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A11 Induced pluripotent stem cells for basic and translational research on HD
  1. VB Mattis1,
  2. SP Svendsen1,
  3. A Ebert2,
  4. CN Svendsen1,
  5. AR King3,
  6. M Casale3,
  7. ST Winokur3,
  8. G Batugedara3,
  9. M Vawter3,
  10. PJ Donovan3,
  11. LF Lock3,
  12. LM Thompson3,
  13. Y Zhu4,
  14. E Fossale4,
  15. RS Atwal4,
  16. T Gillis4,
  17. J Mysore4,
  18. J-h Li4,
  19. IS Seong4,
  20. Y Shen4,
  21. X Chen4,
  22. VC Wheeler4,
  23. Marcy E MacDonald4,
  24. JF Gusella4,
  25. S Akimov5,
  26. N Arbez5,
  27. T Juopperi6,
  28. T Ratovitski5,
  29. JH Chiang6,
  30. WR Kim6,
  31. E Chighladze5,
  32. E Watkin5,
  33. C Zhong6,
  34. G Makri6,
  35. RN Cole6,
  36. RL Margolis4,8,
  37. H Song6,
  38. G Ming6,
  39. CA Ross5,8,9,
  40. JA Kaye10,11,
  41. A Daub10,11,
  42. P Sharma10,11,
  43. AR Mason10,11,
  44. S Finkbeiner10,11,
  45. J Yu12,
  46. JA Thomson13,
  47. D Rushton14,
  48. SP Brazier14,
  49. AA Battersby14,
  50. A Redfern14,
  51. H-E Tseng14,
  52. AW Harrison14,
  53. PJ Kemp14,
  54. ND Allen14,
  55. M Onorati15,
  56. V Castiglioni15,
  57. E Cattaneo15,
  58. J Arjomand16
  1. 1The Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
  2. 2Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
  3. 3Departments of Neurobiology and Behavior, Psychiatry and Human Behavior, Developmental and Cell Biology and Biological Chemistry, University of California, Irvine, California, USA
  4. 4Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
  5. 5Division of Neurobiology and Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  6. 6Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  7. 7Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  8. 8Department of Neurology and Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  9. 9Departments of Neuroscience and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  10. 10Gladstone Institute of Neurological Disease, Taube-Koret Center of Huntington's Disease Research, Hellman Family Foundation Program in Alzheimer's Disease, Roddenberry Stem Cell Research Program, San Francisco, California, USA
  11. 11Departments of Neurology and Physiology, University of California, San Francisco, California, USA
  12. 12Cellular Dynamics International, Madison, Wisconsin, USA
  13. 13Morgridge Institute for Research, Madison, Wisconsin, USA
  14. 14School of Biosciences, Cardiff University, Cardiff, UK
  15. 15Department of Pharmacological Sciences and Center for Stem Cell Research, Università degli Studi di Milano, Milano, Italy
  16. 16CHDI Management/CHDI Foundation, Princeton, New Jersey, USA


Background The expression of mutant HTT leads to many cellular alterations, including abnormal vesicle recycling, loss of signalling by brain-derived neurotrophic factor, excitotoxicity, perturbation of Ca2+ signalling, decreases in intracellular ATP, alterations of gene transcription, inhibition of protein clearance pathways, mitochondrial and metabolic disturbances, and ultimately cell death. While robust mammalian systems have been developed to model disease and extensive mechanistic insights have emerged, significant differences between rodent and human cells and between non-neuronal cells and neurons limit the utility of these models for accurately representing human disease. Human pluripotent stem cells can generate highly specified cell populations, including DARPP32-positive MSNs of the striatum, and provide a method for modelling HD in human neurons carrying the mutation. As it is caused by one single gene, HD is an ideal disorder for exploring the utility of modelling disease in induced pluripotent stem cells (iPSCs) through reprogramming adult cells from HD patients with known patterns of disease onset and duration.

Aims Generate iPSC lines from HD patients and controls and identify CAG-repeat expansion associated phenotypes.

Methods/techniques Through the efforts of an international consortium effort, 14 lines were generated, differentiated into neuronal populations and assessed for CAG-repeat dependent outcome measures.

Results/outcomes HD iPSC lines have reproducible CAG expansion–associated phenotypes upon differentiation, including CAG expansion-associated changes in gene expression patterns and alterations in electrophysiology, metabolism, cell adhesion, and ultimately an increased risk of cell death. While the lines with the longest repeats (HD180) showed a phenotype across all assays, those with shorter repeats (HD60) showed phenotypes in a specific sub set of assays. The most sensitive assay for establishing repeat dependent effects was found to be calcium responses to stress.

Conclusions This HD iPSC collection represents a unique and well-characterised resource to elucidate disease mechanisms in HD and provides a novel human stem cell platform for screening new candidate therapeutics.

Funding NIH, CHDI, CIRM.

  • Stem cells
  • HD
  • pluripotent
  • human cell model
  • CAG phenotypes

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