Long-term selective stimulation of transplanted neural stem/progenitor cells for spinal cord injury improves locomotor function

Kawai, Momotaro; Imaizumi, Kent; Ishikawa, Mitsuru; Shibata, Shinsuke; Shinozaki, Munehisa; Shibata, Takahiro; Hashimoto, Shogo; Kitagawa, Takahiro; Ago, Kentaro; Kajikawa, Keita; Shibata, Reo; Kamata, Yasuhiro; Ushiba, Junichi; Koga, Katsumi; Furue, Hidemasa; Matsumoto, Morio; Nakamura, Masaya; Nagoshi, Narihito; Okano, Hideyuki

doi:10.1016/j.celrep.2021.110019

Cited by 46 publications

(35 citation statements)

References 106 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our previous works reported that the grafted cells migrated rostrally and caudally in mice (Ishii et al, 2006; Ito et al, 2021; Kawai et al, 2021; Kitagawa et al, 2022) and marmoset (Iwanami et al, 2005), which increased the connection between grafted cell‐derived neurons and host spared interneurons and fibers around lesion area. Although the tendency of circuit formation between grafted cells and rostral thoracic‐projection or lumbar‐projection supraspinal neurons as well as which way contributes more function recovery needs to be further studied, this work provided a kind of anatomical distribution pattern of supraspinal inputs to rostral and caudal spinal segments, which mapped the relative location of CSNs and RNs projecting to T9‐vertebral (rostral) and T13‐vertebral level (caudal).…”

Section: Discussionmentioning

confidence: 98%

3Dimaging of supraspinal inputs to the thoracic and lumbar spinal cord mapped by retrograde tracing and light‐sheet microscopy

Tao

Shinozaki

Nagoshi

et al. 2022

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

The supraspinal inputs play a major role in tuning the hindlimb locomotion function. While most research on spinal cord injury (SCI) with rodents is based on thoracic segments, the difference in connectivity of the supraspinal centers to the thoracic and lumbar cord is still unknown. Here, we combined retrograde tracing and 3D imaging to map the connectivity of supraspinal neurons projecting to thoracic (T9‐vertebral) and lumbar (T13‐vertebral) spinal levels in adult female mice. We dissected the difference in connections of corticospinal neurons (CSNs), rubrospinal neurons, and reticulospinal neurons projecting to thoracic and lumbar cords. The ratio of double‐labeled neurons is higher in T13‐vertebral projection CSNs and parvocellular part of the red nucleus (RPC) than in T9‐vertebral projection. Using the Cre‐DIO system, we precisely targeted CSNs projecting to T9‐vertebral or T13‐vertebral. We found that abundant axon branches communicated with the red nucleus and reticular formation and distributed from cervical gray matter to the lumbar cord. Their collateral branches showed a distinct innervation pattern in thoracic and lumbar gray matters and a similar distribution pattern in the cervical spinal cord. These results revealed the difference in connectivity between the thoracic and lumbar projection supraspinal centers and clarified the collateralization of thoracic/lumbar projection CSNs throughout the brain and spinal cord. This study highlights brain‐spinal cord neural networks and the complexity of the axon terminals of spinal projection CSNs, which could contribute to the development of targeted therapeutic strategies connecting CST fibers and hindlimb function recovery. Cover Image for this issue: https://doi.org/10.1111/jnc.15414

show abstract

Section: Discussionmentioning

confidence: 98%

3Dimaging of supraspinal inputs to the thoracic and lumbar spinal cord mapped by retrograde tracing and light‐sheet microscopy

Tao

Shinozaki

Nagoshi

et al. 2022

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although the CST is the main component contributing to motor control, we recognize that a one-time CST stimulation is not sufficient in improving the behaviour of mice given that neuronal plasticity is not supposed to be altered. Instead, a consecutive hM3Dq stimulation of the CST may achieve simultaneous amelioration of circuit/behavioural activities enhancing synaptic activity 45 , 46 . Furthermore, inactivating CST function by CST-DREADDs would better help provide evidence of the host-to-graft connectivity 47 .…”

