Astrocytes from the Contused Spinal Cord Inhibit Oligodendrocyte Differentiation of Adult Oligodendrocyte Precursor Cells by Increasing the Expression of Bone Morphogenetic Proteins

Promotion of remyelination is an important therapeutic strategy to facilitate functional recovery after traumatic spinal cord injury (SCI). Transplantation of neural stem cells (NSCs) or oligodendrocyte precursor cells (OPCs) has been used to enhance remyelination after SCI. However, the microenvironment in the injured spinal cord is inhibitory for oligodendrocyte (OL) differentiation of NSCs or OPCs. Identifying the signaling pathways that inhibit OL differentiation in the injured spinal cord could lead to new therapeutic strategies to enhance remyelination and functional recovery after SCI. In the present study, we show that reactive astrocytes from the injured rat spinal cord or their conditioned media inhibit OL differentiation of adult OPCs with concurrent promotion of astrocyte differentiation. The expression of bone morphogenetic proteins (BMP) is dramatically increased in the reactive astrocytes and their conditioned media. Importantly, blocking BMP activity by BMP receptor antagonist, noggin, reverse the effects of active astrocytes on OPC differentiation by increasing the differentiation of OL from OPCs while decreasing the generation of astrocytes. These data indicate that the upregulated bone morphogenetic proteins in the reactive astrocytes are major factors to inhibit OL differentiation of OPCs and to promote its astrocyte differentiation. These data suggest that manipulation of BMP signaling in the endogenous or grafted NSCs or OPCs may be a useful therapeutic strategy to increase their OL differentiation and remyelination and enhance functional recovery after SCI.

[1]  M. Stangel,et al.  Cerebellar Cortical Demyelination in the Murine Cuprizone Model , 2010, Brain pathology.

[2]  Robin J. M. Franklin,et al.  Remyelination in the CNS: from biology to therapy , 2008, Nature Reviews Neuroscience.

[3]  S. Chandran,et al.  Abnormally phosphorylated tau is associated with neuronal and axonal loss in experimental autoimmune encephalomyelitis and multiple sclerosis. , 2008, Brain : a journal of neurology.

[4]  B. Trapp,et al.  Multiple sclerosis: an immune or neurodegenerative disorder? , 2008, Annual review of neuroscience.

[5]  Multiple sclerosis: Classification revisited reveals homogeneity and recapitulation , 2008, Annals of neurology.

[6]  D. Pleasure,et al.  Bone morphogenetic proteins 4, 6, and 7 are up‐regulated in mouse spinal cord during experimental autoimmune encephalomyelitis , 2008, Journal of neuroscience research.

[7]  S. Whittemore,et al.  Bone Morphogenetic Protein Signaling and Olig1/2 Interact to Regulate the Differentiation and Maturation of Adult Oligodendrocyte Precursor Cells , 2007, Stem cells.

[8]  Anna C. Williams,et al.  Astrocytes—Friends or foes in multiple sclerosis? , 2007, Glia.

[9]  A. K. Hall,et al.  Bone morphogenetic proteins promote gliosis in demyelinating spinal cord lesions , 2007, Annals of neurology.

[10]  S. Whittemore,et al.  Schwann cell‐like differentiation by adult oligodendrocyte precursor cells following engraftment into the demyelinated spinal cord is BMP‐dependent , 2006, Glia.

[11]  C. Raine,et al.  Co-expression of PDGF α receptor and NG2 by oligodendrocyte precursors in human CNS and multiple sclerosis lesions , 2006, Journal of Neuroimmunology.

[12]  R. Fields,et al.  Astrocytes Promote Myelination in Response to Electrical Impulses , 2006, Neuron.

[13]  Mahendra S Rao,et al.  Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation , 2005, Nature Medicine.

[14]  Oswald Steward,et al.  Human Embryonic Stem Cell-Derived Oligodendrocyte Progenitor Cell Transplants Remyelinate and Restore Locomotion after Spinal Cord Injury , 2005, The Journal of Neuroscience.

[15]  W. Blakemore,et al.  Inflammation stimulates remyelination in areas of chronic demyelination. , 2005, Brain : a journal of neurology.

[16]  T. Takizawa,et al.  Treatment of spinal cord injury by transplantation of fetal neural precursor cells engineered to express BMP inhibitor , 2004, Experimental Neurology.

[17]  J. Golden,et al.  Oligodendrocyte maturation is inhibited by bone morphogenetic protein , 2004, Molecular and Cellular Neuroscience.

[18]  A. K. Hall,et al.  Emerging roles for bone morphogenetic proteins in central nervous system glial biology , 2004, Journal of neuroscience research.

[19]  H. Takebayashi,et al.  Negative regulatory effect of an oligodendrocytic bHLH factor OLIG2 on the astrocytic differentiation pathway , 2004, Cell Death and Differentiation.

[20]  A. Crang,et al.  The presence of astrocytes in areas of demyelination influences remyelination following transplantation of oligodendrocyte progenitors , 2003, Experimental Neurology.

[21]  P. Cochard,et al.  Bone morphogenetic proteins negatively control oligodendrocyte precursor specification in the chick spinal cord. , 2002, Development.

[22]  C. Brosnan,et al.  Multiple sclerosis: Re-expression of a developmental pathway that restricts oligodendrocyte maturation , 2002, Nature Medicine.

[23]  G. Wolswijk,et al.  Oligodendrocyte precursor cells in the demyelinated multiple sclerosis spinal cord. , 2002, Brain : a journal of neurology.

[24]  R. Rudick,et al.  Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. , 2002, The New England journal of medicine.

[25]  F. Murakami,et al.  Dorsal spinal cord inhibits oligodendrocyte development. , 2000, Developmental biology.

[26]  W. Kisseberth,et al.  Ubiquitous expression of marker transgenes in mice and rats. , 1999, Developmental biology.

[27]  B. Barres,et al.  Notch Receptor Activation Inhibits Oligodendrocyte Differentiation , 1998, Neuron.

[28]  M. Mehler,et al.  Bone Morphogenetic Proteins Induce Astroglial Differentiation of Oligodendroglial–Astroglial Progenitor Cells , 1997, The Journal of Neuroscience.

[29]  R. Kucherlapati,et al.  GFAP Is Necessary for the Integrity of CNS White Matter Architecture and Long-Term Maintenance of Myelination , 1996, Neuron.