Establishment of novel stem cell and pharmacological therapies for traumatic spinal cord injury

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dc.contributor.authorHosseini, Seyed Mojtaba
dc.contributor.examiningcommitteeEftekharpour, Eftekhar (Physiology and Pathophysiology)
dc.contributor.examiningcommitteeLindsey, Benjamin (Human Anatomy and Cell Science)
dc.contributor.examiningcommitteeChopek, Jeremy (Physiology and Pathophysiology)
dc.contributor.examiningcommitteeMorshead, Cindi (University of Toronto)
dc.contributor.supervisorKarimi-Abdolrezaee, Soheila
dc.date.accessioned2025-03-25T20:03:08Z
dc.date.available2025-03-25T20:03:08Z
dc.date.issued2025-03-20
dc.date.submitted2025-03-21T00:24:29Zen_US
dc.degree.disciplinePhysiology and Pathophysiology
dc.degree.levelDoctor of Philosophy (Ph.D.)
dc.description.abstractSpinal cord injury (SCI) is a leading cause of long-term neurological impairment due to extensive post-injury cell loss, disorganization of the neuroglial network, and disruption of spinal circuits. Transplantation of neural precursor cells (NPCs) has emerged as a promising approach since NPCs possess the ability to differentiate into the three main neural lineages. However, the outcomes of NPC engraftment for SCI remain modest due to 1) low long-term survival of transplanted NPCs, 2) restricted neurogenesis, and 3) limited functional integration of newly generated neurons into the host spinal network. Our group originally discovered that upregulation and deposition of chondroitin sulfate proteoglycans (CSPGs) inhibit the regenerative capacity of transplanted NPCs. In addition, activation of serotonin receptor 5-HT1/2/7 increases neuronal maturity and synapse formation, and it enhances circuit re-assembly following SCI. Thus, we hypothesized that combining NPC transplantation with inhibition of CSPGs signaling and activation of 5-HT1/2/7 receptors would optimize survival, neurogenesis, and circuit integration of NPC-derived neurons. Using extensive in vitro and in vivo experiments, we demonstrated that pharmacological blockade of CSPG signaling substantially enhances the survival and neurogenesis of transplanted NPCs, and significantly improves functional recovery in SCI rats. Although this approach increases neurogenesis in NPCs, a sizable number of NPCs still differentiate into astrocytes. In the second part of this thesis, we showed that NPC-derived astrocytes exhibit a pro-regenerative phenotype, supporting the NPC-mediated repair process and neuronal replacement. Lastly, our extensive animal studies reveal that suppressing CSPG signaling combined with activation of 5-HT1/2/7 receptors significantly enhances the integration of transplanted NPC-derived neurons into the host's local network and supraspinal tracts. Altogether, this thesis provides new insights into the mechanisms of exogenous NPC-mediated repair in the injured spinal cord and establishes a novel, targeted, and effective cellular and pharmacological approach to enhance neuronal replacement and circuit reintegration following SCI.
dc.description.noteMay 2025
dc.description.sponsorshipWings for Life Foundation for Spinal Cord Injury
dc.identifier.urihttp://hdl.handle.net/1993/38949
dc.language.isoeng
dc.subjectSpinal cord injury
dc.subjectneural precursor cells
dc.subjectchondroitin sulfate proteoglycans
dc.subjectcircuite reconstructions
dc.titleEstablishment of novel stem cell and pharmacological therapies for traumatic spinal cord injury
local.subject.manitobano
oaire.awardTitleNovel therapies to augment neurological benefits of cellular therapies for traumatic spinal cord injury
project.funder.identifierhttps://doi.org/10.13039/501100000024
project.funder.nameCanadian Institutes of Health Research
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