Transplantation of human glial-restricted neural precursors into injured spinal cord promotes functional and sensory recovery without causing allodynia

Alexanian, Arshak R.; Svendsen, Clive N.; Crowe, Maria J.; Kurpad, Shekar N.

doi:10.3109/14653249.2010.510504

Cited by 31 publications

(27 citation statements)

References 28 publications

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“…8,[13][14][15][16][17]19,36,40,44 Given this therapeutic potential, there has been a growing interest not only in defining astrocyte populations in terms of their phenotypic and functional properties but also in the development of protocols for efficient cell preparation and effective transplantation strategies. We therefore carried out a systematic analysis of astrocyte differentiation using clinical grade hGRP, manufactured and cryopreserved using a GMP process to meet the U. S. Food and Drug Administration (FDA) guidelines.…”

Section: Discussionmentioning

confidence: 99%

“…18 Studies using hGRP also have demonstrated the therapeutic potential of GRP derived from human tissue on the injury environment, facilitating neuroprotection, remyelination, and recovery of function. [12][13][14] Importantly, transplantation studies of hGRP and hGRP-derived astrocytes in a contusion model of SCI showed no major differences between naïve hGRP and hGRP pre-differentiated with BMP-4. Our current study examined the transplantation of naïve hGRP and hGRP pre-differentiated into astrocytes with BMP-4 or CNTF and demonstrated similar therapeutic capability in terms of axonal regeneration, comparable to our previous studies using rodent GRP.…”

Section: Evidence For the Plasticity Of Pre-differentiated Hgrpmentioning

confidence: 95%

“…In addition, human GRP (hGRP) have been transplanted into the injured spinal cord and have demonstrated cell survival and differentiation into astrocytes and oligodendrocytes, as well as an ability to limit post-injury scar formation, 12 promote motor and sensory recovery, 13 limit hyperactive autonomic responses, 12 and preserve electrophysiological function. 14 Despite the potential benefits of rodent and human GRP described by numerous studies, disagreement remains regarding the therapeutic application of GRP.…”

Section: Introductionmentioning

confidence: 99%

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Human Astrocytes Derived from Glial Restricted Progenitors Support Regeneration of the Injured Spinal Cord

Haas

Fischer

2013

Journal of Neurotrauma

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Cellular transplantation using neural stem cells and progenitors is a promising therapeutic strategy that has the potential to replace lost cells, modulate the injury environment, and create a permissive environment for the regeneration of injured host axons. Our research has focused on the use of human glial restricted progenitors (hGRP) and derived astrocytes. In the current study, we examined the morphological and phenotypic properties of hGRP prepared from the fetal central nervous system by clinically-approved protocols, compared with astrocytes derived from hGRP prepared by treatment with ciliary neurotrophic factor or bone morphogenetic protein 4. These differentiation protocols generated astrocytes that showed morphological differences and could be classified along an immature to mature spectrum, respectively. Despite these differences, the cells retained morphological and phenotypic plasticity upon a challenge with an alternate differentiation protocol. Importantly, when hGRP and derived astrocytes were transplanted acutely into a cervical dorsal column lesion, they survived and promoted regeneration of long ascending host sensory axons into the graft/lesion site, with no differences among the groups. Further, hGRP taken directly from frozen stocks behaved similarly and also supported regeneration of host axons into the lesion. Our results underscore the dynamic and permissive properties of human fetal astrocytes to promote axonal regeneration. They also suggest that a time-consuming process of pre-differentiation may not be necessary for therapeutic efficacy, and that the banking of large quantities of readily available hGRP can be an appropriate source of permissive cells for transplantation.

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Section: Discussionmentioning

confidence: 99%

Section: Evidence For the Plasticity Of Pre-differentiated Hgrpmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Human Astrocytes Derived from Glial Restricted Progenitors Support Regeneration of the Injured Spinal Cord

Haas

Fischer

2013

Journal of Neurotrauma

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“…Transplantation of glial progenitor and glial progenitorderived cells has been shown to have beneficial effects in a number of conditions, such as amyotrophic lateral sclerosis, transverse myelitis, and multiple sclerosis, and also enhances regeneration after spinal cord injury [13][14][15][16][17][21][22][23][24][25][26]. Additionally, our group recently showed that GRPs are able to improve structural as well as functional outcomes in a mouse model of ischemic neonatal white matter injury [18].…”

