIC-NEURONS; MIDBRAIN; DISEASE; MODEL; PROGENITORS; DERIVATION; DEFICIT; TISSUE;
D O I
10.1073/pnas.1010209107
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Recent advances in deriving induced pluripotent stem(iPS) cells from patients offer new possibilities for biomedical research and clinical applications, as these cells could be used for autologous transplantation. We differentiated iPS cells from patients with Parkinson's disease (PD) into dopaminergic (DA) neurons and show that these DA neurons can be transplanted without signs of neurodegeneration into the adult rodent striatum. The PD patient iPS (PDiPS) cell-derived DA neurons survived at high numbers, showed arborization, and mediated functional effects in an animal model of PD as determined by reduction of amphetamine-and apomorphine-induced rotational asymmetry, but only a few DA neurons projected into the host striatum at 16 wk after transplantation. We next applied FACS for the neural cell adhesion molecule NCAM on differentiated PDiPS cells before transplantation, which resulted in surviving DA neurons with functional effects on amphetamine-induced rotational asymmetry in a 6-OHDA animal model of PD. Morphologically, we found that PDiPS cell-derived non-DA neurons send axons along white matter tracts into specific close and remote gray matter target areas in the adult brain. Such findings establish the transplantation of human PDiPS cell-derived neurons as a long-term in vivo method to analyze potential disease-related changes in a physiological context. Our data also demonstrate proof of principle of survival and functional effects of PDiPS cell-derived DA neurons in an animal model of PD and encourage further development of differentiation protocols to enhance growth and function of implanted PDiPS cell-derived DA neurons in regard to potential therapeutic applications.
引用
收藏
页码:15921 / 15926
页数:6
相关论文
共 33 条
  • [1] Recent advances in cell-based therapy for Parkinson disease
    Astradsson, Arnar
    Cooper, Oliver
    Vinuela, Angel
    Isacson, Ole
    [J]. NEUROSURGICAL FOCUS, 2008, 24 (3-4)
  • [2] Transplantation of human embryonic stem cell-derived neural progenitors improves behavioral deficit in Parkinsonian rats
    Ben-Hur, T
    Idelson, M
    Khaner, H
    Pera, M
    Reinhartz, E
    Itzik, A
    Reubinoff, BE
    [J]. STEM CELLS, 2004, 22 (07) : 1246 - 1255
  • [3] BRUNDIN P, 1986, EXP BRAIN RES, V65, P235
  • [4] COOPER O, 2010, MOL CELL NEUROS 0723
  • [5] Induced pluripotent stem cells from a spinal muscular atrophy patient
    Ebert, Allison D.
    Yu, Junying
    Rose, Ferrill F., Jr.
    Mattis, Virginia B.
    Lorson, Christian L.
    Thomson, James A.
    Svendsen, Clive N.
    [J]. NATURE, 2009, 457 (7227) : 277 - U1
  • [6] RETRACTED: Efficient Derivation of Functional Floor Plate Tissue from Human Embryonic Stem Cells (Retracted article. See vol. 30, pg. 905, 2023)
    Fasano, Christopher A.
    Chambers, Stuart M.
    Lee, Gabsang
    Tomishima, Mark J.
    Studer, Lorenz
    [J]. CELL STEM CELL, 2010, 6 (04) : 336 - 347
  • [7] Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner
    Ferri, Anna L. M.
    Lin, Wei
    Mavromatakis, Yannis E.
    Wang, Julie C.
    Sasaki, Hiroshi
    Whitsett, Jeffrey A.
    Ang, Siew-Lan
    [J]. DEVELOPMENT, 2007, 134 (15): : 2761 - 2769
  • [8] Specific axon guidance factors persist in the adult brain as demonstrated by pig neuroblasts transplanted to the rat
    Isacson, O
    Deacon, TW
    [J]. NEUROSCIENCE, 1996, 75 (03) : 827 - 837
  • [9] TRANSPLANTED XENOGENEIC NEURAL CELLS IN NEURODEGENERATIVE DISEASE-MODELS EXHIBIT REMARKABLE AXONAL TARGET SPECIFICITY AND DISTINCT GROWTH-PATTERNS OF GLIAL AND AXONAL FIBERS
    ISACSON, O
    DEACON, TW
    PAKZABAN, P
    GALPERN, WR
    DINSMORE, J
    BURNS, LH
    [J]. NATURE MEDICINE, 1995, 1 (11) : 1189 - 1194
  • [10] Generation of Human Induced Pluripotent Stem Cells by Direct Delivery of Reprogramming Proteins
    Kim, Dohoon
    Kim, Chun-Hyung
    Moon, Jung-Il
    Chung, Young-Gie
    Chang, Mi-Yoon
    Han, Baek-Soo
    Ko, Sanghyeok
    Yang, Eungi
    Cha, Kwang Yul
    Lanza, Robert
    Kim, Kwang-Soo
    [J]. CELL STEM CELL, 2009, 4 (06) : 472 - 476