Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice

Abstract

We report that prospectively isolated, human CNS stem cells grown as neurospheres (hCNS-SCns) survive, migrate, and express differentiation markers for neurons and oligodendrocytes after longterm engraftment in spinal cord-injured NOD-scid mice. hCNS-SCns engraftment was associated with locomotor recovery, an observation that was abolished by selective ablation of engrafted cells by diphtheria toxin. Remyelination by hCNS-SCns was found in both the spinal cord injury NOD-scid model and myelin-deficient shiverer mice. Moreover, electron microscopic evidence consistent with synapse formation between hCNS-SCns and mouse host neurons was observed. Glial fibrillary acidic protein-positive astrocytic differentiation was rare, and hCNS-SCns did not appear to contribute to the scar. These data suggest that hCNS-SCns may possess therapeutic potential for CNS injury and disease.behavioral assessment ͉ differentiation ͉ stem cell transplantation R ecent studies have used a variety of immortalized, engineered, or isolated rodent-derived precursor͞stem cells transplanted into rodent models of spinal cord injury. Many of these studies focused on cell survival and did not address differentiation, functional recovery, or the causal relationship between successful engraftment and observed behavioral improvements. When differentiation was investigated, embryonic and adult neural stem cells were reported to principally assume glial fibrillary acidic protein (GFAP)-positive astrocytic phenotypes after grafting into nonneurogenic regions of uninjured adult CNS (1, 2) or injured spinal cord (3-5). Furthermore, although in vitro predifferentiation paradigms designed to generate neural lineage restricted precursors successfully generated ␤-tubulin III (Tuj-1)-positive neuronal phenotypes either in vitro or after transplantation into uninjured spinal cord, this commitment was overridden by environmental cues in the injured spinal cord (6).Transplants of human brain-derived stem cells or human spinal cord tissue into injured rat spinal cord have been described (7-9). Moreover, several human cell transplantation paradigms recently have been reported to promote locomotor recovery: human umbilical cell infusion in a rat spinal cord injury model, although only within 3 weeks or less postgrafting (10); neurons differentiated in vitro under retinoic acid from human embryonal teratocarcinoma cells and transplanted into a rat spinal cord injury model (11); human ES cells differentiated in vitro to oligoprogenitors and transplanted into a rat spinal cord injury model (12); and human neural stem͞progenitor cells transplanted into a monkey spinal cord injury model (13). In general, these studies lack some or all of the following: definitive identification of transplanted cells, longterm survival and engraftment data, evidence of differentiation, and͞or direct evidence of functional integration of human cells in the injured spinal cord. The current study addresses three previously unexplored issues in stem cell transplantation research for spinal co...

Cell Therapy for Multiple Sclerosis

“…Similarly, adult human SVZ precursors remyelinated the adult rat spinal cord [142]. Finally, multipotential NSC also showed a capacity to perform efficient myelination in the spinal cords of shiverer mouse, md rat, and sh pup [143][144][145], as well as in adult animals with traumatic spinal cord injury [146,147]. However, before discussing which cell type is the optimal remyelinating cell for clinical translation in MS, it is important to point out that many of these studies have not yet established the necessary proof-of-concept for cell therapy-based myelin repair in MS.…”

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

“…Transplantation into injured spinal cords of several different types of human NS/progenitor cells, derived from human fetal tissue [3,4] or from human embryonic stem cells (hESCs) [5,6], promotes functional recovery in animal models. Nonetheless, the mechanism underlying such functional improvement remains to be fully elucidated.…”

Oligodendrocyte Fate after Spinal Cord Injury

“…When transplanted, these cells survived, differentiated into OLs, remyelinated axons, and mediated locomotor improvements in injured Severe Combined Immunodeficiency (SCID) mice [166]. Keirstead et al [167] differentiated human ESCs into a pure population of OPCs in vitro and transplanted the cells at 1 week or 10 months after SCI in rats.…”