A potential role for bone morphogenetic protein signalling in glial cell fate determination following adult central nervous system injury in vivo

Bone morphogenetic proteins (BMPs) and their endogenous inhibitors, including noggin, chordin and follistatin, have roles in pattern formation and fate specification of neuronal and glial cells during nervous system development. We have examined their influence on glial reactions in the injured central nervous system (CNS). We show that penetrating injuries to the brain and spinal cord resulted in the upregulation of BMP‐2/4, BMP‐7, and noggin, with the latter being expressed almost exclusively by reactive astrocytes at the injury site, and we show that astrocytes in vitro produce noggin. As BMPs have been shown to drive cultured NG2‐positive oligodendrocyte precursors (OPCs) towards a multipotential phenotype (type II astrocytes), we investigated the effects of inhibiting noggin with a function‐blocking antibody (noggin‐FbAb). In vitro, BMP‐driven conversion of OPCs to type 2 astrocytes was inhibited by noggin, an effect that was reversed by noggin‐FbAb. Noggin‐FbAb also increased the number of type 2 astrocytes generated from cultured OPCs exposed to an astrocyte feeder layer, consistent with astrocytes producing both BMPs and noggin. In knife cut injuries in vivo, noggin‐FbAb treatment resulted in an increase in the number of NG2‐positive cells and small GFAP‐positive cells in the injury site, and the appearance of glial cells with the morphological and antigenic characteristics of type 2 astrocytes (as generated in vitro), with coexpression of both GFAP and NG2. This potential conversion of inhibitory OPCs to type 2 astrocyte‐like cells in vivo suggests that endogenous BMPs, unmasked by noggin antagonism, might be exploited to manipulate cell fate following CNS trauma.

[1]  J. Fawcett,et al.  Spinally upregulated noggin suppresses axonal and dendritic plasticity following dorsal rhizotomy , 2007, Experimental Neurology.

[2]  J. Fawcett,et al.  Astrocytes promote neurogenesis from oligodendrocyte precursor cells , 2006, The European journal of neuroscience.

[3]  D. Sellers,et al.  Instructive niches: environmental instructions that confound NG2 proteoglycan expression and the fate‐restriction of CNS progenitors , 2005, Journal of anatomy.

[4]  Chad H. Koonce,et al.  BMP4 substitutes for loss of BMP7 during kidney development. , 2005, Developmental biology.

[5]  J. Fawcett,et al.  Delivery of a lentiviral vector in a Pluronic F127 gel to cells of the central nervous system. , 2005, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[6]  S. Whittemore,et al.  Consequences of noggin expression by neural stem, glial, and neuronal precursor cells engrafted into the injured spinal cord , 2005, Experimental Neurology.

[7]  J. Fawcett,et al.  Identification of unique reciprocal and non reciprocal cross packaging relationships between HIV-1, HIV-2 and SIV reveals an efficient SIV/HIV-2 lentiviral vector system with highly favourable features for in vivo testing and clinical usage , 2005, Retrovirology.

[8]  B. Hoffer,et al.  Stroke and TGF-beta proteins: glial cell line-derived neurotrophic factor and bone morphogenetic protein. , 2005, Pharmacology & therapeutics.

[9]  J. Borisoff,et al.  Deafferentation and neurotrophin‐mediated intraspinal sprouting: a central role for the p75 neurotrophin receptor , 2005, The European journal of neuroscience.

[10]  J. Fawcett,et al.  The responses of oligodendrocyte precursor cells, astrocytes and microglia to a cortical stab injury, in the brain , 2004, Neuroscience.

[11]  J. Fawcett,et al.  Altered CNS response to injury in the MRL/MpJ mouse , 2004, Neuroscience.

[12]  A. Fasolo,et al.  Expression of the secreted factors noggin and bone morphogenetic proteins in the subependymal layer and olfactory bulb of the adult mouse brain , 2004, Neuroscience.

[13]  V. Botchkarev,et al.  BMP signaling in the control of skin development and hair follicle growth. , 2004, Differentiation; research in biological diversity.

[14]  J. Borisoff,et al.  Rho-Kinase Inhibition Enhances Axonal Plasticity and Attenuates Cold Hyperalgesia after Dorsal Rhizotomy , 2004, The Journal of Neuroscience.

[15]  Hui Yang,et al.  SVZa neural stem cells differentiate into distinct lineages in response to BMP4 , 2004, Experimental Neurology.

[16]  L. T. McPhail,et al.  A soluble Nogo receptor differentially affects plasticity of spinally projecting axons , 2004, The European journal of neuroscience.

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

[18]  Hui Yang,et al.  Antisense Noggin oligodeoxynucleotide administration decreases cell proliferation in the dentate gyrus of adult rats , 2004, Neuroscience Letters.

[19]  John L. Hudson,et al.  Beneficial effects of intraventricularly administered BMP-7 following a striatal 6-hydroxydopamine lesion , 2004, Brain Research.

[20]  M. Raff,et al.  A role for Noggin in the development of oligodendrocyte precursor cells. , 2004, Developmental biology.

[21]  J. Fawcett,et al.  Inhibiting cell proliferation during formation of the glial scar: effects on axon regeneration in the CNS , 2003, Neuroscience.

[22]  V. Gallo,et al.  Postnatal NG2 proteoglycan–expressing progenitor cells are intrinsically multipotent and generate functional neurons , 2003, The Journal of cell biology.

[23]  M. Koster,et al.  Roles of TGFβ signaling in epidermal/appendage development , 2003 .

