title: Astrocytic tissue inhibitor of metalloproteinase-1 (TIMP-1) promotes oligodendrocyte differentiation and enhances CNS myelination.
abstract: Tissue inhibitor of metalloproteinase-1 (TIMP-1) is an extracellular protein and endogenous regulator of matrix metalloproteinases (MMPs) secreted by astrocytes in response to CNS myelin injury. We have previously reported that adult TIMP-1 knock-out (KO) mice exhibit poor myelin repair following demyelinating injury. This observation led us to hypothesize a role for TIMP-1 in oligodendrogenesis and CNS myelination. Herein, we demonstrate that compact myelin formation is significantly delayed in TIMP-1 KO mice, a situation that coincided with dramatically reduced numbers of white matter astrocytes in the developing CNS. Analysis of differentiation in CNS progenitor cells (neurosphere) cultures from TIMP-1 KO mice revealed a specific deficit of NG2(+) oligodendrocyte progenitor cells. Application of recombinant murine TIMP-1 (rmTIMP-1) to TIMP-1 KO neurosphere cultures evoked a dose-dependent increase in NG2(+) cell numbers, while treatment with GM6001, a potent broad-spectrum MMP inhibitor did not. Similarly, administration of rmTIMP-1 to A2B5(+) immunopanned oligodendrocyte progenitors significantly increased the number of differentiated O1(+) oligodendrocytes, while antisera to TIMP-1 reduced oligodendrocyte numbers. We also determined that A2B5(+) oligodendrocyte progenitors grown in conditioned media derived from TIMP-1 KO primary glial cultures resulted in reduced differentiation of mature O1(+) oligodendrocytes. Finally, we report that addition of rmTIMP-1 to primary glial cultures resulted in a dose-dependent proliferative response of astrocytes. Together, these findings describe a previously uncharacterized role for TIMP-1 in the regulation of oligodendrocytes and astrocytes during development and provide a novel function for TIMP-1 on myelination in the developing CNS.
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Moore
authors.forename: Richard
authors.initials: R
authors.lastname: Milner
authors.forename: Akiko
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Ricardo F
authors.initials: RF
authors.lastname: Frausto
authors.forename: David R
authors.initials: DR
authors.lastname: Serwanski
authors.forename: Roberto R
authors.initials: RR
authors.lastname: Pagarigan
authors.forename: J Lindsay
authors.initials: JL
authors.lastname: Whitton
authors.forename: Robert H
authors.initials: RH
authors.lastname: Miller
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Crocker
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009186:Myelin Sheath / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1