Characterization of Ectopic Colonies That Form in Widespread Areas of the Nervous System with Neural Stem Cell Transplants into the Site of a Severe Spinal Cord Injury

Steward, Oswald; Sharp, Kelli; Yee, Kelly Matsudaira; Hatch, Maya N.; Bonner, Joseph F.

doi:10.1523/jneurosci.3066-14.2014

Cited by 46 publications

(37 citation statements)

References 29 publications

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“…Ectopic cell collections were rare. It has been reported that grafts of NSCs can form ectopic cell deposits remote from the site of grafting (45,46). In this experiment, remote cell deposits occurred in 2 of 18 animals (11%) (Supplemental Figure 9, C-F), and local extra-pial cell spreading was confined to 1 to 2 spinal segments from the graft site in 5 of 18 animals (28%).…”

Section: Resultssupporting

confidence: 49%

“…Previously, Goldman and colleagues reported long-term safety and efficacy after administration of human glial progenitor cells in rodent demyelinating disease models (15), and Zhang and colleagues reported the functional integration of human-derived astrocytes into intact rodent spinal cord, including investment of astrocytic processes around host neurons and extension of end feet around blood vessels (44). Similarly, ectopic clusters of cells that have been previously reported (45,46) with our grafting technique were only rarely observed at prolonged time points (2 of 12 animals surviving 6 months or longer) and did not compress jci. The NSC graft area was measured using ImageJ software (NIH) on images of fixed box size at 1,600 × 1,200 pixels and ×20 magnification, using every sixth horizontal section that contained GFPexpressing graft.…”

Section: Discussionmentioning

confidence: 79%

See 1 more Smart Citation

Prolonged human neural stem cell maturation supports recovery in injured rodent CNS

Ceto²,

Wang³

et al. 2017

Journal of Clinical Investigation

100

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Section: Resultssupporting

confidence: 49%

Section: Discussionmentioning

confidence: 79%

Prolonged human neural stem cell maturation supports recovery in injured rodent CNS

Ceto²,

Wang³

et al. 2017

Journal of Clinical Investigation

100

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“…A recent study from the Steward lab reported that transplantation of a mixed population of glial and neuronal progenitors into a transection model of SCI resulted in ectopic engraftment of large numbers of graft-derived cells in locations such as the central canal, ventricles and pial surface of the spinal cord (Steward et al, 2014), providing a note of caution when using transplantation of any class of NSC/NPC in SCI. This issue is particularly relevant to strategies employing cells derived from pluripotent sources such as ES and iPS cells given the possibility of incomplete and/or inefficient differentiation (Tsuji et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Human iPS cell-derived astrocyte transplants preserve respiratory function after spinal cord injury

Javed

Scura

et al. 2015

Experimental Neurology

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Transplantation-based replacement of lost and/or dysfunctional astrocytes is a promising therapy for spinal cord injury (SCI) that has not been extensively explored, despite the integral roles played by astrocytes in the central nervous system (CNS). Induced pluripotent stem (iPS) cells are a clinically-relevant source of pluripotent cells that both avoid ethical issues of embryonic stem cells and allow for homogeneous derivation of mature cell types in large quantities, potentially in an autologous fashion. Despite their promise, the iPS cell field is in its infancy with respect to evaluating in vivo graft integration and therapeutic efficacy in SCI models. Astrocytes express the major glutamate transporter, GLT1, which is responsible for the vast majority of glutamate uptake in spinal cord. Following SCI, compromised GLT1 expression/function can increase susceptibility to excitotoxicity. We therefore evaluated intraspinal transplantation of human iPS cell-derived astrocytes (hIPSAs) following cervical contusion SCI as a novel strategy for reconstituting GLT1 expression and for protecting diaphragmatic respiratory neural circuitry. Transplant-derived cells showed robust long-term survival post-injection and efficiently differentiated into astrocytes in injured spinal cord of both immunesuppressed mice and rats. However, the majority of transplant-derived astrocytes did not express high levels of GLT1, particularly at early times post-injection. To enhance their ability to modulate extracellular glutamate levels, we engineered hIPSAs with lentivirus to constitutively express GLT1. Overexpression significantly increased GLT1 protein and functional GLT1-mediated glutamate uptake levels in hIPSAs both in vitro and in vivo post-transplantation. Compared to human fibroblast control and unmodified hIPSA transplantation, GLT1-overexpressing hIPSAs reduced (1) lesion size within the injured cervical spinal cord, (2) morphological denervation by respiratory phrenic motor neurons at the diaphragm neuromuscular junction, and (3) functional diaphragm denervation as measured by recording of spontaneous EMGs and evoked compound muscle action potentials. Our findings demonstrate that hiPSA transplantation is a therapeutically-powerful approach for SCI.

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“…The replication study clarified some methodological issues regarding transplantation techniques and demonstrated the need for follow-up studies to improve formation of continuous tissue bridges between rostral and caudal segments. Interestingly, during the replication study, we also discovered ectopic colonies of graft-derived cells at long distances from the transplant in the central canal, 4 th ventricle and the subdural surface of the spinal cord and brain stem (Steward et al, 2014a; Steward et al, 2014b). It remains to be seen whether these colonies reflect the unique conditions of the experiment, for example the treatment of cells with growth factor cocktail, or whether fetal cells that are still capable of self-renewal (i.e.…”

Section: Introductionmentioning

confidence: 96%

Repair of spinal cord injury with neuronal relays: From fetal grafts to neural stem cells

Bonner

Steward

2015

Brain Research

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Spinal cord injury (SCI) disrupts the long axonal tracts of the spinal cord leading to devastating loss of function. Cell transplantation in the injured spinal cord has the potential to lead to recovery after SCI via a variety of mechanisms. One such strategy is the formation of neuronal relays between injured long tract axons and denervated neurons. The idea of creating a neuronal relay was first proposed over 25 years ago when fetal tissue was first successfully transplanted into the injured rodent spinal cord. Advances in labeling of grafted cells and the development of neural stem cell culturing techniques have improved the ability to create and refine such relays. Several recent studies have examined the ability to create a novel neuronal circuit between injured axons and denervated targets. This approach is an alternative to long-distance regeneration of damaged axons that may provide a meaningful degree of recovery without direct recreation of lost pathways. This brief review will examine the contribution of fetal grafting to current advances in neuronal grafting. Of particular interest will be the ability of transplanted neurons derived from fetal grafts, neural precursor cells and neural stem cells to reconnect long distance motor and sensory pathways of the injured spinal cord.

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Characterization of Ectopic Colonies That Form in Widespread Areas of the Nervous System with Neural Stem Cell Transplants into the Site of a Severe Spinal Cord Injury

Cited by 46 publications

References 29 publications

Prolonged human neural stem cell maturation supports recovery in injured rodent CNS

Prolonged human neural stem cell maturation supports recovery in injured rodent CNS

Human iPS cell-derived astrocyte transplants preserve respiratory function after spinal cord injury

Repair of spinal cord injury with neuronal relays: From fetal grafts to neural stem cells

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