Efficient expansion and dopaminergic differentiation of human fetal ventral midbrain neural stem cells by midbrain morphogens

Diogo Ribeiro, Rocio Laguna Goya, Geeta Ravindran, Romina Vuono, Clare L. Parish, Claire Foldi, Tobias Piroth, Shanzheng Yang, Malin Parmar, Guido Nikkhah, Jens Hjerling-Leffler, Olle Lindvall, Roger A Barker, Ernest Arenas

Research output: Contribution to journalArticleResearchpeer-review

27 Citations (Scopus)

Abstract

Human fetal midbrain tissue grafting has provided proof-of-concept for dopamine cell replacement therapy (CRT) in Parkinson's disease (PD). However, limited tissue availability has hindered the development and widespread use of this experimental therapy. Here we present a method for generating large numbers of midbrain dopaminergic (DA) neurons based on expanding and differentiating neural stem/progenitor cells present in the human ventral midbrain (hVM) tissue. Our results show that hVM neurospheres (hVMN) with low cell numbers, unlike their rodent counterparts, expand the total number of cells 3-fold, whilst retaining their capacity to differentiate into midbrain DA neurons. Moreover, Wnt5a promoted DA differentiation of expanded cells resulting in improved morphological maturation, midbrain DA marker expression, DA release and electrophysiological properties. This method results in cell preparations that, after expansion and differentiation, can contain 6-fold more midbrain DA neurons than the starting VM preparation. Thus, our results provide evidence that by improving expansion and differentiation of progenitors present in the hVM it is possible to greatly enrich cell preparations for DA neurons. This method could substantially reduce the amount of human fetal midbrain tissue necessary for CRT in patients with PD, which could have major implications for the widespread adoption of this approach.

Original languageEnglish
Pages (from-to)118-127
Number of pages10
JournalNeurobiology of Disease
Volume49
Issue number1
DOIs
Publication statusPublished - Jan 2013
Externally publishedYes

Keywords

  • Dopaminergic
  • Human fetal ventral midbrain

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