Suppressing CSPG/LAR/PTPr Axis Facilitates Neuronal Replacement and Synaptogenesis by Human Neural Precursor Grafts and Improves Recovery after Spinal Cord Injury

The Journal of Neuroscience, 2022 · DOI: https://doi.org/10.1523/JNEUROSCI.2177-21.2022 · Published: April 13, 2022

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

Spinal cord injuries often lead to permanent disabilities because damaged neurons are not replaced. Transplantation of neural precursor cells (NPCs) offers a potential solution; however, these cells often fail to differentiate into neurons and integrate into the spinal cord. The study found that molecules called CSPGs, which increase after spinal cord injury, prevent NPCs from becoming neurons via LAR and PTPr receptors. Blocking these receptors allowed transplanted human NPCs to develop into spinal cord neurons and connect to the existing network. Blocking CSPG signaling improved recovery of movement and sensory functions in rats with spinal cord injury. This suggests that targeting CSPG/LAR/PTPr could enhance cell-based therapies for spinal cord injury.

Study Duration

16 weeks

Participants

50 adult female Sprague Dawley rats

Evidence Level

Level 2: Experimental study in animal model

Key Findings

1
CSPGs inhibit neurogenesis and synaptogenesis of human drNPC-O2 through activation of LAR and PTPr receptors in vitro.
2
Co-inhibition of LAR and PTPs enhances graft survival and neuronal replacement by transplanted human drNPC-O2 in rat SCI.
3
CSPGs inhibit neuronal differentiation of human drNPC-O2 by suppressing Wnt/b-catenin signaling pathway that can be reversed by co-blockage of LAR and PTPr receptors.

Research Summary

This study investigates the role of CSPG/LAR/PTPr signaling in limiting neurogenesis and synaptic integration of transplanted human neural precursor cells (NPCs) in a rat model of spinal cord injury (SCI). The researchers found that CSPGs, upregulated after SCI, inhibit neuronal differentiation and synaptogenesis of NPCs through LAR and PTPr receptors. Co-inhibition of these receptors promotes NPC survival, neuronal differentiation, and synaptic connectivity, leading to improved functional recovery. Transcriptomic analysis revealed that LAR/PTPs inhibition activates a gene expression program supporting neuronal differentiation and synaptic plasticity, potentially by modulating the Wnt/b-catenin pathway. These findings suggest that targeting CSPG/LAR/PTPr could enhance NPC-based therapies for SCI.

Practical Implications

Therapeutic Target

LAR and PTPr receptors are potential targets for therapeutic intervention to enhance the efficacy of NPC-based cell therapies for spinal cord injury.

Improved Cell Therapies

Co-inhibition of LAR and PTPs could be used as an adjunct treatment to optimize neuronal replacement, synaptic re-connectivity, and neurologic recovery in NPC-based strategies.

Clinical Translation

Systemic administration of ILP/ISP peptides targeting LAR and PTPs represents a clinically feasible therapeutic approach for SCI, especially in conjunction with human drNPC-O2 transplantation.

Study Limitations

1
Study conducted on female rats; results may not be generalizable to males.
2
The long-term effects of ILP/ISP treatment and drNPC-O2 transplantation beyond 15 weeks were not evaluated.
3
The specific trans-synaptic connections between transplanted drNPCs-O2-derived neurons and host descending CST axons require further confirmation.

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