The Regrowth of Axons within Tissue Defects in the CNS Is Promoted by Implanted Hydrogel Matrices That Contain BDNF and CNTF Producing Fibroblasts

Loh, Nini; Woerly, S.; Bunt, Stuart; Wilton, Steve D.; Harvey, Alan R.

doi:10.1006/exnr.2001.7692

Cited by 84 publications

(42 citation statements)

References 68 publications

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“…It supports cell survival and proliferation and protects NPCs from inflammatory or immune cells in vivo. Cell survival and differentiation can be enhanced by adding neurotrophic factors into the matrix (Loh et al, 2001). However, because MG is derived from mouse sarcomas, it cannot be used clinically owing to potential immunogenicity and pathogen transmission.…”

Section: Discussionmentioning

confidence: 99%

Matrigel supports survival and neuronal differentiation of grafted embryonic stem cell‐derived neural precursor cells

Uemura

Refaat

Shinoyama

et al. 2009

J of Neuroscience Research

140

128

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Cell replacement therapy holds great promise as a means of treating neurological disorders, including Parkinson's disease. However, one of the major obstacles to the success of this treatment is the low survival rate of grafted cells, which probably results from mechanical damage, acute inflammation, and immunological rejection. To overcome this problem, we investigated the effect of different types of extracellular matrix (ECM) on the survival and differentiation of embryonic stem (ES) cell-derived neural precursor cells (NPCs). We tested materials from natural sources, including collagen, ornithine/laminin, and growth factor-reduced Matrigel (gfrMG), as well as the synthetic biomaterial PuraMatrix, which consists of self-assembling polypeptides. GfrMG efficiently supported cell survival, migration, and neurite outgrowth in vitro and promoted proliferation of grafted cells in vivo, resulting in larger graft volume and an increase in the number of TH-positive dopaminergic neurons in the graft. GfrMG did not induce dopaminergic differentiation directly; rather, it reduced the invasion of pan-leukocytic CD45-positive cells into the graft. Insofar as the inflammatory or immune response in the host brain inhibits neuronal differentiation of grafted NPCs, gfrMG may increase the number of TH-positive cells by suppressing this effect. Thus, gfrMG appears to provide a suitable scaffold that supports survival and differentiation of NPCs. However, because it is derived from mouse sarcomas, a human-derived matrix or synthetic biomaterial must be developed for clinical applications.

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Section: Discussionmentioning

confidence: 99%

Matrigel supports survival and neuronal differentiation of grafted embryonic stem cell‐derived neural precursor cells

Uemura

Refaat

Shinoyama

et al. 2009

J of Neuroscience Research

140

128

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“…This approach has been used with success in rats with spinal cord lesion: encapsulation of genetically modified fibroblasts may be an effective strategy for delivering therapeutic products to the injured spinal cord; 35 however, the different nature of the neurodegenerative process (acute for the spinal cord lesion versus chronic for AD) does not allow one to make predictions about the suitability of this technique for AD. A successful attempt has been made to combine biocompatible polymers with fibroblasts that are genetically engineered to produce BDNF to ameliorate the optic tract of injured animals 36 or bladder and hindlimb function following spinal contusion in rats. 37 These methods should supply BDNF locally, an essential prerequisite of a therapy with the neurotrophin.…”

Section: Exogenous Administration Of Bdnf: Pros and Consmentioning

confidence: 99%

The expanding role of BDNF: a therapeutic target for Alzheimer's disease?

