Grafted human-induced pluripotent stem-cell–derived neurospheres promote motor functional recovery after spinal cord injury in mice

TLDR

Human‑induced pluripotent stem cells, once proven safe, offer an ethically unproblematic and potentially preferred source for regenerative medicine. The study examined whether transplanting hiPSC‑derived neurospheres into NOD‑SCID mice could treat spinal cord injury. The neurospheres were generated from the 201B7 hiPSC clone, created by introducing Oct3/4, Sox2, Klf4, and c‑Myc into adult human fibroblasts. Grafted neurospheres survived, differentiated into neurons, astrocytes, and oligodendrocytes, formed synapses with host neurons, induced neurotrophic factor expression, angiogenesis, axonal regrowth, and myelination, and produced significantly better functional recovery without tumor formation over 112 days, supporting hiPSCs as a promising therapeutic source for spinal cord injury.

Abstract

Once their safety is confirmed, human-induced pluripotent stem cells (hiPSCs), which do not entail ethical concerns, may become a preferred cell source for regenerative medicine. Here, we investigated the therapeutic potential of transplanting hiPSC-derived neurospheres (hiPSC-NSs) into nonobese diabetic (NOD)-severe combined immunodeficient (SCID) mice to treat spinal cord injury (SCI). For this, we used a hiPSC clone (201B7), established by transducing four reprogramming factors (Oct3/4, Sox2, Klf4, and c-Myc) into adult human fibroblasts. Grafted hiPSC-NSs survived, migrated, and differentiated into the three major neural lineages (neurons, astrocytes, and oligodendrocytes) within the injured spinal cord. They showed both cell-autonomous and noncell-autonomous (trophic) effects, including synapse formation between hiPSC-NS–derived neurons and host mouse neurons, expression of neurotrophic factors, angiogenesis, axonal regrowth, and increased amounts of myelin in the injured area. These positive effects resulted in significantly better functional recovery compared with vehicle-treated control animals, and the recovery persisted through the end of the observation period, 112 d post-SCI. No tumor formation was observed in the hiPSC-NS–grafted mice. These findings suggest that hiPSCs give rise to neural stem/progenitor cells that support improved function post-SCI and are a promising cell source for its treatment.