Following spinal cord section, precursor cells can be transplanted into the spinal cord to enable the control of denervated motoneurons. In animal experiments, neuronal stem cells form a large number of axons that extend caudally over distances of up to 50 mm and synapse with the recipient's nerve cells there. Conversely, host axons sprout into the grafts and establish contacts, so that a partial restoration of function after spinal cord injury is sometimes observed.
In a study published last year in Experimental Neurology, the laboratories of Paul Lu and Mark Tuszynski in San Diego (USA) examined the hypothesis that trophic gradients of growth factors can guide stem cell axons to the motor areas of the gray matter of the spinal cord to improve connectivity. The authors chose brain-derived neurotrophic factor (BDNF) because this molecule plays a crucial role in directed axon growth during development and its receptor, trkB, is produced by the neurons in the spinal cord.
The scientists performed a human stem cell graft in immunodeficient rats 14 days after a partial lesion (hemisection) in the C5 segment of the spinal cord. One month after the lesion, AAV2 vectors expressing full-length BDNF were injected into three spinal cord segments caudal to the lesion site. Three months after the injury, BDNF expression significantly increased the number of graft-originating axons that entered the host mid- and ventral gray matter (by 5.5-fold), with no effect on axonal density in the functionally mismatched dorsal spinal cord. Interestingly, a >20-fold increase in the number of synaptic contacts on motor neurons was observed.
This study demonstrates that BDNF application in combination with neural stem cell transplantation improves the number of connections between recipient and graft in the context of a transverse spinal cord lesion. However, it cannot be ruled out that trophic stimulation has stabilized existing graft-recipient connections or reduced neuronal degeneration associated with injury. Furthermore, future studies would also need to determine whether this approach actually improves functional outcomes.
Reference:
Li Y, Tran A, Graham L, Brock J, Tuszynski MH, Lu P (2023) BDNF guides neural stem cell-derived axons to ventral interneurons and motor neurons after spinal cord injury. Experimental Neurology 359:114259
Image credit: iStock/K_E_N
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