Recovery from paralysis in adult rats using embryonic stem cells

Abstract

We conclude that restoration of functional motor units by embryonic stem cells is possible and represents a potential therapeutic strategy for patients with paralysis. To our knowledge, this is the first report of the anatomical and functional replacement of a motor neuron circuit within the adult mammalian host.

Transplanted Mouse Embryonic Stem-Cell-Derived Motoneurons Form Functional Motor Units and Reduce Muscle Atrophy

“…Studies investigating either human or mouse ES-cell-derived MNs transplanted into rat spinal cords in which a subset of endogenous MNs were killed demonstrated axons that exited the spinal cord, entered host muscle, and reinnervated some NMJs (Gao et al, 2005(Gao et al, , 2007Deshpande et al, 2006). However, the presence of endogenous MNs, axons, and endogenously innervated NMJs in these studies precluded the assessment of newly formed MUs, and their influence on host muscle.…”

“…We next showed that these cells preferentially differentiate into MNs of a specific phenotype (medial motor column or MMC), and that after transplantation into the developing chick spinal cord, they projected to muscles normally innervated by MMC MNs (axial muscle, (Soundararajan et al, 2006)). Implantation of these neurons into the adult spinal cord has proven challenging, but some success was recently reported (Deshpande et al, 2006). However, the degree to which implanted ES-cell-derived neurons innervate muscle, the force the reinnervated muscle can produce, the effects on muscle fiber type, and any resultant protection from muscle atrophy have not been assessed.…”

Cytochrome P450 Cyp26a1 Alters Spinal Motor Neuron Subtype Identity in Differentiating Embryonic Stem Cells

“…WT ESCs, treated with RA and SHH to differentiate them into MNs, migrated to the MMC and functioned like endogenous MMC MNs (9,11). Furthermore, ESCderived MNs sent axons that reached target muscles and partially reversed paralysis in a rat model of virus-induced MN death (69). Although we used a genetic approach in this study to block Cyp26a1 function, specific inhibitors of Cyp26a1 could potentially be used to enhance differentiation of ESCs to brachial LMC MNs that extend axons into the limbs.…”

Stem Cells: Current Approach and Future Prospects in Spinal Cord Injury Repair

“…In addition, Keirstead et al showed that transplantation of oligodendrocyte progenitor cells (OPCs) derived from human ESCs into adult rat spinal cord injuries enhanced remyelination and promoted improvement of motor function (Keirstead et al, 2005). Deshpande et al (2006) explored the potential of motor neurons derived from ESCs to functionally replace those cells destroyed in paralyzed adult rats, demonstrating the potential of restoring functional motor units by ESCs. Recently, Cui et al used a rat sciatic nerve transection model to show that the transplanted ESCs differentiated into myelin-forming cells and offered a potential therapy for severely injured peripheral nerves.…”

“…Human embryonic and adult stem cells have been coaxed into becoming types of cells that repair damaged spinal cord insulation and replace damaged spinal cord nerve cells (Kerr et al, 2003;Li et al, 2005;Deshpande et al, 2006). To date, several types of stem cells have been transplanted into the injured spinal cord, including foetal nervous tissue, embryonic stem cells (ESCs), bone marrow mesenchymal stem cells (MSCs), Schwann cells, peripheral nervous tissue, collagen-based matrices containing cells, and neuroactive substances.…”