Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury

Ziv, Yaniv; Avidan, Hila; Pluchino, ﻿Stefano; Martino, Gianvito; Schwartz, Michal

doi:10.1073/pnas.0603747103

Cited by 259 publications

(206 citation statements)

References 45 publications

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“…Five of these six studies reported significant improvement with the transplantation of aNPCs, three in rats (Hofstetter et al, 2005;Karimi-Abdolrezaee et al, 2006;Parr et al, 2008) and two in mice (Bottai et al, 2008;Ziv et al, 2006). However, it needs to be pointed out that in some of these studies, co-treatments were also applied, such as myelin vaccination (Ziv et al, 2006) or a cocktail of trophic factors infused intrathecally for 1 week (Karimi-Abdolrezaee et al, 2006). Of note, Hofstetter and colleagues (2005) reported an alarming lowering of sensory thresholds to non-noxious stimuli (i.e., allodynia) in the naïve aNPCs transplanted animals, illustrating the very real potential that such cells may promote neuropathic pain.…”

Section: Neural Stem=progenitor Cells From Embryonic Stem Cellsmentioning

confidence: 99%

A Systematic Review of Cellular Transplantation Therapies for Spinal Cord Injury

Tetzlaff

Okon

Karimi-Abdolrezaee

et al. 2011

Journal of Neurotrauma

483

463

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Cell transplantation therapies have become a major focus in pre-clinical research as a promising strategy for the treatment of spinal cord injury (SCI). In this article, we systematically review the available pre-clinical literature on the most commonly used cell types in order to assess the body of evidence that may support their translation to human SCI patients. These cell types include Schwann cells, olfactory ensheathing glial cells, embryonic and adult neural stem=progenitor cells, fate-restricted neural=glial precursor cells, and bone-marrow stromal cells. Studies were included for review only if they described the transplantation of the cell substrate into an in-vivo model of traumatic SCI, induced either bluntly or sharply. Using these inclusion criteria, 162 studies were identified and reviewed in detail, emphasizing their behavioral effects (although not limiting the scope of the discussion to behavioral effects alone). Significant differences between cells of the same ''type'' exist based on the species and age of donor, as well as culture conditions and mode of delivery. Many of these studies used cell transplantations in combination with other strategies. The systematic review makes it very apparent that cells derived from rodent sources have been the most extensively studied, while only 19 studies reported the transplantation of human cells, nine of which utilized bone-marrow stromal cells. Similarly, the vast majority of studies have been conducted in rodent models of injury, and few studies have investigated cell transplantation in larger mammals or primates. With respect to the timing of intervention, nearly all of the studies reviewed were conducted with transplantations occurring subacutely and acutely, while chronic treatments were rare and often failed to yield functional benefits.

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Section: Neural Stem=progenitor Cells From Embryonic Stem Cellsmentioning

confidence: 99%

A Systematic Review of Cellular Transplantation Therapies for Spinal Cord Injury

Tetzlaff

Okon

Karimi-Abdolrezaee

et al. 2011

Journal of Neurotrauma

483

463

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“…S7). Three cell culture types were evaluated in 3D encapsulation studies: PC-12 cells as a reproducible model cell line, human umbilical vein endothelial cells (HUVECs) as a clinically relevant human cell type (36), and murine adult NSCs as cells used in animal models of central nervous system regeneration (37). After encapsulation, z-stack confocal imaging of calcein-AM-labeled living cells and ethidium-homodimer-labeled dead cells showed highly viable cells distributed throughout the gels (Fig.…”

Section: Microrheology and Bulk Rheology Of Protein-engineered Hydrogmentioning

confidence: 99%

“…Unlike many other tissues, the adult central nervous system has a limited capacity for self-repair (35). Transplantation of many cell types including endothelial cells (36) and adult neural stem cells (37) have produced partial functional recovery in animal models with a wide spectrum of lesions. However, most cell transplantation protocols inject cells suspended in liquid medium, which often results in low viability after implantation (15-35%) and unpredictable outcomes (38)(39)(40).…”