[24]  W. Gomes,et al.  Transgenic overexpression of BMP4 increases astroglial and decreases oligodendroglial lineage commitment. , 2003, Developmental biology.

[25]  M. Morales,et al.  Intravenous Administration of Bone Morphogenetic Protein-7 After Ischemia Improves Motor Function in Stroke Rats , 2003, Stroke.

[26]  J. Bertram,et al.  Organisation of Bone Morphogenetic Proteins in Renal Development , 2003, Nephron Experimental Nephrology.

[27]  Markus Affolter,et al.  Structural basis of BMP signalling inhibition by the cystine knot protein Noggin , 2002, Nature.

[28]  W. Van Hul,et al.  Extracellular regulation of BMP signaling in vertebrates: a cocktail of modulators. , 2002, Developmental biology.

[29]  M. Morales,et al.  Bone morphogenetic proteins are involved in fetal kidney tissue transplantation-induced neuroprotection in stroke rats , 2002, Neuropharmacology.

[30]  Fred H. Gage,et al.  Astroglia induce neurogenesis from adult neural stem cells , 2002, Nature.

[31]  K. Yone,et al.  Traumatic injury-induced BMP7 expression in the adult rat spinal cord , 2001, Brain Research.

[32]  D. Higgins,et al.  Bone morphogenetic protein-5 (BMP-5) promotes dendritic growth in cultured sympathetic neurons , 2001, BMC Neuroscience.

[33]  V. Sorrenti,et al.  Expression of bone morphogenetic protein-6 and transforming growth factor-β1 in the rat brain after a mild and reversible ischemic damage , 2001, Brain Research.

[34]  Richard Reynolds,et al.  The oligodendrocyte precursor cell in health and disease , 2001, Trends in Neurosciences.

[35]  J. García-Verdugo,et al.  Noggin Antagonizes BMP Signaling to Create a Niche for Adult Neurogenesis , 2000, Neuron.

[36]  M. Raff,et al.  Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. , 2000, Science.

[37]  J. Seylaz,et al.  Distribution of bone morphogenetic protein and bone morphogenetic protein receptor transcripts in the rodent nervous system and up-regulation of bone morphogenetic protein receptor type II in hippocampal dentate gyrus in a rat model of global cerebral ischemia , 2000, Neuroscience.

[38]  D. Kallmes,et al.  Bone morphogenetic proteins and bone morphogenetic protein gene therapy in neurological surgery: a review. , 2000, Neurosurgery.

[39]  J. Fawcett,et al.  Neurocan Is Upregulated in Injured Brain and in Cytokine-Treated Astrocytes , 2000, The Journal of Neuroscience.

[40]  R. Jilka,et al.  Essential Requirement of BMPs‐2/4 for Both Osteoblast and Osteoclast Formation in Murine Bone Marrow Cultures from Adult Mice: Antagonism by Noggin , 2000, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[41]  M. Mehler,et al.  Developmental Changes in Progenitor Cell Responsiveness to Bone Morphogenetic Proteins Differentially Modulate Progressive CNS Lineage Fate , 2000, Developmental Neuroscience.

[42]  G. Banker,et al.  Bone morphogenetic protein‐7 enhances dendritic growth and receptivity to innervation in cultured hippocampal neurons , 2000, The European journal of neuroscience.

[43]  S. Wilson,et al.  Bmp activity establishes a gradient of positional information throughout the entire neural plate. , 1999, Development.

[44]  J. Fawcett,et al.  The glial scar and central nervous system repair , 1999, Brain Research Bulletin.

[45]  E. Canalis,et al.  Bone morphogenetic proteins induce the expression of noggin, which limits their activity in cultured rat osteoblasts. , 1998, The Journal of clinical investigation.

[46]  M. Mehler,et al.  Bone morphogenetic proteins in the nervous system , 1997, Trends in Neurosciences.

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

[48]  L. Hillered,et al.  Expression of serine/threonine kinase receptors in traumatic brain injury , 1997, Neuroreport.

[49]  R. Harland,et al.  The Spemann Organizer Signal noggin Binds and Inactivates Bone Morphogenetic Protein 4 , 1996, Cell.

[50]  A. Economides,et al.  Identification of mammalian noggin and its expression in the adult nervous system , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[51]  F. Jensen,et al.  Neuroprotective effect of human osteogenic protein-1 in a rat model of cerebral hypoxia/ischemia , 1995, Neuroscience Letters.

[52]  M. Raff,et al.  Glial Cells in the Rat Optic Nerve , 1991, Annals of the New York Academy of Sciences.

[53]  Guy McKhann,et al.  Fetal and adult human oligodendrocyte progenitor cell isolates myelinate the congenitally dysmyelinated brain , 2004, Nature Medicine.

[54]  V. Botchkarev.  Bone morphogenetic proteins and their antagonists in skin and hair follicle biology. , 2003, The Journal of investigative dermatology.

[55]  M. Koster,et al.  Roles of TGFbeta signaling in epidermal/appendage development. , 2003, Cytokine & growth factor reviews.

[56]  Maiken Nedergaard,et al.  Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain , 2003, Nature Medicine.

[57]  A. Economides,et al.  Heparan Sulfate Proteoglycans Retain Noggin at the Cell Surface A POTENTIAL MECHANISM FOR SHAPING BONE MORPHOGENETIC PROTEIN GRADIENTS* , 2002 .

[58]  T. Jessell,et al.  The specification of dorsal cell fates in the vertebrate central nervous system. , 1999, Annual review of neuroscience.