25-07-08(16:35:23)
Authors:
Ernest Arenas
Institutions:
Laboratory of Molecular Neurobiology, MBB, CEDB, Karolinska Institute, Stockholm, Sweden.
Title of abstract : Wnt5a, a key pro-differentiation factor that reduces tumor formation and enhances the engraftment of stem cell-derived DA neurons
Abstract text:
Wnt5a is a morphogen that activates the Wnt/planar cell polarity (PCP) pathway and serves multiple functions during development. We previously found that Wnt5a promotes differentiation of ventral midbrain (VM) dopaminergic (mDA) precursors in vitro. More recently, we found that Wnt-5a activates Wnt/PCP signaling in mDA cells. Moreover, analysis of the developing ventral midbrain (VM) of Wnt5a-/- mice revealed that Wnt5a regulates VM morphogenesis, inhibits mDA progenitor proliferation, and promotes differentiation of Nurr1+ DA precursors in vivo.
These findings prompted us to examine the application of Wnt5a in protocols to generate stem cell-derived mDA neurons. We first examined VM neural stem cells grown as neurospheres (VMN), expanded with basic fibroblast growth factor (bFGF), and patterned with sonic hedgehog and FGF8. These preparations generated 10-fold more DA neurons compared to conventional bFGF-treated VMNs, enhanced the transcriptional profile of Mid DA cells in vivo, and contributed to the cellular and functional recovery of parkinsonian mice beyond previous reports. Importantly, no tumors were detected and the number of nestin+ cells were dramatically reduced after by 2 months after grafting. Thus, our findings show that Wnt5 enhances both safety (reduced tumor formation) and efficiency of neural stem cells (enhanced number of cells with mDA phenotype). Human VMN and ES cells are currently being examined for their capacity to respond to Wnt5a in a similar manner. Based on our results, we propose that Wnt5a may significantly contribute to enhance the application of stem cell-derived mDA neurons in drug development and cell replacement therapy for PD.
