Research

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20 pages, 5467 KiB

Open AccessArticle

Activation of Neuroprotective Microglia and Astrocytes at the Lesion Site and in the Adjacent Segments Is Crucial for Spontaneous Locomotor Recovery after Spinal Cord Injury

by Alexandra Kisucká, Katarína Bimbová, Mária Bačová, Ján Gálik and Nadežda Lukáčová

Cells 2021, 10(8), 1943; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10081943 - 30 Jul 2021

Cited by 47 | Viewed by 3230

Abstract

Microglia and astrocytes play an important role in the regulation of immune responses under various pathological conditions. To detect environmental cues associated with the transformation of reactive microglia (M1) and astrocytes (A1) into their polarization states (anti-inflammatory M2 and A2 phenotypes), we studied [...] Read more.

Microglia and astrocytes play an important role in the regulation of immune responses under various pathological conditions. To detect environmental cues associated with the transformation of reactive microglia (M1) and astrocytes (A1) into their polarization states (anti-inflammatory M2 and A2 phenotypes), we studied time-dependent gene expression in naive and injured spinal cord. The relationship between astrocytes and microglia and their polarization states were studied in a rat model after Th9 compression (40 g/15 min) in acute and subacute stages at the lesion site, and both cranially and caudally. The gene expression of microglia/macrophages and M1 microglia was strongly up-regulated at the lesion site and caudally one week after SCI, and attenuated after two weeks post-SCI. GFAP and S100B, and A1 astrocytes were profoundly expressed predominantly two weeks post-SCI at lesion site and cranially. Gene expression of anti-inflammatory M2a microglia (CD206, CHICHI, IL1rn, Arg-1), M2c microglia (TGF-β, SOCS3, IL4R α) and A2 astrocytes (Tgm1, Ptx3, CD109) was greatly activated at the lesion site one week post-SCI. In addition, we observed positive correlation between neurological outcome and expression of M2a, M2c, and A2 markers. Our findings indicate that the first week post-injury is critical for modulation of reactive microglia/astrocytes into their neuroprotective phenotypes. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Dorsal Root Injury and Injured Spinal Cord)

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28 pages, 3987 KiB

Open AccessArticle

Spinal Cord Injury Significantly Alters the Properties of Reticulospinal Neurons: I. Biophysical Properties, Firing Patterns, Excitability, and Synaptic Inputs

by Ryan A. Hough, Timothee Pale, Jessica A. Benes and Andrew D. McClellan

Cells 2021, 10(8), 1921; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10081921 - 29 Jul 2021

Cited by 4 | Viewed by 2106

Abstract

Following spinal cord injury (SCI) for larval lampreys, descending axons of reticulospinal (RS) neurons regenerate, and locomotor function gradually recovers. In the present study, the electrophysiological properties of uninjured (left)-injured (right) pairs of large, identified RS neurons were compared following rostral, right spinal [...] Read more.

Following spinal cord injury (SCI) for larval lampreys, descending axons of reticulospinal (RS) neurons regenerate, and locomotor function gradually recovers. In the present study, the electrophysiological properties of uninjured (left)-injured (right) pairs of large, identified RS neurons were compared following rostral, right spinal cord hemi-transections (HTs). First, changes in firing patterns of injured RS neurons began in as little as 2–3 days following injury, these changes were maximal at ~2–3 weeks (wks), and by 12–16 wks normal firing patterns were restored for the majority of neurons. Second, at ~2–3 wks following spinal cord HTs, injured RS neurons displayed several significant changes in properties compared to uninjured neurons: (a) more hyperpolarized V_REST; (b) longer membrane time constant and larger membrane capacitance; (c) increased voltage and current thresholds for action potentials (APs); (d) larger amplitudes and durations for APs; (e) higher slope for the repolarizing phase of APs; (f) virtual absence of some afterpotential components, including the slow afterhyperpolarization (sAHP); (g) altered, injury-type firing patterns; and (h) reduced average and peak firing (spiking) frequencies during applied depolarizing currents. These altered properties, referred to as the “injury phenotype”, reduced excitability and spiking frequencies of injured RS neurons compared to uninjured neurons. Third, artificially injecting a current to add a sAHP waveform following APs for injured neurons or removing the sAHP following APs for uninjured neurons did not convert these neurons to normal firing patterns or injury-type firing patterns, respectively. Fourth, trigeminal sensory-evoked synaptic responses recorded from uninjured and injured pairs of RS neurons were not significantly different. Following SCI, injured lamprey RS neurons displayed several dramatic changes in their biophysical properties that are expected to reduce calcium influx and provide supportive intracellular conditions for axonal regeneration. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Dorsal Root Injury and Injured Spinal Cord)

