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Pigment epithelium–derived factor is a niche signal for neural stem cell renewal

Nature Neuroscience volume 9, pages 331–339 (2006)Cite this article

Abstract

Adult stem cells are characterized by self-renewal and multilineage differentiation, and these properties seem to be regulated by signals from adjacent differentiated cell types and by extracellular matrix molecules, which collectively define the stem cell “niche.” Self-renewal is essential for the lifelong persistence of stem cells, but its regulation is poorly understood. In the mammalian brain, neurogenesis persists in two germinal areas, the subventricular zone (SVZ) and the hippocampus, where continuous postnatal neuronal production seems to be supported by neural stem cells (NSCs). Here we show that pigment epithelium–derived factor (PEDF) is secreted by components of the murine SVZ and promotes self-renewal of adult NSCs in vitro. In addition, intraventricular PEDF infusion activated slowly dividing stem cells, whereas a blockade of endogenous PEDF decreased their cycling. These data demonstrate that PEDF is a niche-derived regulator of adult NSCs and provide evidence for a role for PEDF protein in NSC maintenance.

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Figure 1: PEDF is expressed by ependymal and endothelial cells, but not by NSCs, of the adult SVZ.
Figure 2: PEDF promotes self-renewal, but not proliferation, of adult NSCs isolated from the SVZ.
Figure 3: PEDF induces molecular changes that are associated with multipotentiality in adult NSCs.
Figure 4: C-ter PEDF blocks the effects of PEDF on a neurosphere assay.
Figure 5: Endogenous PEDF can promote self-renewal of adult NSCs.
Figure 6: PEDF activates B-cells in vivo.
Figure 7: PEDF modulates NSC self-renewal in vivo.

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Acknowledgements

We thank C. Hermenegildo for help with cultures of umbilical cord vascular cells, F. Sánchez-Madrid for antibodies to V-cadherin and M. Cano-Jaimez and I. Marín for reading the manuscript. This work was supported by grants from the Ministerio de Educación y Ciencia (MEC; SAF2002-03355) and Ministerio de Sanidad y Consumo (G03/167 and 210) to I.F., and from the Ministerio de Ciencia y Tecnología (SAF2002-03086), Consejería de Sanidad de la Junta de Comunidades de Castilla-La Mancha (GC-03-014 and 02021-00) and Spanish Network for Neurological Research (CIEN, C03/06) to J.E. C.R.-C. was supported by a MEC Postdoctoral Fellowship, and C.A.-A. and J.D.A.-A. are predoctoral fellows of the MEC-FPU (Formación de Profesorado Universitairo) Program and the Consejeria de Sanidad de Castilla-La Mancha, Spain, respectively. P.S. and H.M. are investigators of the Programa Ramón y Cajal from the MEC.

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Author notes

  1. Carmen Ramírez-Castillejo

    Present address: Laboratorio de Oncología Molecular, Facultad de Medicina and CRIB, UCLM,

  2. Pilar Sánchez, Helena Mira & Isabel Fariñas

    Present address: Unidad Mixta CIPF-UVEG (Centro de Investigación Príncipe Felipe-Universidad de Valencia Estudio General) and Departamento de Biología Celular, Centro de Investigación Príncipe Felipe, Departamento de Biología Celular, Universidad de Valencia, Burjassot, 46100, Spain

  3. Carmen Ramírez-Castillejo, Francisco Sánchez-Sánchez, Celia Andreu-Agulló and Sacri R Ferrón: These authors contributed equally to this work.

Authors and Affiliations

  1. Departamento de Biología Celular, Universidad de Valencia, Burjassot, 46100, Spain

    Carmen Ramírez-Castillejo, Celia Andreu-Agulló, Sacri R Ferrón, Pilar Sánchez, Helena Mira & Isabel Fariñas

  2. Área de Genética, Facultad de Medicina and Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla-La Mancha (UCLM), Albacete, 02006, Spain

    Francisco Sánchez-Sánchez, J Daniel Aroca-Aguilar & Julio Escribano

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The authors of the paper are filing a patent on the effect of PEDF on stem cell renewal.

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Ramírez-Castillejo, C., Sánchez-Sánchez, F., Andreu-Agulló, C. et al. Pigment epithelium–derived factor is a niche signal for neural stem cell renewal. Nat Neurosci 9, 331–339 (2006). https://doi.org/10.1038/nn1657

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