Transplanted Human Stem Cell-Derived Interneuron Precursors Mitigate Mouse Bladder Dysfunction and Central Neuropathic Pain after Spinal Cord Injury

Abstract

Neuropathic pain and bladder dysfunction represent significant quality-of-life issues for many spinal cord injury patients. Loss of GABAergic tone in the injured spinal cord may contribute to the emergence of these symptoms. Previous studies have shown that transplantation of rodent inhibitory interneuron precursors from the medial ganglionic eminence (MGE) enhances GABAergic signaling in the brain and spinal cord. Here we look at whether transplanted MGE-like cells derived from human embryonic stem cells (hESC-MGEs) can mitigate the pathological effects of spinal cord injury. We find that 6 months after transplantation into injured mouse spinal cords, hESC-MGEs differentiate into GABAergic neuron subtypes and receive synaptic inputs, suggesting functional integration into host spinal cord. Moreover, the transplanted animals show improved bladder function and mitigation of pain-related symptoms. Our results therefore suggest that this approach may be a valuable strategy for ameliorating the adverse effects of spinal cord injury.

Heterotopic Transplantations Reveal Environmental Influences on Interneuron Diversity and Maturation

“…The success in grafting interneuron precursors into numerous brain regions to inhibit the local circuitry shows promise for treating a variety of diseases (Tyson and Anderson, 2014). Numerous labs have found similar results with human stem cell-derived interneuron precursors (Cunningham et al, 2014; Fandel et al, 2016; Liu et al, 2013), encouraging the pursuit of this approach for clinical applications. While these initial results are promising, a better understanding of how these transplanted interneurons differentiate into the proper interneuron subtypes and integrate into the circuitry is critical for potential long-term therapeutic avenues.…”

Stem Cell Transplantation Helps Alleviate Spinal Cord Injury Sequelae in Mice

“…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 (hESCMGEs) are equally potent.…”

Transplantation of GABAergic interneurons for cell-based therapy

“…The generation of safe human interneurons will also be crucial for clinical transition. Recent reports demonstrating the in vitro production of transplantable MGE-like interneurons from human pluripotent stem cells (Maroof et al, 2013; Nicholas et al, 2013) have generated great excitement, which was further reinforced by studies showing therapeutic efficacy for such cells in mouse models of disease (Cunningham et al, 2014; Fandel et al, 2016; Liu et al, 2013). …”