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22 pages, 2820 KiB

Open AccessArticle

In Vitro Study of Human Immune Responses to Hyaluronic Acid Hydrogels, Recombinant Spidroins and Human Neural Progenitor Cells of Relevance to Spinal Cord Injury Repair

by Chenhong Lin, Åsa Ekblad-Nordberg, Jakob Michaëlsson, Cecilia Götherström, Chia-Chen Hsu, Hua Ye, Jan Johansson, Anna Rising, Erik Sundström and Elisabet Åkesson

Cells 2021, 10(7), 1713; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10071713 - 06 Jul 2021

Cited by 12 | Viewed by 3515

Abstract

Scaffolds of recombinant spider silk protein (spidroin) and hyaluronic acid (HA) hydrogel hold promise in combination with cell therapy for spinal cord injury. However, little is known concerning the human immune response to these biomaterials and grafted human neural stem/progenitor cells (hNPCs). Here, [...] Read more.

Scaffolds of recombinant spider silk protein (spidroin) and hyaluronic acid (HA) hydrogel hold promise in combination with cell therapy for spinal cord injury. However, little is known concerning the human immune response to these biomaterials and grafted human neural stem/progenitor cells (hNPCs). Here, we analyzed short- and long-term in vitro activation of immune cells in human peripheral blood mononuclear cells (hPBMCs) cultured with/without recombinant spidroins, HA hydrogels, and/or allogeneic hNPCs to assess potential host–donor interactions. Viability, proliferation and phenotype of hPBMCs were analyzed using NucleoCounter and flow cytometry. hPBMC viability was confirmed after exposure to the different biomaterials. Short-term (15 h) co-cultures of hPBMCs with spidroins, but not with HA hydrogel, resulted in a significant increase in the proportion of activated CD69⁺ CD4⁺ T cells, CD8⁺ T cells, B cells and NK cells, which likely was caused by residual endotoxins from the Escherichia coli expression system. The observed spidroin-induced hPBMC activation was not altered by hNPCs. It is resource-effective to evaluate human compatibility of novel biomaterials early in development of the production process to, when necessary, make alterations to minimize rejection risk. Here, we present a method to evaluate biomaterials and hPBMC compatibility in conjunction with allogeneic human cells. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Dorsal Root Injury and Injured Spinal Cord)

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16 pages, 2805 KiB

Open AccessArticle

High-Yield Mucosal Olfactory Ensheathing Cells Restore Loss of Function in Rat Dorsal Root Injury

by Kamile Minkelyte, Andrew Collins, Modinat Liadi, Ahmed Ibrahim, Daqing Li and Ying Li

Cells 2021, 10(5), 1186; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10051186 - 12 May 2021

Cited by 5 | Viewed by 2434

Abstract

In a previous study, we reported that no axons were crossing from the severed dorsal roots to the spinal cord using the rat dorsal rhizotomy paradigm. The injury caused ipsilateral deficits of forepaw function. An attempt to restore the function by transplanting cells [...] Read more.

In a previous study, we reported that no axons were crossing from the severed dorsal roots to the spinal cord using the rat dorsal rhizotomy paradigm. The injury caused ipsilateral deficits of forepaw function. An attempt to restore the function by transplanting cells containing 5% olfactory ensheathing cells (OECs) cultured from the olfactory mucosa did not succeed. However, obtaining OECs from the olfactory mucosa has an advantage for clinical application. In the present study, we used the same rhizotomy paradigm, but rats with an injury received cells from a modified mucosal culture containing around 20% OECs mixed in collagen. The forelimb proprioception assessment showed that 80% of the rats receiving the transplants had functional improvement over six weeks of the study. The adhesive removal test showed that the time taken for the rats to notice the adhesive label and remove it almost returned to the normal level after receiving the transplants. Transplanted cells were identified with the expression of green fluorescent protein (ZsGreen). Some regeneration fibres immunostained for neurofilament (NF) or traced by biotinylated dextran amine (BDA) in the injury area were associated with the transplanted cells. The evidence in this study improves the prospect of clinical application using OECs from the olfactory mucosa to treat CNS injuries. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Dorsal Root Injury and Injured Spinal Cord)

