Neural stem/progenitor cells from adult canine cervical spinal cord have the potential to differentiate into neural lineage cells
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ABSTRACT:
SUBMITTER: Kim W
PROVIDER: S-EPMC10557334 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:Adult neural progenitor cells (aNPCs) exhibit limited migration in vivo with the exception of the rostral migratory stream and injury-induced movement. Surprisingly little is known regarding those signals regulating attraction or inhibition of the aNPC. These studies demonstrate that aNPCs respond principally to a repulsive cue expressed at the embryonic floor plate (FP) and also the injured adult CNS. Adult spinal cord progenitor cells (aSCPs) were seeded onto organotypic slice preparations of the intact embryonic or injured adult spinal cord. Cell migration assays combined with genetic and molecular perturbation of FP-derived migration cues or aSCP receptors establish netrin-1 (Ntn-1) but not Slit-2, Shh, or Ephrin-B3 as the primary FP-derived repellant. When slices were prepared from injured spinal cord, aSCP migration away from the injury core was Ntn-1-dependent. These studies establish Ntn-1 as a critical regulator of aSCP migration in the intact and injured CNS.
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Project description:The adult human spinal cord harbors diverse populations of neural stem/progenitor cells (NSPCs) essential for neuroregeneration and central nervous system repair. While induced pluripotent stem cell (iPSC)-derived NSPCs offer significant therapeutic potential, understanding their molecular and functional alignment with bona fide spinal cord NSPCs is crucial for developing autologous cell therapies that enhance spinal cord regeneration and minimize immune rejection. In this study, we present the first direct transcriptomic and functional comparison of syngeneic adult human NSPC populations, including bona fide spinal cord NSPCs and iPSC-derived NSPCs regionalized to the spinal cord (iPSC-SC) and forebrain (iPSC-Br). RNA sequencing analysis revealed distinct transcriptomic profiles and functional disparities among NSPC types. iPSC-Br NSPCs exhibited a close resemblance to bona fide spinal cord NSPCs, characterized by enriched expression of neurogenesis, axon guidance, synaptic signaling, and voltage-gated calcium channel activity pathways. Conversely, iPSC-SC NSPCs displayed significant heterogeneity, suboptimal regional specification, and elevated expression of neural crest and immune response-associated genes. Functional assays corroborated the transcriptomic findings, demonstrating superior neurogenic potential in iPSC-Br NSPCs. Additionally, we assessed donor-specific influences on NSPC behavior by analyzing gene expression and differentiation outcomes across syngeneic populations from multiple individuals. Donor-specific factors significantly modulated transcriptomic profiles, with notable variability in the alignment of iPSC-derived NSPCs to bona fide spinal cord NSPCs. Enrichment of pathways related to neurogenesis, axon guidance, and synaptic signaling varied across donors, highlighting the impact of genetic and epigenetic individuality on NSPC behavior.
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Project description:Spinal cord injury remains a scientific and therapeutic challenge with great cost to individuals and society. The goal of research in this field is to find a means of restoring lost function. Recently we have seen considerable progress in understanding the injury process and the capacity of CNS neurons to regenerate, as well as innovations in stem cell biology. This presents an opportunity to develop effective transplantation strategies to provide new neural cells to promote the formation of new neuronal networks and functional connectivity. Past and ongoing clinical studies have demonstrated the safety of cell therapy, and preclinical research has used models of spinal cord injury to better elucidate the underlying mechanisms through which donor cells interact with the host and thus increase long-term efficacy. While a variety of cell therapies have been explored, we focus here on the use of neural progenitor cells obtained or derived from different sources to promote connectivity in sensory, motor and autonomic systems.
