title: Recovery of behavioral symptoms in hemi-parkinsonian rhesus monkeys through combined gene and stem cell therapy.
abstract: OBJECTIVE
  The use of adipose mesenchymal stromal cells (ASCs) in cellular and genic therapy has attracted considerable attention as a possible treatment for neurodegenerative disorders, including Parkinson disease. However, the effects of gene therapy combined with intracerebral cell transplantation have not been well defined. Recent studies have demonstrated the respective roles of LIM homeobox transcription factor 1, alpha (LMX1A) and Neurturin (NTN) in the commitment of embryonic stem cells (ESCs) to a midbrain dopaminergic neuronal fate and the commitment of mesenchymal stromal cells to cells supporting the nutrition and protection of neurons.
  
  
  METHODS
  We investigated a novel in vitro neuronal differentiation strategy with the use of LMX1A and Neurturin. We were able to elicit a neural phenotype regarding cell morphology, specific gene/protein expression and physiological function. Neuronal-primed ASCs derived from rhesus monkey (rASCs) combined with adenovirus containing NTN and tyrosine hydroxylase (TH) (Ad-NTN-TH) were implanted into the striatum and substantia nigra of methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-lesioned hemi-parkinsonian rhesus monkeys. Monkeys were monitored with the use of behavioral tests and health measures until the fourth month after implantation.
  
  
  RESULTS
  The differentiated cells transcribed and expressed a variety of dopaminergic neuron-specific genes involved in the SHH/LMX1A pathway. Single-photon emission computed tomography analysis and postmortem analysis revealed that the grafting of rASCs combined with Ad-NTN-TH had neuroprotective effects compared with Ad-NTN-TH or rASCs alone. Behavioral measures demonstrated autograft survival and symptom amelioration.
  
  
  CONCLUSIONS
  These findings may lead to cellular sources for autologous transplantation of Parkinson disease. Combined transplantation of Ad-NTN-TH and induced rASCs expressing LMX1A and NTN may be a better therapy candidate for the treatment of Parkinson disease.
authors: Institute of Medical Biology, Peking Union Medical College, Chinese Academy of Medical Science, Kunming, China.
authors: Yan
authors: Y
authors: Zhou
authors: Maosheng
authors: M
authors: Sun
authors: Hongjun
authors: H
authors: Li
authors: Min
authors: M
authors: Yan
authors: Zhanlong
authors: Z
authors: He
authors: Wenju
authors: W
authors: Wang
authors: Wanpu
authors: W
authors: Wang
authors: Shuaiyao
authors: S
authors: Lu
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D017667:Adipocytes / Q000166:cytology; D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D001522:Behavior, Animal; D002454:Cell Differentiation; D059290:Dopaminergic Neurons / Q000502:physiology*; D005260:Female; D015316:Genetic Therapy; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D020267:MPTP Poisoning / Q000628:therapy*; D008253:Macaca mulatta; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D055495:Neurogenesis; D051101:Neurturin / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology; D011897:Random Allocation; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D060850:LIM-Homeodomain Proteins; C078021:LMX1A protein, human; D051101:Neurturin; D014157:Transcription Factors; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase