Bone morphogenetic proteins mediate cellular response and, together with Noggin, regulate astrocyte differentiation after spinal cord injury

Exp Neurol. 2010 Feb;221(2):353-66. doi: 10.1016/j.expneurol.2009.12.003. Epub 2009 Dec 11.

Abstract

Bone morphogenetic proteins (BMPs) play a critical role in regulating cell fate determination during central nervous system (CNS) development. In light of recent findings that BMP-2/4/7 expressions are upregulated after spinal cord injury, we hypothesized that the BMP signaling pathway is important in regulating cellular composition in the injured spinal cord. We found that BMP expressions were upregulated in neural stem cells (NSCs), neurons, oligodendrocytes and microglia/macrophages. Increased expression levels of pSmad1/5/8 (downstream molecules of BMP) were detected in neurons, NSCs, astrocytes, oligodendrocytes and oligodendroglial progenitor cells (OPCs). Active astrocytes which form the astroglial scar were probably derived from NSCs, OPCs and resident astrocytes. Since quiescent NSCs in the normal adult spinal cord will proliferate and differentiate actively into neural cells after traumatic injury, we proposed that BMPs can regulate cellular components by controlling NSC differentiation. Neurosphere culture from adult mouse spinal cord showed that BMP-4 promoted astrocyte differentiation from NSCs while suppressing production of neurons and oligodendrocytes. Conversely, inhibition of BMP-4 by Noggin notably decreased the ratio of astrocyte to neuron numbers. However, intrathecal administration of Noggin in the injured spinal cord failed to attenuate glial fibrillar acidic protein (GFAP) expression even though it effectively reduced pSmad expression. Noggin treatment did not block phosphorylation of Stat3 and the induction of GFAP in the injured spinal cord, suggesting that in addition to the BMP/Smad pathway, the JAK/STAT pathway may also be involved in the regulation of GFAP expression after spinal cord injury.

MeSH terms

  • Animals
  • Astrocytes / drug effects*
  • Bone Morphogenetic Proteins / pharmacology*
  • Bone Morphogenetic Proteins / therapeutic use*
  • Bromodeoxyuridine / metabolism
  • Carrier Proteins / pharmacology*
  • Carrier Proteins / therapeutic use*
  • Cell Differentiation / drug effects*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Myelin Basic Protein / genetics
  • Myelin Basic Protein / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Oligodendroglia / drug effects
  • RNA, Messenger / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Spinal Cord Injuries* / drug therapy
  • Spinal Cord Injuries* / pathology
  • Spinal Cord Injuries* / physiopathology
  • Stem Cells / drug effects
  • Time Factors

Substances

  • Bone Morphogenetic Proteins
  • Carrier Proteins
  • Myelin Basic Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • RNA, Messenger
  • noggin protein
  • Bromodeoxyuridine