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Project description:Traumatic spinal cord injury (SCI) results in the loss of neurons, oligodendrocytes, and astrocytes. Present interventions for SCI include decompressive surgery, anti-inflammatory therapies, and rehabilitation programs. Nonetheless, these approaches do not offer regenerative solutions to replace the lost cells, fiber tracts, and circuits. Neural stem/progenitor cell (NPC) transplantation is a promising strategy that aims to encourage regeneration. However, NPC differentiation remains inconsistent, thus, contributing to suboptimal functional recovery. As such, we have previously engineered oligodendrogenically biased NPCs (oNPCs) and demonstrated their efficacy in a thoracic model of SCI. Since the majority of patients with SCI experience cervical injuries, our objective in the current study was to generate human induced pluripotent stem cell-derived oNPCs (hiPSC-oNPCs) and to characterize these cells in vitro and in vivo, utilizing a clinically relevant rodent model of cervical SCI. Following transplantation, the oNPCs engrafted, migrated to the rostral and caudal regions of the lesion, and demonstrated preferential differentiation toward oligodendrocytes. Histopathological evaluations revealed that oNPC transplantation facilitated tissue preservation while diminishing astrogliosis. Moreover, oNPC transplantation fostered remyelination of the spared tissue. Functional analyses indicated improved forelimb grip strength, gait, and locomotor function in the oNPC-transplanted rats. Importantly, oNPC transplantation did not exacerbate neuropathic pain or induce tumor formation. In conclusion, these findings underscore the therapeutic potential of oNPCs in promoting functional recovery and histopathological improvements in cervical SCI. This evidence warrants further investigation to optimize and advance this promising cell-based therapeutic approach.
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Project description:Advances in stem cell technology, including the use of induced pluripotent stem cells (iPSC) to produce neurons and glial cells, offer new hope for patients with neurological disease and injuries. Pet dogs with spinal cord injuries provide an important spontaneous animal model for evaluating new approaches to stem cell therapy. Therefore, studies were conducted to identify optimal conditions for generating neural progenitor cells (NPC) from canine induced pluripotent stem cells (iPSC) for preliminary evaluation in animals with spinal cord injury. We found that canine NPC could be induced to differentiate into mature neural cells, including glia and neurons. In addition, canine NPC did not form teratomas when injected in NOD/SCID mice. In a pilot study, two dogs with chronic spinal cord injury underwent fluoroscopically guided intrathecal injections of canine NPC. In follow-up MRI evaluations, tumor formation was not observed at the injection sites. However, none of the animals experienced meaningful clinical or electrophysiological improvement following NPC injections. These studies provide evidence that canine iPSC can be used to generate NPC for evaluation in cellular therapy of chronic spinal cord injury in the dog spontaneous injury model. Further refinements in the cell implantation procedure are likely required to enhance stem cell treatment efficacy.
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Project description:We report that prospectively isolated, human CNS stem cells grown as neurospheres (hCNS-SCns) survive, migrate, and express differentiation markers for neurons and oligodendrocytes after long-term engraftment in spinal cord-injured NOD-scid mice. hCNS-SCns engraftment was associated with locomotor recovery, an observation that was abolished by selective ablation of engrafted cells by diphtheria toxin. Remyelination by hCNS-SCns was found in both the spinal cord injury NOD-scid model and myelin-deficient shiverer mice. Moreover, electron microscopic evidence consistent with synapse formation between hCNS-SCns and mouse host neurons was observed. Glial fibrillary acidic protein-positive astrocytic differentiation was rare, and hCNS-SCns did not appear to contribute to the scar. These data suggest that hCNS-SCns may possess therapeutic potential for CNS injury and disease.
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Project description:Neural progenitor cell (NPC) transplantation is a promising approach for repairing spinal cord injury (SCI). However, cell survival, maturation and integration after transplantation are still major challenges. Here, we produced a novel centimeter-scale human spinal cord neural tissue (hscNT) construct with human spinal cord neural progenitor cells (hscNPCs) and human spinal cord astrocytes (hscAS) on a linearly ordered collagen scaffold (LOCS). The hscAS promoted hscNPC adhesion, survival and neurite outgrowth on the LOCS, to form a linearly ordered spinal cord-like structure consisting of mature neurons and glia cells. When transplanted into rats with SCI, the hscNT created a favorable microenvironment by inhibiting inflammation and glial scar formation, and promoted neural and vascular regeneration. Notably, the hscNT promoted neural circuit reconstruction and motor functional recovery. Engineered human spinal cord implants containing astrocytes and neurons assembled on axon guidance scaffolds may therefore have potential in the treatment of SCI.
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