Promoting directional axon growth from neural progenitors grafted into the injured spinal cord

Abstract

Spinal cord injury (SCI) is a devastating condition characterized by disruption of axonal connections, failure of axonal regeneration, and loss of motor and sensory function. The therapeutic promise of neural stem cells has been focused on cell replacement but many obstacles remain in getting neuronal integration following transplantation into the injured CNS. In this study we investigated the neurotransmitter identity and axonal growth potential of neural progenitors following grafting into adult rats with a dorsal column lesion. We found that using a combination of neuronal and glial restricted progenitors (NRP and GRP) produced graft-derived glutamatergic and GABAergic neurons within the injury site with minimal axonal extension. Administration of brain derived neurotrophic factor (BDNF) with the graft promoted modest axonal growth from grafted cells. In contrast, injecting a lentiviral vector expressing BDNF rostral to the injury generated a neurotrophin gradient and promoted directional growth of axons for up to 9 mm. Analysis of animals injected with BDNF lentivirus (at 2.5 and 5.0 mm) showed significantly more axons and significantly longer axons than in control animals injected with GFP lentivirus. However, only the 5.0 mm BDNF group showed preference for extension in the rostral direction. We concluded that NRP/GRP grafts can be used to produce excitatory and inhibitory neurons while neurotrophin gradients can guide axonal growth from graft-derived neurons toward putative targets. Together, they can serve as a building block for neuronal cell replacement of local circuits and formation of neuronal relays.

Grafted human-induced pluripotent stem-cell–derived neurospheres promote motor functional recovery after spinal cord injury in mice

“…Our present data support the potential for grafted hiPSC-NSs to form synapses with host neurons in the injured spinal cord. Previous studies have shown post-SCI functional improvements associated with intraspinal grafts containing neuronal progenitors either alone or in combination with other cells or interventions (4,7,(39)(40)(41)(42)(43). Such studies also report that graft-derived human neurons can receive projections from host mouse neurons and that their extended processes make synapses with host neurons (39).…”

Spatiotemporally limited BDNF and GDNF overexpression rescues motoneurons destined to die and induces elongative axon growth

“…Local application of recombinant GDNF, a member of the transforming growth factor beta family induced rescue of the injured motoneurons and satisfactory reinnervation of the target muscle when applied in co-treatment with riluzole (Bergerot et al 2004). Other strategies involved the use of progenitor and stem cells in the vicinity of the reimplanted ventral root (Hell et al 2009, Su et al 2009, Bonner et al 2010.…”

Stem Cell-Based Therapies for Spinal Cord Regeneration

“…However, these effects were investigated in a peripheral nerve lesion model (lumbar rhizotomy and excitotoxic root lesion), not in a SCI model. E13.5 rat spinal cord-derived NRPs/GRPs differentiated into GABAergic and glutamatergic neurons after grafting into a rat spinal cord lesion model (dorsal column transection) (Bonner et al 2010 ). Axonal outgrowth over a limited distance into the host spinal cord from these neurons was promoted by injection of a lentiviral vector expressing the neurotrophic factor BDNF.…”