Neural Stem Cell Grafts Form Extensive Synaptic Networks that Integrate with Host Circuits after Spinal Cord Injury

Abstract

Neural stem/progenitor cell grafts integrate into sites of spinal cord injury (SCI) and form anatomical and electrophysiological neuronal relays across lesions. To determine how grafts become synaptically organized and connect with host systems, we performed calcium imaging of neural progenitor cell grafts within sites of SCI, using both in vivo imaging and spinal cord slices. Stem cell grafts organize into localized synaptic networks that are spontaneously active. Following optogenetic stimulation of host corticospinal tract axons regenerating into grafts, distinct and segregated neuronal networks respond throughout the graft. Moreover, optogenetic stimulation of graft axons extending out from the lesion into the denervated spinal cord also trigger responses in local host neuronal networks. In vivo imaging reveals that behavioral stimulation of host elicits focal synaptic responses within grafts. Thus, remarkably, neural progenitor cell grafts form functional synaptic subnetworks in patterns paralleling the normal spinal cord.

Synaptic repair and vision restoration in advanced degenerating eyes by transplantation of retinal progenitor cells

“…The patch clamp is an accurate method to examine the function of graft-host synapses, but it is not applicable to test a massive amount of cells. Yet calcium imaging can detect graft neurons responding to neural input ( Ceto et al., 2020 ). GCaMP5, a GECI, is a powerful tool for testing neurofunction, especially in cortical neurons.…”

Optogenetic Modulation of Neural Progenitor Cells Improves Neuroregenerative Potential

“…In our study, ChR2-NPCs displayed increased proliferation following short BL stimulation for three consecutive days compared to unstimulated ChR2-NPCs. The discrete but significant proliferative effect in stimulated ChR2-NPCs could contribute to improve cell survival rates rather than tumorigenic complications, despite the already large number of studies employing NPCs [ 4 , 7 , 9 , 11 , 32 ].…”

“…The transplantation of neural progenitor cells (NPCs) as a treatment for central nervous system disorders such as spinal cord injury (SCI) has been widely studied [ 1 ]. Transplanted cells can promote neuroprotection [ 2 ], immunomodulation [ 3 ], and neuroregeneration [ 4 ] by secreting trophic factors, regulating inflammation, and creating new synaptic interactions that form part of host neuronal networks. Important challenges associated with NPC-based therapies remain, including poor cell survival, limited differentiation, and reduced functional engraftment, which, in turn, limits functional regeneration, offering many times discrete benefits, attributed more to early neuroprotection rather than progressive neuroregeneration due to the short transplant survival (reviewed in [ 2 ]).…”

Elucidating the Pivotal Neuroimmunomodulation of Stem Cells in Spinal Cord Injury Repair

“…Lu et al demonstrated that stem cells transplanted into the cavity and/or surrounding tissue regenerated as well as expressed neurotropic factors that triggered the growth of axons, both endogenous and graft-derived, across the lesion to form synapses as well as repaired spinal cord connectivity [212]. Studies have also shown that one of the mechanisms via which functional recovery happened in subjects with SCI was via neural plasticity or the capability of the CNS to regenerate its circuits over time [213][214][215]. Bonner et al established that the neurons that differentiated from transplanted NSPCs prolonged axons as well as form new synapses with host neurons.…”