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

• Published in: Cell stem cell 2020-09, Vol.27 (3), p.430-440.e5
• Main Authors: Ceto, Steven, Sekiguchi, Kohei J., Takashima, Yoshio, Nimmerjahn, Axel, Tuszynski, Mark H.
• Format: Article
• Language: English
• Subjects: all-optical; Axons; calcium imaging; graft; Humans; neural progenitor cell; neural stem cell; Neural Stem Cells - transplantation; neuronal relay; Neurons; optogenetics; slice preparation; Spinal Cord; Spinal Cord Injuries - therapy; spinal cord injury; transplant
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2020.07.007

Neural stem/progenitor cell (NSPC) grafts can integrate into sites of spinal cord injury (SCI) and generate neuronal relays across lesions that can provide functional benefit. To determine if and how grafts become synaptically organized and connect with host systems, we performed calcium imaging of NSPC grafts in SCI sites in vivo and in adult spinal cord slices. NSPC grafts organize into localized and spontaneously active synaptic networks. Optogenetic stimulation of host corticospinal tract axons regenerating into grafts elicited distinct and segregated neuronal network responses throughout the graft. Moreover, optogenetic stimulation of graft-derived axons extending from the graft into the denervated spinal cord also triggered local host neuronal network responses. In vivo imaging revealed that behavioral stimulation likewise elicited focal synaptic responses within grafts. Thus neural progenitor grafts can form functional synaptic subnetworks whose activity patterns resemble intact spinal cord. [Display omitted] •Calcium imaging demonstrates host-to-stem cell graft synaptic connectivity•Host inputs to grafts activate intra-graft neuronal networks•Grafts in turn activate host neurons below the lesion•Behavioral stimulation of the host elicits neuronal responses in the graft Ceto et al. find that host inputs to stem cell grafts in sites of spinal cord injury activate distinct ensembles of grafted neurons. Grafted neurons are also activated by sensory inputs and are capable of activating host neurons below the injury, supporting their ability to restore trans-lesion synaptic connectivity.