Generation of spinal motor neurons from human fetal brain‐derived neural stem cells: Role of basic fibroblast growth factor

Abstract

Neural stem cells (NSCs) have some specified properties, but are generally uncommitted and so can change their fate after exposure to environmental cues. It is unclear to what extent this NSC plasticity can be modulated by extrinsic cues and what are the molecular mechanisms underlying neuronal fate determination. Basic fibroblast growth factor (bFGF) is a well known mitogen for proliferating NSCs. However, its role in guiding stem cells for neuronal subtype specification is undefined. Here we report that in vitro expanded human fetal forebrain-derived neural stem cells can generate cholinergic neurons with spinal motor neuron properties when treated with bFGF within a specific time window. bFGF induces NSCs to express the motor neuron marker Hb9, which is blocked by specific FGF receptor inhibitors and bFGF neutralizing antibodies. This development of spinal motor neuron properties is independent of selective proliferation or survival and does not require high levels of MAPK activation. Thus our study indicates that bFGF can play an important role in modulating plasticity and neuronal fate of human NSCs and presumably has implications for exploring the full potential of brain NSCs for clinical applications, particularly spinal motor neuron regeneration.

Stem cells in human neurodegenerative disorders — time for clinical translation?

“…There is no effective treatment. Motor neurons have been generated in vitro from stem cells from various sources, including mouse and human ES cells (39)(40)(41)(42)(43), NSCs derived from fetal rat spinal cord (44) and human forebrain (45), and human iPS cells (46,47). Stem cellderived motor neuron precursors and neuroblasts establish functional synapses with muscle fibers in vitro (48,49), extend axons to ventral roots after transplantation into the spinal cord of adult rats with motor neuron injury (44,48,50), form neuromuscular junctions with host muscle, and give rise to partial recovery from paralysis (50).…”

“…Over the past few years, there has been continuous progress in developing approaches to generate the types of human-derived neurons and glial cells that are needed for cell replacement therapy based on pathology in the respective diseases (13,17,40,42,45,88,89,92,93,(135)(136)(137)143). Patient-specific cells that may be useful for transplantation can now be produced from iPS cells (4,27,32,46,47).…”

Adult human neural stem cell therapeutics: Current developmental status and prospect

“…For the regeneration and/ or supplementation of motor neurons, motor neurons were generated in vitro from ESCs [94][95][96][97] , fetal NSCs [98][99][100] , and iPSCs [101,102] . Recently, transplantation of fetal spinal cord-or iPSCderived NSCs was reported to be effective in slowing down the disease progression of ALS animal models [103,104] .…”

Dopaminergic Neurons Derived from Human Embryonic Stem Cell Derived Neural Progenitors: Biological Relevance and Application

“…Bone morphogenetic proteins are often inhibited by the antagonist Noggin, which leads to development of the neural phenotype in the mouse (Pera et al, 2004, Itsykson et al, 2005. bFGF signaling maintains the proliferative capacity of neural cells as well as involvement in induction and patterning (Jordan et al, 2009). bFGF was used in a neural differentiation protocol for its known caualzaling factors.…”

“…Originally, bFGF was shown to be important in the brain as a neural growth factor that maintained the pluripotency of immortalized NSCs (Figure 2.2) (Li et al, 2000). Later, bFGF has been shown to be a caudalizing factor within the neural plate and the neural floor (Jordan et al, 2009). Epidermal growth factor (EGF) is a mitogen that was used in many hESC neural differentiation protocols to maintain self-renewal potentially through crosstalk with Notch or through EGF's suppression of apoptosis (Carpenter et al, 2003, Elkabetz et al, 2008.…”