Section: Discussionmentioning

confidence: 99%

“…These cells have been proposed as a potential therapeutic approach for a series of neurological disorders, including neonatal brain injury, which is characterized by disturbances in both white and gray matter of the central nervous system [13][14][15][16][17]. We have previously shown that GRPs improve neurobehavioral and neuropathological outcomes after neonatal ischemia-induced white matter injury in mice [18].…”

Section: Introductionmentioning

confidence: 99%

Glial-Restricted Precursors Protect Neonatal Brain Slices from Hypoxic-Ischemic Cell Death Without Direct Tissue Contact

Sweda

Phillips

Marx

et al. 2016

Stem Cells and Development

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Glial-Restricted Precursors (GRPs) are tripotential progenitors that have been shown to exhibit beneficial effects in several preclinical models of neurological disorders, including neonatal brain injury. The mechanisms of action of these cells, however, require further study, as do clinically relevant questions such as timing and route of cell administration. Here, we explored the effects of GRPs on neonatal hypoxia-ischemia during acute and subacute stages, using an in vitro transwell co-culture system with organotypic brain slices exposed to oxygen-glucose deprivation (OGD). OGD-exposed slices that were then co-cultured with GRPs without direct cell contact had decreased tissue injury and cortical cell death, as evaluated by lactate dehydrogenase (LDH) release and propidium iodide (PI) staining. This effect was more pronounced when cells were added during the subacute phase of the injury. Furthermore, GRPs reduced the amount of glutamate in the slice supernatant and changed the proliferation pattern of endogenous progenitor cells in brain slices. In summary, we show that GRPs exert a neuroprotective effect on neonatal hypoxia-ischemia without the need for direct cell-cell contact, thus confirming the rising view that beneficial actions of stem cells are more likely attributable to trophic or immunomodulatory support rather than to long-term integration.

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Perfluorocarbon Labeling of Human Glial-Restricted Progenitors for 19F Magnetic Resonance Imaging

Richard

Hussain

Gross

et al. 2019

Stem Cells Translational Medicine

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One of the fundamental limitations in assessing potential efficacy in Central Nervous System (CNS) transplantation of stem cells is the capacity for monitoring cell survival and migration noninvasively and longitudinally. Human glial‐restricted progenitor (hGRP) cells (Q‐Cells) have been investigated for their utility in providing neuroprotection following transplantation into models of amyotrophic lateral sclerosis (ALS) and have been granted a Food and Drug Administration (FDA) Investigational New Drug (IND) for intraspinal transplantation in ALS patients. Furthermore, clinical development of these cells for therapeutic use will rely on the ability to track the cells using noninvasive imaging methodologies as well as the verification that the transplanted GRPs have disease‐relevant activity. As a first step in development, we investigated the use of a perfluorocarbon (PFC) dual‐modal (19F magnetic resonance imaging [MRI] and fluorescence) tracer agent to label Q‐Cells in culture and following spinal cord transplantation. PFCs have a number of potential benefits that make them appealing for clinical use. They are quantitative, noninvasive, biologically inert, and highly specific. In this study, we developed optimized PFC labeling protocols for Q‐Cells and demonstrate that PFCs do not significantly alter the glial identity of Q‐Cells. We also show that PFCs do not interfere with the capacity for differentiation into astrocytes either in vitro or following transplantation into the ventral horn of the mouse spinal cord, and can be visualized in vivo by hot spot 19F MRI. These studies provide a foundation for further preclinical development of PFCs within the context of evaluating Q‐Cell transplantation in the brain and spinal cord of future ALS patients using 19F MRI. Stem Cells Translational Medicine 2019;8:355–365

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Transplantation of human glial-restricted neural precursors into injured spinal cord promotes functional and sensory recovery without causing allodynia

Cited by 31 publications

References 28 publications

Human Astrocytes Derived from Glial Restricted Progenitors Support Regeneration of the Injured Spinal Cord

Human Astrocytes Derived from Glial Restricted Progenitors Support Regeneration of the Injured Spinal Cord

Glial-Restricted Precursors Protect Neonatal Brain Slices from Hypoxic-Ischemic Cell Death Without Direct Tissue Contact

Perfluorocarbon Labeling of Human Glial-Restricted Progenitors for 19F Magnetic Resonance Imaging

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