Treatment of a Mouse Model of Spinal Cord Injury by Transplantation of Human Induced Pluripotent Stem Cell-Derived Long-Term Self-Renewing Neuroepithelial-Like Stem Cells

Abstract

Because of their ability to self-renew, to differentiate into multiple lineages, and to migrate toward a damaged site, neural stem cells (NSCs), which can be derived from various sources such as fetal tissues and embryonic stem cells, are currently considered to be promising components of cell replacement strategies aimed at treating injuries of the central nervous system, including the spinal cord. Despite their efficiency in promoting functional recovery, these NSCs are not homogeneous and possess variable characteristics depending on their derivation protocols. The advent of induced pluripotent stem (iPS) cells has provided new prospects for regenerative medicine. We used a recently developed robust and stable protocol for the generation of long-term, self-renewing, neuroepithelial-like stem cells from human iPS cells (hiPS-lt-NES cells), which can provide a homogeneous and well-defined population of NSCs for standardized analysis. Here, we show that transplanted hiPS-lt-NES cells differentiate into neural lineages in the mouse model of spinal cord injury (SCI) and promote functional recovery of hind limb motor function. Furthermore, using two different neuronal tracers and ablation of the transplanted cells, we revealed that transplanted hiPS-lt-NES cell-derived neurons, together with the surviving endogenous neurons, contributed to restored motor function. Both types of neurons reconstructed the corticospinal tract by forming synaptic connections and integrating neuronal circuits. Our findings indicate that hiPS-lt-NES transplantation represents a promising avenue for effective cell-based treatment of SCI. Disclosure of potential conflicts of interest is found at the end of this article.

Cell transplantation therapies for spinal cord injury focusing on induced pluripotent stem cells

“…Furthermore, to confirm the long-term safety of 201B7-iPS-neurospheres transplantation, follow-up was continued for ~4 months after the SCI, which revealed that the functional recovery was maintained without tumor formation [34]. Consistently, Fujimoto et al [35] also confirmed the efficacy and safety of human iPS-NS/ PC transplantation for SCI treatment in immunodeficient mice.…”

Localized Delivery of Brain-Derived Neurotrophic Factor-Expressing Mesenchymal Stem Cells Enhances Functional Recovery following Cervical Spinal Cord Injury

“…Recent studies have transplanted human iPSC-derived neurospheres or monolayer cultures into the spinal cord after injury, and demonstrated extensive incorporation, improved locomotor recovery, increased expression of neurotrophic factors, angiogenesis, axonal outgrowth, and remyelination. [84][85][86] The beneficial effects of iPSCs after spinal cord injury may enhance the extent of recovery during eupnea, and possibly permit greater levels of recovery of more forceful, nonventilatory behaviors promoting functional recovery of rhythmic diaphragm activity after SH beyond levels achievable even with BDNF-MSCs transplantation.…”

Allogeneic Neural Stem/Progenitor Cells Derived From Embryonic Stem Cells Promote Functional Recovery After Transplantation Into Injured Spinal Cord of Nonhuman Primates

“…Previous studies have demonstrated that NS/PC transplantation for SCI affects histological and/or functional outcomes in several processes, including neurotrophic support [32,33], angiogenesis [34,35], axonal regrowth [24,36], neural circuit reconstruction [37][38][39], and remyelination [40,41]. Most of these previous studies involved the use of rodent SCI models.…”