Mutually beneficial effects of intensive exercise and GABAergic neural progenitor cell transplants in reducing neuropathic pain and spinal pathology in rats with spinal cord injury

Spinal cord injuries leave patients with lifelong paralysis. To date, there are no therapies that promote the critical step required for the recovery of voluntary motor function: corticospinal axon regeneration. Spinal cord-derived neural progenitor cell (NPC) grafts integrate into the injured host spinal cord, enable robust corticospinal axon regeneration, and restore forelimb function following spinal cord injury in rodents. Consequently, engineered stem cell differentiation and transplantation techniques harbor promising potential for the design and implementation of therapies promoting corticospinal axon regeneration. However, in order to optimize the outcome of clinical trials, it is critical to fully understand the cellular and molecular mechanisms underlying this regeneration. Our recent study highlights the unexpected intrinsic potential of corticospinal neurons to regenerate and allows us to investigate new hypotheses exploiting this newly discovered potential.

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Optimizing fibrin hydrogel toward effective neural progenitor cell delivery in spinal cord injury

Biomedical Materials ◽

10.1088/1748-605x/ac3680 ◽

2021 ◽

Author(s):

Tara Sudhadevi ◽

Harikrishnan Vijayakumar Sreelatha ◽

Easwer V Hariharan ◽

Samavedam Sandhyamani ◽

Lissy K Krishnan

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Immune Response ◽

Progenitor Cell ◽

Cell Attachment ◽

Neural Progenitor Cell ◽

Neural Progenitor ◽

Cell Delivery ◽

Cord Injury

Abstract Transplantation of neural progenitor cell (NPC) possessing the potential to differentiate into neurons may guard against spinal cord injury (SCI)- associated neuronal trauma. We propose that autologous-like NPC may reduce post-transplant immune response. The study used the rat SCI model to prove this concept. For isolation and expansion of rat NPC for cell-based SCI therapy, the in vitro protocol standardized with human NPC seemed suitable. The primary aim of this study is to select a cell/neural tissue-compatible biomaterial for improving NPC survival in vivo. The composition of the fibrin hydrogel is adjusted to obtain degradable, porous, and robust fibrin strands for supporting neural cell attachment, migration, and tissue regeneration. This study employed NPC culture to evaluate the cytocompatibility and suitability of the hydrogel, composed by adding graded concentrations of thrombin to a fixed fibrinogen concentration. The microstructure evaluation by scanning electron microscope guided the selection of a suitable composition for delivering the embedded cells. On adding more thrombin, fibrinogen clotted quickly but reduced porosity, pore size, and fiber strand thickness. The high activity of thrombin also affected NPC morphology and the in vitro cell survival. The selected hydrogel carried viable NPC and retained them at the injury site post-transplantation. The fibrin hydrogel played a protective role throughout the transfer process by providing cell attachment sites and survival signals. The fibrin and NPC together regulated the immune response at the SCI site reducing ED1+ve/ED2+ve macrophages in the early period of 8 to 16 days after injury. Migration of β-III tubulin+ve neural-like cells into the fibrin-injected control SCI is evident. The continuous use of a non-neurotoxic fibrin matrix could be a convenient strategy for in vitro NPC preparation, minimally invasive cell delivery, and better transplantation outcome.

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Calcium Imaging Reveals Host-Graft Synaptic Network Formation in Spinal Cord Injury

10.1101/795583 ◽

2019 ◽

Cited By ~ 2

Author(s):

S Ceto ◽

KJ Sekiguchi ◽

Y Takashima ◽

A Nimmerjahn ◽

MH Tuszynski

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Calcium Imaging ◽

Progenitor Cell ◽

Neural Progenitor Cell ◽

Neural Progenitor ◽

Optogenetic Stimulation ◽

Cord Injury ◽

Stimulation Of

SummaryNeural stem/progenitor cell grafts integrate into sites of spinal cord injury (SCI) and form anatomical and electrophysiological neuronal relays across lesions. To determine how grafts become synaptically organized and connect with host systems, we performed calcium imaging of neural progenitor cell grafts within sites of SCI, using both in vivo imaging and spinal cord slices. Stem cell grafts organize into localized synaptic networks that are spontaneously active. Following optogenetic stimulation of host corticospinal tract axons regenerating into grafts, distinct and segregated neuronal networks respond throughout the graft. Moreover, optogenetic stimulation of graft axons extending out from the lesion into the denervated spinal cord also trigger responses in local host neuronal networks. In vivo imaging reveals that behavioral stimulation of host elicits focal synaptic responses within grafts. Thus, remarkably, neural progenitor cell grafts form functional synaptic subnetworks in patterns paralleling the normal spinal cord.

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Human embryonic Stem Cell-Derived Oligodendrocyte Progenitor Cell Transplants Improve Recovery after Cervical Spinal Cord Injury

Stem Cells ◽

10.1002/stem.245 ◽

2009 ◽

pp. N/A-N/A ◽

Cited By ~ 35

Author(s):

Jason Sharp ◽

Jennifer Frame ◽

Monica Siegenthaler ◽

Gabriel Nistor ◽

Hans S. Keirstead

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Stem Cell ◽

Embryonic Stem Cell ◽

Progenitor Cell ◽

Human Embryonic Stem Cell ◽

Cervical Spinal Cord ◽

Embryonic Stem ◽

Cord Injury ◽

Cell Transplants

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Beneficial Effects of Electroacupuncture on Neuropathic Pain Evoked by Spinal Cord Injury and Involvement of PI3K-mTOR Mechanisms

Biological Research For Nursing ◽

10.1177/1099800418804896 ◽

2018 ◽

Vol 21 (1) ◽

pp. 5-13 ◽

Cited By ~ 3

Author(s):

Yujie Wang ◽

Yu Zhao ◽

Xiaohui Ma ◽

Jing Li ◽

Junling Hou ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Neuropathic Pain ◽

Dorsal Horn ◽

Molecular Mechanisms ◽

Mtor Signaling ◽

Superficial Dorsal Horn ◽

Beneficial Effects ◽

Thermal Pain ◽

Cord Injury

The purpose of this study was to examine the beneficial effects of electroacupuncture (EA) on neuropathic pain evoked by spinal cord injury (SCI) and determine the underlying molecular mechanisms of these effects. SCI was induced in rats. Behavioral tests were performed to examine pain responses induced by mechanical and thermal stimulation. Western blot analysis was used to measure the protein expression of phosphorylated mammalian target of rapamycin (p-mTOR), mTOR-mediated phosphorylated ribosomal protein S6 kinase beta-1 (p-S6K1), and phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p-4E-BP1) in the superficial dorsal horn of the spinal cord. We showed that SCI increased the expression of p-mTOR, p-S6K1, and p-4E-BP1. The EA intervention attenuated the upregulation of mTOR signaling and alleviated mechanical and thermal pain responses in SCI rats. Blocking spinal mTOR by intrathecal injection of rapamycin also inhibited mechanical and thermal pain. In addition, blocking spinal phosphorylated phosphatidylinositide 3-kinase (p-PI3K) pathway attenuated p-mTOR pathways and mechanical and thermal hyperalgesia in SCI rats. EA also decreased the enhanced p-PI3K in the superficial dorsal horn of SCI rats. In conclusion, findings revealed specific signaling pathways that lead to neuropathic pain in response to SCI, including activation of PI3K-mTOR signaling. Further, results link the beneficial role of EA in alleviating SCI-induced neuropathic pain to its effect on these molecular mechanisms.

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