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Review

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18 pages, 1230 KiB

Open AccessReview

Dorsal Root Injury—A Model for Exploring Pathophysiology and Therapeutic Strategies in Spinal Cord Injury

by Håkan Aldskogius and Elena N. Kozlova

Cells 2021, 10(9), 2185; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10092185 - 25 Aug 2021

Cited by 4 | Viewed by 3671

Abstract

Unraveling the cellular and molecular mechanisms of spinal cord injury is fundamental for our possibility to develop successful therapeutic approaches. These approaches need to address the issues of the emergence of a non-permissive environment for axonal growth in the spinal cord, in combination [...] Read more.

Unraveling the cellular and molecular mechanisms of spinal cord injury is fundamental for our possibility to develop successful therapeutic approaches. These approaches need to address the issues of the emergence of a non-permissive environment for axonal growth in the spinal cord, in combination with a failure of injured neurons to mount an effective regeneration program. Experimental in vivo models are of critical importance for exploring the potential clinical relevance of mechanistic findings and therapeutic innovations. However, the highly complex organization of the spinal cord, comprising multiple types of neurons, which form local neural networks, as well as short and long-ranging ascending or descending pathways, complicates detailed dissection of mechanistic processes, as well as identification/verification of therapeutic targets. Inducing different types of dorsal root injury at specific proximo-distal locations provide opportunities to distinguish key components underlying spinal cord regeneration failure. Crushing or cutting the dorsal root allows detailed analysis of the regeneration program of the sensory neurons, as well as of the glial response at the dorsal root-spinal cord interface without direct trauma to the spinal cord. At the same time, a lesion at this interface creates a localized injury of the spinal cord itself, but with an initial neuronal injury affecting only the axons of dorsal root ganglion neurons, and still a glial cell response closely resembling the one seen after direct spinal cord injury. In this review, we provide examples of previous research on dorsal root injury models and how these models can help future exploration of mechanisms and potential therapies for spinal cord injury repair. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Dorsal Root Injury and Injured Spinal Cord)

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20 pages, 807 KiB

Open AccessReview

Lentiviral Vectors Delivered with Biomaterials as Therapeutics for Spinal Cord Injury

by Ciara Shortiss, Linda Howard and Siobhan S. McMahon

Cells 2021, 10(8), 2102; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10082102 - 16 Aug 2021

Cited by 3 | Viewed by 4005

Abstract

Spinal cord injury (SCI) is a devastating trauma that can cause permanent disability, life-long chronic issues for sufferers and is a big socioeconomic burden. Regenerative medicine aims to overcome injury caused deficits and restore function after SCI through gene therapy and tissue engineering [...] Read more.

Spinal cord injury (SCI) is a devastating trauma that can cause permanent disability, life-long chronic issues for sufferers and is a big socioeconomic burden. Regenerative medicine aims to overcome injury caused deficits and restore function after SCI through gene therapy and tissue engineering approaches. SCI has a multifaceted pathophysiology. Due to this, producing therapies that target multiple different cellular and molecular mechanisms might prove to be a superior approach in attempts at regeneration. Both biomaterials and nucleic acid delivery via lentiviral vectors (LVs) have proven to promote repair and restoration of function post SCI in animal models. Studies indicate that a combination of biomaterials and LVs is more effective than either approach alone. This review presents studies supporting the use of LVs and LVs delivered with biomaterials in therapies for SCI and summarises methods to combine LVs with biomaterials for SCI treatment. By summarising this knowledge this review aims to demonstrate how LV delivery with biomaterials can augment/compliment both LV and biomaterial therapeutic effects in SCI. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Dorsal Root Injury and Injured Spinal Cord)

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10 pages, 277 KiB

Open AccessReview

Plasticity of the Injured Spinal Cord

by Nicolas Guérout

Cells 2021, 10(8), 1886; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10081886 - 26 Jul 2021

Cited by 16 | Viewed by 3485

Abstract

Complete spinal cord injury (SCI) leads to permanent motor, sensitive and sensory deficits. In humans, there is currently no therapy to promote recovery and the only available treatments include surgical intervention to prevent further damage and symptomatic relief of pain and infections in [...] Read more.

