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• W2610253119 abstract "In the long history of human disease and injury, spinal cord injury (SCI) has persisted as an entity to be feared. Mortality remained high into the 1900s, and while modern treatments have reduced SCI mortality, we have not yet developed effective therapies for various sequelae of these injuries. Even with prompt treatment, SCI victims suffer a number of unbearable conditions not limited to paralysis. Among these, bladder dysfunction and neuropathic pain have proven particular burdens for already troubled patients.1 To address these conditions, a multidisciplinary team based at the University of California, San Francisco, has recently investigated the effect of administering therapeutic interneuron precursors following SCI in a rodent model.2 As previous research shows that rodent-derived precursors from the medial ganglionic eminence (MGE) enhance GABAergic signals in the brain and spinal cord, this study extends those findings to assess whether similar precursors derived from human embryonic stem cells (hESC-MGEs) are equally potent. Using established protocols, hESCs were successfully converted to MGE-like cells. Differentiation was confirmed at 2 to 3 weeks and 5 to 6 weeks by standard genetic and immunohistochemical markers. Following 6 to 8 weeks of differentiation, cells were isolated for transplantation. Cells with the highest expression of markers indicating GABAergic and inhibitory function were identified and preferentially selected for use. Having successfully developed hESC-MGEs, high- and low-dose transplantations were introduced to uninjured mice at the L3-5 level in order to identify any change in function due to the transplantation itself. Following transplantation, mice were repeatedly assessed over a 6-month period for changes in weight and both gross and fine motor function; there were no deficits observed, and no differences between transplanted and vehicle-treated animals. As the rodent spinal micturition centers (at L6-S1) were near to the site of injection, bladder function was assessed with various metrics at 6 months after transplantation, showing normal function in all groups. Six months after transplantation into the uninjured mice, the cellular fate and spatial distribution of transplanted hESC-MGEs were assessed. hESC-MGEs could be identified by expression of human nuclear antigen (HNA). Cells were found 1 mm beyond the transplant site, distributed rostrocaudally. A number of recognized markers confirmed that cells generally differentiated into neuronal and oligodendroglial lines. In particular, a known marker for MGE-derived GABAergic neurons, SOX6, was identified in many HNA+ cells. Transplanted hESC-MGEs, therefore, successfully survive and proliferate into GABAergic neuronal and glial cells in an uninjured cord, with no alteration of function in the host. Although the mice were injured at the T13 level, cells were injected into the lumbosacral region. The transplant was assessed 6 months after injury, and cells were found approximately 10 mm from the site of introduction (L3-5) in a broad rostrocaudal distribution, which was focused rostral to the transplantation site. This may suggest that the transplanted cells were attracted to the injury locus. The transplanted cells persisted well, and large numbers differentiated into SOX6+ GABAergic neurons. Fewer oligodendroglial cells were found. A small population of cells expressed markers consistent with MGE-type progenitors, suggesting a possible reservoir of potential residual progenitor cells. To assess tumorgenicity of the transplanted hESC-MGEs, 200-μm sections along the entire cord were examined. There were no signs of tumor formation: HNA+ were distributed singularly with no focal accumulations, and with very little evidence of proliferation. Transplanted cells were identified with a number of markers indicating GABAergic function, as well as markers for maturation beyond the migratory stage. These findings suggest that transplanted hESC-MGEs successfully migrate into the injured region and differentiate in the desired GABAergic cell types. Transplanted cell function and integration were assessed by electrophysiology 6 months after transplantation, with recor-dings of individual cells and longitudinal sections of the cord. The majority of cells displayed synaptic activity and functional action potentials. Electrical stimulation of cord sections successfully evoked synaptic currents in transplanted cells, consisting of either glutamatergic or GABAergic responses. These findings demonstrate successful hESC-MGE function and syna- ptic integration in the injured mouse cord. Injured mice showed consistent behavioral signs of tactile allodynia and thermal hyperalgesia beginning 2 weeks postinjury, which continued over 6 months of observation before transplantation. In observations at 3 and 6 months post-transplantation, tactile allodynia was reduced. Hyperalgesia was alleviated in observations at 6 months posttransplantation. Analysis showed only weak correlations between the number of transplanted cells with markers of mature neurons/interneurons and the functional pain improvements. Although statistically insignificant, there was a trend favoring reduced allodynia with over 200 000 surviving mature neurons. Although cell number did not predict an effect, these findings do demonstrate a reduction in neuropathic pain following hESC-MGE transplantation. Bladder function was also assessed at 6 months post-transplantation. hESC-MGE-treated mice displayed urinary behaviors markedly similar to uninjured mice, consistent with restored bladder control. Vehicle-treated animals showed no improvement in bladder function. There was a weak correlation between transplanted cells with mature neuron/interneuron markers and bladder control. Bladder function was further assessed by conscious cystometry. hESC-MGE-treated mice showed decreased maximal voiding pressures, nonvoiding contractions, and residual urine, and therefore had improved voiding efficiency. These improvements were associated with less remodeling of the bladder wall. Overall, these findings demonstrate improvements in bladder function following hESC-MGE transplantation. This study has demonstrated the capacity of human-derived stem cells to survive, differentiate, and integrate into the injured cord of a preclinical model animal. Further, the introduction and integration of these cells produced measurable reductions in neuropathic pain and bladder dysfunction. The successful translation of these findings to human subjects may improve the quality of life of chronic SCI patients; however, caution is required, as unregulated stem cell therapy has exhibited the potential to form an unrecognizable neoplasm in the spinal cord.3Figure.: Scheme of the experimental process. Human ESC-derived interneuron precursors were transplanted and then integrated into an injured mouse spinal cord. Most of the stem cells would differentiate into human GABAergic neurons, and relieve injury-related neurogenic bladder dysfunction and central neuropathic pain. Reprinted from Cell Stem Cell,2 Copyright (2016), with permission from Elsevier." @default.
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• W2610253119 date "2017-02-18" @default.
• W2610253119 modified "2023-10-18" @default.
• W2610253119 title "Stem Cell Transplantation Helps Alleviate Spinal Cord Injury Sequelae in Mice" @default.
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• W2610253119 doi "https://doi.org/10.1093/neuros/nyx236" @default.
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