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차의과학대학교, 현 Harvard Medical School

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Stem Cells, Volume 30, Issue 9, September 2012, Pages 2054-2062 | https://doi.org/10.1002/stem.1135 Neuronal Properties, In Vivo Effects, and Pathology of a Huntington's Disease Patient‐Derived Induced Pluripotent Stem Cells

IKSOO JEON,^a NAYEON LEE,^a JIA‐YI LI,^b,c IN‐HYUN PARK,^d,e KYOUNG SUN PARK,^f JISOOK MOON,^a SUNG HAN SHIM,^a CHUNGGAB CHOI,^a DA‐JEONG CHANG,^a JIHYE KWON,^a SEUNG‐HUN OH,^a DONG AH SHIN,^g HYUN SOOK KIM,^a JEONG TAE DO,^a DONG RYUL LEE,^a MANHO KIM,^h KYUNG‐SUN KANG,ⁱ GEORGE Q. DALEY,^d PATRIK BRUNDIN,^b,j JIHWAN SONG^a

^aCHA Stem Cell Institute, CHA University, Seoul, Korea; ^bNeuronal Survival Unit, and ^cNeural Plasticity and Repair Unit, Wallenberg Neuroscience Center, Lund University, Lund, Sweden; ^dDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, USA; ^eDepartment of Genetics, Yale University School of Medicine, New Haven, USA; ^fDivision of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology, Pohang, Korea; ^gDepartment of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea; ^hDepartment of Neurology, Seoul National University, College of Medicine; ⁱAdult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, Korea; ^jCenter for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, USA

I.J., N.L., and J.-Y.L. contributed equally to this article.

Correspondence: Jihwan Song or Patrik Brundin

Abstract

Induced pluripotent stem cells (iPSCs) generated from somatic cells of patients can be used to model different human diseases. They may also serve as sources of transplantable cells that can be used in novel cell therapies. Here, we analyzed neuronal properties of an iPSC line derived from a patient with a juvenile form of Huntington's disease (HD) carrying 72 CAG repeats (HD‐iPSC). Although its initial neural inducing activity was lower than that of human embryonic stem cells, we found that HD‐iPSC can give rise to GABAergic striatal neurons, the neuronal cell type that is most susceptible to degeneration in HD. We then transplanted HD‐iPSC‐derived neural precursors into a rat model of HD with a unilateral excitotoxic striatal lesion and observed a significant behavioral recovery in the grafted rats. Interestingly, during our in vitro culture and when the grafts were examined at 12 weeks after transplantation, no aggregate formation was detected. However, when the culture was treated with a proteasome inhibitor (MG132) or when the cells engrafted into neonatal brains were analyzed at 33 weeks, there were clear signs of HD pathology. Taken together, these results indicate that, although HD‐iPSC carrying 72 CAG repeats can form GABAergic neurons and give rise to functional effects in vivo, without showing an overt HD phenotype, it is highly susceptible to proteasome inhibition and develops HD pathology at later stages of transplantation. These unique features of HD‐iPSC will serve as useful tools to study HD pathology and develop novel therapeutics.

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