mentioning

confidence: 99%

Two-component protein-engineered physical hydrogels for cell encapsulation

Foo

Lee

Mulyasasmita

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

283

255

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Current protocols to encapsulate cells within physical hydrogels require substantial changes in environmental conditions (pH, temperature, or ionic strength) to initiate gelation. These conditions can be detrimental to cells and are often difficult to reproduce, therefore complicating their use in clinical settings. We report the development of a two-component, molecular-recognition gelation strategy that enables cell encapsulation without environmental triggers. Instead, the two components, which contain multiple repeats of WW and proline-rich peptide domains, undergo a sol-gel phase transition upon simple mixing and hetero-assembly of the peptide domains. We term these materials mixing-induced, two-component hydrogels. Our results demonstrate use of the WW and proline-rich domains in protein-engineered materials and expand the library of peptides successfully designed into engineered proteins. Because both of these association domains are normally found intracellularly, their molecular recognition is not disrupted by the presence of additional biomolecules in the extracellular milieu, thereby enabling reproducible encapsulation of multiple cell types, including PC-12 neuronal-like cells, human umbilical vein endothelial cells, and murine adult neural stem cells. Precise variations in the molecular-level design of the two components including (i) the frequency of repeated association domains per chain and (ii) the association energy between domains enable tailoring of the hydrogel viscoelasticity to achieve plateau shear moduli ranging from Ϸ9 to 50 Pa. Because of the transient physical crosslinks that form between association domains, these hydrogels are shear-thinning, injectable, and self-healing. Neural stem cells encapsulated in the hydrogels form stable three-dimensional cultures that continue to self-renew, differentiate, and sprout extended neurites.biomaterial ͉ cell transplantation ͉ protein engineering

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“…1,15,27 Importantly, the activity of such immune cells can be detrimental if not well regulated. 28,29 In line with this concept, a study in humans demonstrated an association between the incidence of myelin-specific T cells and improved recovery from traumatic brain injury. 30 Recent studies have shown that ischemic brain injury can trigger neural cell renewal also in areas outside of the classic neurogenic compartments (the hippocampal dentate gyrus and the subventricular zone), 22 including in the poststroke human brain.…”

Section: Ziv Et Almentioning

confidence: 71%

A Novel Immune-Based Therapy for Stroke Induces Neuroprotection and Supports Neurogenesis

Ziv

Finkelstein

Geffen

et al. 2007

Stroke

Self Cite

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Abstract-The ability of the central nervous system to cope with stressful conditions was shown to be dependent on proper T-cell-mediated immune response. Because the therapeutic window for neuroprotection after acute insults such as stroke is relatively narrow, we searched for a procedure that would allow the relevant T cells to be recruited rapidly. Permanent middle cerebral artery occlusion was induced in adult rats. To facilitate a rapid poststroke T cell activity, rats were treated with poly-YE using different regimens. Control and poly-YE-treated rats were assessed for functional recovery using neurological severity score and Morris water maze. Neuroprotection, neurogenesis, growth factor expression, and microglial phenotype were assessed using histological and immunofluorescence methods. Administration of poly-YE as late as 24 hours after middle cerebral artery occlusion yielded a beneficial effect manifested by better neurological performance, reduced neuronal loss, attenuation of behavioral deficits, and increased hippocampal and cortical neurogenesis. This compound affected the subacute phase by modulating microglial response and by increasing local production of insulin-like growth factor-I, known to be a key player in neuronal survival and neurogenesis. The relative wide therapeutic window, coupled with its efficacy in attenuating further degeneration and enhancing restoration, makes poly-YE a promising immune-based candidate for stroke therapy. Key Words: neuroprotection Ⅲ neurogenesis Ⅲ reactive microglia Ⅲ stroke P reviously, we have demonstrated that central nervous system (CNS) trauma spontaneously evokes a beneficial, T-cell-mediated immune response, which reduces neuronal loss. 1 In the damaged CNS tissue, CNS-specific T cells accumulate and become reactivated on recognizing and interacting with their corresponding autoantigens presented to them by local antigen-presenting cells. 2,3 This in turn leads to the production of specific neurotrophic factors (eg, brainderived neurotrophic factor) by T cells, and to the proper activation of microglia/macrophages. 4,5 Enhancing the activity of CNS-specific T cells (by a well-regulated passive or active immunization) was found to be beneficial in various animal models of CNS injuries. 6 -8 The ability to maintain autoimmunity in healthy individuals, without developing autoimmune disease, was shown to be regulated by naturally occurring CD4 ϩ CD25 ϩ regulatory T cells. However, recovery from CNS injury can benefit from a transient elimination or decreased activity of these cells. 9 Compounds that can downregulate the constitutive suppression of regulatory T cells (Treg) were therefore considered by us as potential candidates.We found that poly-YE, a high-molecular-weight (22 to 45 kDa) copolymer that was shown to exert modulatory effects on the immune system, 10,11 is capable of downregulating the activity of the regulatory T cells, and used this copolymer to facilitate the spontaneous response of effector T cells recognizing antigens associated with a ...

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Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury

Cited by 259 publications

References 45 publications

A Systematic Review of Cellular Transplantation Therapies for Spinal Cord Injury

A Systematic Review of Cellular Transplantation Therapies for Spinal Cord Injury

Two-component protein-engineered physical hydrogels for cell encapsulation

A Novel Immune-Based Therapy for Stroke Induces Neuroprotection and Supports Neurogenesis

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