title: Hepatocyte growth factor activator inhibitor-1 is induced by bone morphogenetic proteins and regulates proliferation and cell fate of neural progenitor cells.
abstract: BACKGROUND
  Neural progenitor cells (NPCs) in the developing neuroepithelium are regulated by intrinsic and extrinsic factors. There is evidence that NPCs form a self-supporting niche for cell maintenance and proliferation. However, molecular interactions and cell-cell contacts and the microenvironment within the neuroepithelium are largely unknown. We hypothesized that cellular proteases especially those associated with the cell surface of NPCs play a role in regulation of progenitor cells in the brain.
  
  
  RESULTS
  In this work, we show that NPCs, isolated from striatal anlage of developing rat brain, express hepatocyte growth factor activator inhibitor-1 and -2 (HAI-1 and HAI-2) that are cell surface-linked serine protease inhibitors. In addition, radial glia cells derived from mouse embryonic stem cells also express HAI-1 and HAI-2. To study the functional significance of HAI-1 and HAI-2 in progenitor cells, we modulated their levels using expression plasmids or silencing RNA (siRNA) transfected into the NPCs. Data showed that overexpression of HAI-1 or HAI-2 decreased cell proliferation of cultured NPCs, whilst their siRNAs had opposite effects. HAI-1 also influenced NPC differentiation by increasing the number of glial fibrillary acidic protein (GFAP) expressing cells in the culture. Expression of HAI-1 in vivo decreased cell proliferation in developing neuroepithelium in E15 old animals and promoted astrocyte cell differentiation in neonatal animals. Studying the regulation of HAI-1, we observed that Bone morphogenetic protein-2 (BMP-2) and BMP-4 increased HAI-1 levels in the NPCs. Experiments using HAI-1-siRNA showed that these BMPs act on the NPCs partly in a HAI-1-dependent manner.
  
  
  CONCLUSIONS
  This study shows that the cell-surface serine protease inhibitors, HAI-1 and HAI-2 influence proliferation and cell fate of NPCs and their expression levels are linked to BMP signaling. Modulation of the levels and actions of HAI-1 in NPCs may be of a potential value in stem cell therapies in various brain diseases.
authors: Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland.
authors: Raili
authors: R
authors: Koivuniemi
authors: Johanna
authors: J
authors: Mäkelä
authors: Marie-Estelle
authors: ME
authors: Hokkanen
authors: Céline
authors: C
authors: Bruelle
authors: Tho Huu
authors: TH
authors: Ho
authors: Roxana
authors: R
authors: Ola
authors: Laura
authors: L
authors: Korhonen
authors: Jim
authors: J
authors: Schröder
authors: Hiroaki
authors: H
authors: Kataoka
authors: Dan
authors: D
authors: Lindholm
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology*; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D046569:Neuroepithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D008562:Membrane Glycoproteins; C504592:Spint1 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D052004:Bone Morphogenetic Protein Receptors