Axon responses of embryonic stem cell‐derived dopaminergic neurons to semaphorins 3A and 3C

Abstract

Class 3 Semaphorins are a subfamily of chemotropic molecules implicated in the projection of dopaminergic neurons from the ventral mesencephalon and in the formation of the nigrostriatal pathway (NSP) during embryonic development. In humans, loss of mesencephalic dopaminergic neurons leads to Parkinson's disease (PD). Cell replacement therapy with dopaminergic neurons generated from embryonic stem cells (ES-TH + ) is being actively explored in models of PD. Among several requisites for this approach to work are the adequate reconstruction of the NSP and the correct innervation of normal striatal targets by dopaminergic axons. In this work, we characterized the response of ES-TH + neurons to Semaphorins 3A, 3C, and 3F, and compared it with that of tyrosine hidroxylase-positive neurons (TH + ) obtained from embryonic ventral mesencephalon (VM-TH + ). We observed that similar proportions of ES-TH + and VM-TH + neurons express Semaphorin receptors Neuropilin 1 and 2. Furthermore, the axons of both populations responded very similarly to Semaphorin exposure: Semaphorin 3A increased axon length, and Semaphorin 3C attracted axons and increased their length. These effects were mediated by Neuropilins, since addition of blocking antibodies against these proteins reduced the effects on axonal growth and attraction, and only TH + axons expressing Neuropilins responded to the Semaphorins analyzed. The observations reported here show phenotypic similarities between VM-TH + and ES-TH + neurons, and suggest that Semaphorins 3A and 3C could be employed to guide axons of grafted ES-TH + in therapeutic protocols for PD.

Phosphodiesterase 2 Inhibitors Promote Axonal Outgrowth in Organotypic Slice Co-Cultures

“…The fiber pathways of the VTA/SN+STR co-cultures developed an innervation pattern similar to that found in vivo [10]. These findings are in accordance with other studies, showing that the projections of axons to their targets follow special stereotypical routes during the development of the central nervous system and that selected guidance molecules support this innervation [32,33,34]. …”

Motoneuronal Sema3C is essential for setting stereotyped motor tract positioning in limb-derived chemotropic semaphorins

“…First, we investigated the currently unknown responsiveness of spinal motoneurons to environmental Sema3C, which can exert both attractive and repulsive effects depending on the cell type (Hernández-Montiel et al, 2008;Tamariz et al, 2010). We observed in brachial explant cultures that treatment by Sema3C-conditioned medium (Sema3C CM ) induced the collapse of about half of the motor growth cones (Fig.…”

Cell Therapy from Bench to Bedside Translation in CNS Neurorestoratology Era

“…The success of cell therapy in PD greatly relies on the discovery of an abundant source of cells capable of DAergic function in the brain. DAergic neuron/precursor cells derived from human embryonic stem (hES) cells, human-induced pluripotent stem (hiPS) cells, neural stem/progenitor cells, human mesenchymal stem cells, and skin-derived stem cells could be increasingly considered as a pivotal choice for transplant (50, 188,227,269,372). It is likely that cell replacement in neurofuture will focus on not only ameliorating symptoms of the disease but also try to slow down the progression of the disease by either neuroprotection or restoration of a favorable microenvironment in the midbrain (319).…”