2005

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Finding an effective treatment for chronic neurodegenerative disorders still represents an unmet goal. There is considerable evidence that such disorders represent a combination of genetic determinants and failure of neuroprotective mechanisms sparking a wider degree of interest in shedding light on the cellular changes responsible for these devastating disorders. Because of their role in survival or differentiation of developing neurons, as well as the recent discovery of their importance in regulating synaptic plasticity during adulthood, neurotrophic factors have been suggested as essential contributors of the etiology of neurodegenerative disorders. Alzheimer's disease (AD) is a complex, chronic, devastating disease that affects a high percentage of the population over 65 years of age. This review will focus on different pharmacological interventions that are currently in use or drugs under development, narrowing the therapeutic agents to those that interfere with the expression of the trophic factor brain-derived neurotrophic factor (BDNF), a molecule playing a pivotal role in synaptic plasticity and cognition. From these findings, it appears clear that BDNF is implicated in the mechanism of action of drugs that improve cognitive deficits in animal models of AD and in AD patients.

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“…Nonetheless some regrowth of RGC axons has been obtained using HPMA hydrogels cross-linked to the arginine-glycine-aspartic acid peptide sequence, which mediates binding to integrin receptors, and infiltrated with fibroblasts genetically modified to express CNTF or BDNF [21] . The most substantial and consistent fibre ingrowth was seen when the hydrogels contained a mixture of CNTF-and BDNF-expressing fibroblasts.…”

Section: Central Injuriesmentioning

confidence: 99%

“…Useful materials that fulfil many of these requirements are hydrogels -hydrophilic polymer-based macromolecular networks swollen in water. We have tested many types of polymer bridging structure after OT lesions, many involving the use of poly N-(2-hydroxypropyl)-methacrylamide (HPMA) or poly (2-hydroxyethyl) methacrylate hydrogels sometimes with the incorporation of signalling peptides, aminosugars or cells genetically modified to express appropriate growth factors [20,21] .…”

Section: Central Injuriesmentioning

confidence: 99%

Combined Therapies in the Treatment of Neurotrauma: Polymers, Bridges and Gene Therapy in Visual System Repair

Harvey

2007

Neurodegener Dis

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Background: The mature central nervous system (CNS) has limited capacity for self-renewal and repair after injury or neurodegeneration, and therapeutic strategies are needed to promote the viability of damaged neurons and the regrowth of their axons. The retina and optic nerve (ON) are part of the CNS, and the visual system is widely used in experimental studies on injury and repair. Objective:To test various cellular and molecular approaches in attempts to replace retinal ganglion cells (RGCs) in depleted retinas or, more usually, promote the survival of endogenous injured RGCs and stimulate axonal regeneration after ON or intracranial optic tract (OT) injury. Methods and Results: Intraocular injections of brain-derived neurotrophic factor and ciliary neurotrophic factor (CNTF) temporarily increase RGC survival after ON injury. More sustained neuroprotection is obtained using adeno-associated viral vectors to transfect RGCs with brain-derived neurotrophic factor or CNTF genes. After ON crush, intravitreal adeno-associated viral CNTF injections also increase RGC axonal regrowth. Additional protective and growth effects are obtained after intraocular elevation of cAMP and by manipulation of protein kinase signalling pathways in RGCs. Regeneration is increased by transplanting a segment of peripheral nerve onto the cut ON. Schwann cells in peripheral nerve grafts can be genetically modified using lentiviral vectors to over-express CNTF, resulting in increased regrowth of RGC axons. After OT lesions, hydrogels have been used to bridge the injury, sometimes with the incorporation of signalling peptides or cells genetically modified to express neurotrophic factors. Conclusions: There is now a general consensus that combinatorial approaches are needed to elicit sustained and effective regenerative responses in injured adult CNS neurons.

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The Regrowth of Axons within Tissue Defects in the CNS Is Promoted by Implanted Hydrogel Matrices That Contain BDNF and CNTF Producing Fibroblasts

Cited by 84 publications

References 68 publications

Matrigel supports survival and neuronal differentiation of grafted embryonic stem cell‐derived neural precursor cells

Matrigel supports survival and neuronal differentiation of grafted embryonic stem cell‐derived neural precursor cells

The expanding role of BDNF: a therapeutic target for Alzheimer's disease?

Combined Therapies in the Treatment of Neurotrauma: Polymers, Bridges and Gene Therapy in Visual System Repair

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