Axonal growth of embryonic stem cell-derived motoneurons
            <i>in vitro</i>
            and in motoneuron-injured adult rats

Harper, James M.; Krishnan, Chitra; Darman, Jessica; Deshpande, Deepa; Peck, Schonze; Shats, Irina; Backovic, Stephanie; Rothstein, Jeffrey D.; Kerr, Douglas A.

doi:10.1073/pnas.0401103101

Cited by 221 publications

(170 citation statements)

References 40 publications

(47 reference statements)

Supporting

Mentioning

157

Contrasting

Unclassified

Order By: Relevance

“…ES-cell-derived MNs exhibit functional characteristics of endogenous MNs in terms of their ion channels, receptors, transmitter expression, and electrophysiological properties (Wichterle et al, 2002;Miles et al, 2004;Li et al, 2005), making them potential candidates for cell replacement strategies. We and others have demonstrated functional innervation in vitro between cocultures of ES-cell-derived MNs and mouse muscle fibers (Miles et al, 2004;Harper et al, 2004;Li et al, 2005). Currently there is little known about the in vivo capacity for ES-cell-derived MNs to form functional NMJs and how this capacity compares to endogenous MNs.…”

Section: Discussionmentioning

confidence: 99%

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

Yohn¹,

Miles²,

Rafuse³

et al. 2008

J. Neurosci.

View full text Add to dashboard Cite

Prolonged muscle denervation resulting from motor neuron (MN) damage leads to atrophy and degeneration of neuromuscular junctions (NMJs), which can impart irreversible damage. In this study, we ask whether transplanted embryonic stem (ES) cells differentiated into MNs can form functional synapses with host muscle, and if so what effects do they have on the muscle. After transplantation into transected tibial nerves of adult mice, ES-cell-derived MNs formed functional synapses with denervated host muscle, which resulted in the ability to produce average tetanic forces of 44% of nonlesioned controls. ES-cell-derived motor units (MUs) had mean force values and ranges similar to control muscles. The number of type I fibers and fatigue resistance of the MUs were increased, and denervationassociated muscle atrophy was significantly reduced. These results demonstrate the capacity for ES-cell-derived MNs not only to incorporate into the adult host tissue, but also to exert changes in the target tissue. By providing the signals normally active during embryonic development and placing the cells in an environment with their target tissue, ES cells differentiate into MNs that give rise to functional MU output which resembles the MU output of endogenous MNs. This suggests that these signals combined with those present in the graft environment, lead to the activation of a program intended to produce a normal range of MU forces.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Yohn¹,

Miles²,

Rafuse³

et al. 2008

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…JOURNAL OF NEUROTRAUMA 26:81-95 ( January 2009) Harper et al, 2004;Mukhopadhyay et al, 1994;Ramer et al, 2004;Schwab et al, 2004;Tanaka et al, 2004;Yamagishi et al, 2005). It remains possible that more complete in vivo inhibition of Rho activation might provide a valuable and effective approach to treat SCI (Baptiste and Fehlings, 2006;McKerracher and Higuchi, 2006;Mueller et al, 2005).…”

mentioning

confidence: 99%

Ibuprofen Enhances Recovery from Spinal Cord Injury by Limiting Tissue Loss and Stimulating Axonal Growth

Wang

Budel

Baughman

et al. 2009

Journal of Neurotrauma

View full text Add to dashboard Cite

The GTP-binding protein RhoA regulates microfilament dynamics in many cell types and mediates the inhibition of axonal regeneration by myelin and chondroitin sulfate proteoglycans. Unlike most other nonsteroidal anti-inflammatory drugs, ibuprofen suppresses basal RhoA activity (Zhou et al., 2003). A recent report suggested that ibuprofen promotes corticospinal axon regeneration after spinal cord injury (Fu et al., 2007). Here, we confirm that ibuprofen reduces ligand-induced Rho signaling and myelin-induced inhibition of neurite outgrowth in vitro. Following 4 weeks of subcutaneous administration of ibuprofen, beginning 3 days after spinal cord contusion, animals recovered walking function to a greater degree, with twice as many rats achieving a hind limb weight-bearing status. We examined the relative role of tissue sparing, axonal sprouting, and axonal regeneration in the action of ibuprofen. Histologically, ibuprofen-treated animals display an increase in spared tissue without an alteration in astrocytic or microglial reaction. Ibuprofen increases axonal sprouting from serotonergic raphespinal axons, and from rostral corticospinal fibers in the injured spinal cord, but does not permit caudal corticospinal regeneration after spinal contusion. Treatment of mice with complete spinal cord transection demonstrates long-distance raphespinal axon regeneration in the presence of ibuprofen. Thus, administration of ibuprofen improves the recovery of rats from a clinically relevant spinal cord trauma by protecting tissue, stimulating axonal sprouting, and allowing a minor degree of raphespinal regeneration.

show abstract

“…Transplantation of such differentiated ES into the spinal cord of rats with induced motoneuron injury showed promising results because these cells survived and produced axons that were able to grow into the ventral root [34]. With the growing understanding of ES cell biology and SMA pathogenesis, ES cells-based therapy is moving closer to clinical application [17,48,61,67].…”

Section: Sma Treatment and Prevention Strategiesmentioning

confidence: 99%

Pathogenesis of proximal autosomal recessive spinal muscular atrophy

Šimić

2008

Acta Neuropathol

View full text Add to dashboard Cite

Although it is known that deletions or mutations of the SMN1 gene on chromosome 5 cause decreased levels of the SMN protein in subjects with proximal autosomal recessive spinal muscular atrophy (SMA), the exact sequence of pathological events leading to selective motoneuron cell death is not fully understood yet. In this review, new findings regarding the dual cellular role of the SMN protein (translocation of β-actin to axonal growth cones and snRNP biogenesis/pre-mRNA splicing) were integrated with recent data obtained by detailed neuropathological examination of SMA and control subjects. A presumptive series of 10 pathogenetic events for SMA is proposed as follows: (1) deletions or mutations of the SMN1 gene, (2) increased SMN mRNA decay and reduction in full-length functional SMN protein, (3) impaired motoneuron axonoand dendrogenesis, (4) failure of motoneurons to form synapses with corticospinal fibers from upper motoneurons, (5) abnormal motoneuron migration towards ventral spinal roots, (6) inappropriate persistence of motoneuron apoptosis due to impaired differentiation and motoneuron displacement, (7) substantial numbers of motoneurons continuing to migrate abnormally ("heterotopic motoneurons") and entering into the ventral roots, (8) attracted glial cells following these heterotopic motoneurons, which form the glial bundles of ventral roots, (9) impaired axonal transport of actin, causing remaining motoneurons to become chromatolytic, and (10) eventual death of all apoptotic, heterotopic and chromatolytic neurons, with apoptosis being more rapid and predominating in the earlier stages, with death of heterotopic and chromatolytic neurons occurring more slowly by necrosis during the later stages of SMA. According to this model, the motoneuron axonopathy is more important for pathogenesis than the ubiquitous nuclear splicing deficit. It is also supposed that individually variable levels of SMN protein, together with influences of other phenotype modifier genes and their products, cause the clinical SMA spectrum through differential degree of motoneuron functional loss.

show abstract

Axonal growth of embryonic stem cell-derived motoneurons in vitro and in motoneuron-injured adult rats

Cited by 221 publications

References 40 publications

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

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

Ibuprofen Enhances Recovery from Spinal Cord Injury by Limiting Tissue Loss and Stimulating Axonal Growth

Pathogenesis of proximal autosomal recessive spinal muscular atrophy

Contact Info

Product

Resources

About