TY - JOUR
T1 - Human neural stem cell grafts in the spinal cord of SOD1 transgenic rats
T2 - Differentiation and structural integration into the segmental motor circuitry
AU - Xu, Leyan
AU - Ryugo, David K.
AU - Pongstaporn, Tan
AU - Johe, Karl
AU - Koliatsos, Vassilis E.
PY - 2009/6/1
Y1 - 2009/6/1
N2 - Cell replacement strategies for degenerative and traumatic diseases of the nervous system depend on the functional integration of grafted cells into host neural circuitry, a condition necessary for the propagation of physiological signals and, perhaps, targeting of trophic support to injured neurons. We have recently shown that human neural stem cell (NSC) grafts ameliorate motor neuron disease in SOD1 transgenic rodents. Here we study structural aspects of integration of neuronally differentiated human NSCs in the motor circuitry of SOD1 G93A rats. Human NSCs were grafted into the lumbar protuberance of 8-week-old SOD1 G93A rats; the results were compared to those on control Sprague-Dawley rats. Using pre-embedding immunoelectron microscopy, we found human synaptophysin (+) terminals contacting the perikarya and proximal dendrites of host α motor neurons. Synaptophysin (+) terminals had well-formed synaptic vesicles and were associated with membrane specializations primarily in the form of symmetrical synapses. To analyze the anatomy of motor circuits engaging differentiated NSCs, we injected the retrograde transneuronal tracer Bartha-pseudorabies virus (PRV) or the retrograde marker cholera toxin B (CTB) into the gastrocnemius muscle/sciatic nerve of SOD1 rats before disease onset and also into control rats. With this tracing, NSC-derived neurons were labeled with PRV but not CTB, a pattern suggesting that PRV entered NSC-derived neurons via transneuronal transfer from host motor neurons but not via direct transport from the host musculature. Our results indicate an advanced degree of structural integration, via functional synapses, of differentiated human NSCs into the segmental motor circuitry of SOD1-G93A rats.
AB - Cell replacement strategies for degenerative and traumatic diseases of the nervous system depend on the functional integration of grafted cells into host neural circuitry, a condition necessary for the propagation of physiological signals and, perhaps, targeting of trophic support to injured neurons. We have recently shown that human neural stem cell (NSC) grafts ameliorate motor neuron disease in SOD1 transgenic rodents. Here we study structural aspects of integration of neuronally differentiated human NSCs in the motor circuitry of SOD1 G93A rats. Human NSCs were grafted into the lumbar protuberance of 8-week-old SOD1 G93A rats; the results were compared to those on control Sprague-Dawley rats. Using pre-embedding immunoelectron microscopy, we found human synaptophysin (+) terminals contacting the perikarya and proximal dendrites of host α motor neurons. Synaptophysin (+) terminals had well-formed synaptic vesicles and were associated with membrane specializations primarily in the form of symmetrical synapses. To analyze the anatomy of motor circuits engaging differentiated NSCs, we injected the retrograde transneuronal tracer Bartha-pseudorabies virus (PRV) or the retrograde marker cholera toxin B (CTB) into the gastrocnemius muscle/sciatic nerve of SOD1 rats before disease onset and also into control rats. With this tracing, NSC-derived neurons were labeled with PRV but not CTB, a pattern suggesting that PRV entered NSC-derived neurons via transneuronal transfer from host motor neurons but not via direct transport from the host musculature. Our results indicate an advanced degree of structural integration, via functional synapses, of differentiated human NSCs into the segmental motor circuitry of SOD1-G93A rats.
KW - Amyotrophic lateral sclerosis
KW - Graft
KW - Motor neuron
KW - Synapse
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U2 - 10.1002/cne.22022
DO - 10.1002/cne.22022
M3 - Article
C2 - 19326469
AN - SCOPUS:65649090629
SN - 0021-9967
VL - 514
SP - 297
EP - 309
JO - Journal of Comparative Neurology
JF - Journal of Comparative Neurology
IS - 4
ER -