Complete spinal cord injury (SCI) leads to permanent motor, sensitive and sensory deficits. In humans, there is currently no therapy to promote recovery and the only available treatments include surgical intervention to prevent further damage and symptomatic relief of pain and infections in the acute and chronic phases, respectively. Basically, the spinal cord is classically viewed as a nonregenerative tissue with limited plasticity. Thereby the establishment of the “glial” scar which appears within the SCI is mainly described as a hermetic barrier for axon regeneration. However, recent discoveries have shed new light on the intrinsic functional plasticity and endogenous recovery potential of the spinal cord. In this review, we will address the different aspects that the spinal cord plasticity can take on. Indeed, different experimental paradigms have demonstrated that axonal regrowth can occur even after complete SCI. Moreover, recent articles have demonstrated too that the “glial” scar is in fact composed of several cellular populations and that each of them exerts specific roles after SCI. These recent discoveries underline the underestimation of the plasticity of the spinal cord at cellular and molecular levels. Finally, we will address the modulation of this endogenous spinal cord plasticity and the perspectives of future therapeutic opportunities which can be offered by modulating the injured spinal cord microenvironment. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Dorsal Root Injury and Injured Spinal Cord)

19 pages, 1322 KiB

Open AccessReview

Spinal Cord Repair: From Cells and Tissue Engineering to Extracellular Vesicles

by Shaowei Guo, Idan Redenski and Shulamit Levenberg

Cells 2021, 10(8), 1872; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10081872 - 23 Jul 2021

Cited by 38 | Viewed by 5426

Abstract

Spinal cord injury (SCI) is a debilitating condition, often leading to severe motor, sensory, or autonomic nervous dysfunction. As the holy grail of regenerative medicine, promoting spinal cord tissue regeneration and functional recovery are the fundamental goals. Yet, effective regeneration of injured spinal [...] Read more.

Spinal cord injury (SCI) is a debilitating condition, often leading to severe motor, sensory, or autonomic nervous dysfunction. As the holy grail of regenerative medicine, promoting spinal cord tissue regeneration and functional recovery are the fundamental goals. Yet, effective regeneration of injured spinal cord tissues and promotion of functional recovery remain unmet clinical challenges, largely due to the complex pathophysiology of the condition. The transplantation of various cells, either alone or in combination with three-dimensional matrices, has been intensively investigated in preclinical SCI models and clinical trials, holding translational promise. More recently, a new paradigm shift has emerged from cell therapy towards extracellular vesicles as an exciting “cell-free” therapeutic modality. The current review recapitulates recent advances, challenges, and future perspectives of cell-based spinal cord tissue engineering and regeneration strategies. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Dorsal Root Injury and Injured Spinal Cord)

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13 pages, 342 KiB

Open AccessReview

Neurogenesis after Spinal Cord Injury: State of the Art

by Roxana Rodríguez-Barrera, Monserrat Rivas-González, Julián García-Sánchez, Daniel Mojica-Torres and Antonio Ibarra

Cells 2021, 10(6), 1499; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10061499 - 15 Jun 2021

Cited by 17 | Viewed by 3043

Abstract

Neurogenesis in the adult state is the process of new neuron formation. This relatively infrequent phenomenon comprises four stages: cell proliferation, cell migration, differentiation, and the integration of these cells into an existing circuit. Recent reports suggest that neurogenesis can be found in [...] Read more.

Neurogenesis in the adult state is the process of new neuron formation. This relatively infrequent phenomenon comprises four stages: cell proliferation, cell migration, differentiation, and the integration of these cells into an existing circuit. Recent reports suggest that neurogenesis can be found in different regions of the Central Nervous System (CNS), including the spinal cord (SC). This process can be observed in physiological settings; however, it is more evident in pathological conditions. After spinal cord injury (SCI), the activation of microglial cells and certain cytokines have shown to exert different modulatory effects depending on the presence of inflammation and on the specific region of the injury site. In these conditions, microglial cells and cytokines are considered to play an important role in the regulation of neurogenesis after SCI. The purpose of this article is to present an overview on neural progenitor cells and neurogenic and non-neurogenic zones as well as the cellular and molecular regulation of neurogenesis. Additionally, we will briefly describe the recent advances in the knowledge of neurogenesis after SCI. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Dorsal Root Injury and Injured Spinal Cord)

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