GDNF Secreting Human Neural Progenitor Cells Protect Dying Motor Neurons, but Not Their Projection to Muscle, in a Rat Model of Familial ALS

Abstract

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease characterized by rapid loss of muscle control and eventual paralysis due to the death of large motor neurons in the brain and spinal cord. Growth factors such as glial cell line derived neurotrophic factor (GDNF) are known to protect motor neurons from damage in a range of models. However, penetrance through the blood brain barrier and delivery to the spinal cord remains a serious challenge. Although there may be a primary dysfunction in the motor neuron itself, there is also increasing evidence that excitotoxicity due to glial dysfunction plays a crucial role in disease progression. Clearly it would be of great interest if wild type glial cells could ameliorate motor neuron loss in these models, perhaps in combination with the release of growth factors such as GDNF.Methodology/Principal FindingsHuman neural progenitor cells can be expanded in culture for long periods and survive transplantation into the adult rodent central nervous system, in some cases making large numbers of GFAP positive astrocytes. They can also be genetically modified to release GDNF (hNPCGDNF) and thus act as long-term ‘mini pumps’ in specific regions of the rodent and primate brain. In the current study we genetically modified human neural stem cells to release GDNF and transplanted them into the spinal cord of rats over-expressing mutant SOD1 (SOD1G93A). Following unilateral transplantation into the spinal cord of SOD1G93A rats there was robust cellular migration into degenerating areas, efficient delivery of GDNF and remarkable preservation of motor neurons at early and end stages of the disease within chimeric regions. The progenitors retained immature markers, and those not secreting GDNF had no effect on motor neuron survival. Interestingly, this robust motor neuron survival was not accompanied by continued innervation of muscle end plates and thus resulted in no improvement in ipsilateral limb use.Conclusions/SignificanceThe potential to maintain dying motor neurons by delivering GDNF using neural progenitor cells represents a novel and powerful treatment strategy for ALS. While this approach represents a unique way to prevent motor neuron loss, our data also suggest that additional strategies may also be required for maintenance of neuromuscular connections and full functional recovery. However, simply maintaining motor neurons in patients would be the first step of a therapeutic advance for this devastating and incurable disease, while future strategies focus on the maintenance of the neuromuscular junction.

Cell Therapy for Multiple Sclerosis

“…A similar effect was observed following intracerebral transplantation of NPCs after ischemia/reperfusion injury in mice [155]. In a Parkinson's disease model, transplanted NPCs rescued endogenous dopaminergic neurons of the mesostriatal system [156], and in models of amyotrophic lateral sclerosis transplanted NPCs prevented motor neurons from dying [157][158][159]. Transplantation experiments in models of spinal cord injury have provided several insights to the basic biological mechanisms by which the various types of precursor cells exhibit their therapeutic functions (for more detail see Einstein and Ben-Hur [160]).…”

Interneuron Progenitors Attenuate the Power of Acute Focal Ictal Discharges

“…The strategy of using stem cells as a drug delivery system for brain tumors has been applied in the rodent for >10 years [34]. Additional studies showed that the delivery of glial cell line-derived neurotrophic factor through engineered human neural progenitor cells improved neurons survival and function in the rodent models of Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis [35][36][37][38]. Likewise, transplantation of MGE cells into the epileptic cortex has been proposed as a cell-based therapy for medically intractable epilepsy.…”

Identity, developmental restriction and reactivity of extralaminar cells capping mammalian neuromuscular junctions

“…However, since motor nerve terminals, terminal Schwann cells and neuromuscular transmission appear largely normal in R6/2 mice , denervation, paralysis or muscle atrophy would appear to be sufficient to provoke the kranocyte cell reaction; but the reaction of these cells is evidently not sufficient to trigger the subsequent Schwann cell reaction in this disease model. It would be interesting to know the disposition and fate of kranocytes in other models of neuromuscular disease, particularly models of amyotrophic lateral sclerosis, where neuromuscular synaptic degeneration is among the earliest signs of disease (Fischer et al, 2004;Schaefer et al, 2005;Pun et al, 2006;Suzuki et al, 2007).…”