BMP inhibition enhances axonal growth and functional recovery after spinal cord injury

Matsuura, Iichiro; Taniguchi, Junko; Hata, Katsuhiko; Saeki, Naokatsu; Yamashita, Toshio

doi:10.1111/j.1471-4159.2008.05251.x

Cited by 82 publications

(69 citation statements)

References 14 publications

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“…Although previous studies have shown that manipulation of the BMP pathway locally at the injury site affects astrogliosis (36) and may inhibit regeneration (37), our studies activated the BMP/ Smad1 pathway directly in sensory neurons within DRG, thus demonstrating that enhancing neuronal intrinsic axon growth potential can be used as a strategy to promote axon regeneration in vivo. Our AAV-based in vivo gene delivery method selectively targeting DRG neurons is minimally invasive, clinically applicable, and represents a versatile experimental manipulation for SCI research.…”

Section: Activation Of Smad1 Promotes Axonal Regeneration In Scimentioning

confidence: 82%

Regeneration of axons in injured spinal cord by activation of bone morphogenetic protein/Smad1 signaling pathway in adult neurons

Parikh

Hao

Hosseinkhani

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

142

131

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Axon growth potential is highest in young neurons but diminishes with age, thus becoming a significant obstacle to axonal regeneration after injury in maturity. The mechanism for the decline is incompletely understood, and no effective clinical treatment is available to rekindle innate growth capability. Here, we show that Smad1-dependent bone morphogenetic protein (BMP) signaling is developmentally regulated and governs axonal growth in dorsal root ganglion (DRG) neurons. Down-regulation of the pathway contributes to the age-related decline of the axon growth potential. Reactivating Smad1 selectively in adult DRG neurons results in sensory axon regeneration in a mouse model of spinal cord injury (SCI). Smad1 signaling can be effectively manipulated by an adenoassociated virus (AAV) vector encoding BMP4 delivered by a clinically applicable and minimally invasive technique, an approach devoid of unwanted abnormalities in mechanosensation or pain perception. Importantly, transected axons are able to regenerate even when the AAV treatment is delivered after SCI, thus mimicking a clinically relevant scenario. Together, our results identify a therapeutic target to promote axonal regeneration after SCI.intrinsic axon growth capacity | intrathecal viral vector delivery S pinal cord injury (SCI) disrupts long-projection axons, with devastating neurological outcomes, yet no effective clinical treatment exists. Neurons fail to regenerate axons because of a growth-inhibiting environment at the injury site (1-4) and because of an age-dependent decline in the intrinsic axon growth potential (5, 6). Nevertheless, blocking extracellular inhibitory molecules (7-10) or alleviating the intracellular negative regulators of axonal growth (5, 6, 11, 12) enables only limited axonal regeneration. Thus, additional molecular pathways that can rekindle innate growth capability must exist but remain unidentified (13).Dorsal root ganglion (DRG) neurons are a favored model system to study axonal regeneration. These neurons have an axon with two branches-a peripheral branch that innervates sensory organs and a central branch that relays information to the CNS. The central branches of adult DRG neurons in the spinal cord are refractory to regeneration unless their peripheral branches are severed first. This so-called "conditioning lesion" paradigm activates a transcription program that enhances the intrinsic axonal growth potential (14). Previously, through gene expression profiling, we have demonstrated that Smad1 is induced after peripheral axotomy and that intraganglionic delivery of bone morphogenetic protein 2 or 4 (BMP2 or -4) activates Smad1 and enhances the axon growth potential of adult DRG neurons in cultures. In contrast, severing the central branches of DRGs fails to activate the Smad1 pathway, which correlates with the absence of regeneration after SCI (15).These results suggested a possible involvement of Smad1 in regulating the growth state of DRG neurons. It is not known, however, whether Smad1 governs the axon growth program ...

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Section: Activation Of Smad1 Promotes Axonal Regeneration In Scimentioning

confidence: 82%

Regeneration of axons in injured spinal cord by activation of bone morphogenetic protein/Smad1 signaling pathway in adult neurons

Parikh

Hao

Hosseinkhani

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

142

131

View full text Add to dashboard Cite

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“…The significance of the higher levels of growth factors at 5 d in neutrophil-depleted mice is unknown. Elevated growth factor levels can sometimes be detrimental; for example, inhibitors to BMPs improve outcome after SCI (Matsuura et al, 2008). Similarly, FGFs increase levels of CHL1, an inhibitor of neurite outgrowth, which may hinder SCI repair (Jakovcevski et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Depletion of Ly6G/Gr-1 Leukocytes after Spinal Cord Injury in Mice Alters Wound Healing and Worsens Neurological Outcome

Stirling¹,

Liu²,

Kubes³

et al. 2009

J. Neurosci.

204

155

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Spinal cord injury (SCI) induces a robust inflammatory response and the extravasation of leukocytes into the injured tissue. To further knowledge of the functions of neuroinflammation in SCI in mice, we depleted the early arriving neutrophils using an anti-Ly6G/Gr-1 antibody. Complete blood counts revealed that neutrophils increased ϳ3-fold over uninjured controls and peaked at 6 -12 h after injury, and that anti-Ly6G/Gr-1 treatment reduced circulating neutrophils by Ͼ90% at these time points. Intravital and spinning disk confocal microscopy of the exposed posterior vein and postcapillary venules showed a significant reduction in rolling and adhering neutrophils in vivo after anti-Ly6G/Gr-1 treatment; this was accompanied by a parallel reduction in neutrophil numbers within the injured spinal cord at 24 and 48 h as determined by flow cytometry. The evolution of astrocyte reactivity, a wound healing response, was reduced in anti-Ly6G/Gr-1-treated mice, which also had less spared white matter and axonal preservation compared with isotype controls. These histological outcomes may be caused by alterations of growth factors and chemokines important in promoting wound healing. Importantly, anti-Ly6G/Gr-1 treatment worsened behavioral outcome as determined using the Basso Mouse Scale and subscores. Although the spectrum of cells affected by anti-Ly6G/Gr-1 antibody treatment cannot be fully ascertained at this point, the correspondence of neutrophil depletion and worsened recovery suggests that neutrophils promote recovery after SCI through wound healing and protective events that limit lesion propagation.

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“…In particular, a decrease of MBP indicates demyelination, which is a crucial factor in SCI. 32,33) The increase of MBP expression suggests that Am-80 promoted axonal regrowth (remyelination) and/or prevented cell death. A lot of GFAP-positive cells were observed around the lesion site.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Am-80, a Synthetic Retinoid, on Spinal Cord Injury-Induced Motor Dysfunction in Rats

Takenaga

Ohta

Tokura

et al. 2009

Biological & Pharmaceutical Bulletin

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BMP inhibition enhances axonal growth and functional recovery after spinal cord injury

Cited by 82 publications

References 14 publications

Regeneration of axons in injured spinal cord by activation of bone morphogenetic protein/Smad1 signaling pathway in adult neurons

Regeneration of axons in injured spinal cord by activation of bone morphogenetic protein/Smad1 signaling pathway in adult neurons

Depletion of Ly6G/Gr-1 Leukocytes after Spinal Cord Injury in Mice Alters Wound Healing and Worsens Neurological Outcome

The Effect of Am-80, a Synthetic Retinoid, on Spinal Cord Injury-Induced Motor Dysfunction in Rats

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