Section: Discussionmentioning

confidence: 99%

A non-invasive system to monitor in vivo neural graft activity after spinal cord injury

et al. 2022

Self Cite

View full text Add to dashboard Cite

Expectations for neural stem/progenitor cell (NS/PC) transplantation as a treatment for spinal cord injury (SCI) are increasing. However, whether and how grafted cells are incorporated into the host neural circuit and contribute to motor function recovery remain unknown. The aim of this project was to establish a novel non-invasive in vivo imaging system to visualize the activity of neural grafts by which we can simultaneously demonstrate the circuit-level integration between the graft and host and the contribution of graft neuronal activity to host behaviour. We introduced Akaluc, a newly engineered luciferase, under the control of enhanced synaptic activity-responsive element (E-SARE), a potent neuronal activity-dependent synthetic promoter, into NS/PCs and engrafted the cells into SCI model mice. Through the use of this system, we found that the activity of grafted cells was integrated with host behaviour and driven by host neural circuit inputs. This non-invasive system is expected to help elucidate the therapeutic mechanism of cell transplantation treatment for SCI.

show abstract

“…Connection mapping using trans-synaptic rabies viruses, especially the monosynaptic modified rabies viruses, could provide useful insights about the integration and functional connection of graft-derived neurons [ 41 , 42 ]. In addition, deactivation/activation of grafted neurons using chemo-genetic or optogenetic approaches could be very helpful to determine the contribution of grafted neurons in functional recovery [ 43 , 44 ]. It will be very interesting to determine whether different neuronal phenotypes differentiated from grafted NPCs could play varying roles in restoring functional recovery.…”

Section: Discussionmentioning

confidence: 99%

Transplantation of Human Induced Pluripotent Stem Cell-Derived Neural Progenitor Cells Promotes Forelimb Functional Recovery after Cervical Spinal Cord Injury

Zheng

Gallegos

Han

et al. 2022

Cells

View full text Add to dashboard Cite

Locomotor function after spinal cord injury (SCI) is critical for assessing recovery. Currently, available means to improve locomotor function include surgery, physical therapy rehabilitation and exoskeleton. Stem cell therapy with neural progenitor cells (NPCs) transplantation is a promising reparative strategy. Along this line, patient-specific induced pluripotent stem cells (iPSCs) are a remarkable autologous cell source, which offer many advantages including: great potential to generate isografts avoiding immunosuppression; the availability of a variety of somatic cells without ethical controversy related to embryo use; and vast differentiation. In this current work, to realize the therapeutic potential of iPSC-NPCs for the treatment of SCI, we transplanted purified iPSCs-derived NPCs into a cervical contusion SCI rat model. Our results showed that the iPSC-NPCs were able to survive and differentiate into both neurons and astrocytes and, importantly, improve forelimb locomotor function as assessed by the grooming task and horizontal ladder test. Purified iPSC-NPCs represent a promising cell type that could be further tested and developed into a clinically useful cell source for targeted cell therapy for cervical SCI patients.

show abstract

Long-term selective stimulation of transplanted neural stem/progenitor cells for spinal cord injury improves locomotor function

Cited by 46 publications

References 106 publications

3Dimaging of supraspinal inputs to the thoracic and lumbar spinal cord mapped by retrograde tracing and light‐sheet microscopy

3Dimaging of supraspinal inputs to the thoracic and lumbar spinal cord mapped by retrograde tracing and light‐sheet microscopy

A non-invasive system to monitor in vivo neural graft activity after spinal cord injury

Transplantation of Human Induced Pluripotent Stem Cell-Derived Neural Progenitor Cells Promotes Forelimb Functional Recovery after Cervical Spinal Cord Injury

Contact Info

Product

Resources

About