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Lack of adrenomedullin affects growth and differentiation of adult neural stem/progenitor cells

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Abstract

Adrenomedullin (AM) is a peptide hormone involved in the modulation of cellular growth, migration, apoptosis, and angiogenesis. These characteristics suggest that AM is involved in the control of neural stem/progenitor cell (NSPC) biology. To explore this hypothesis, we have obtained NSPC from the olfactory bulb of adult wild-type animals and brain conditional knockouts for adm, the gene that produces AM. Knockout NSPC contain higher levels of hyperpolymerized tubulin and more abundant filopodia than adm-containing cells, resulting in a different morphology in culture, whereas the size of the knockout neurospheres is smaller than that of the wild-types. Proliferation studies have demonstrated that adm-null NSPC incorporate less 5′-bromodeoxyuridine (BrdU) than their wild-type counterparts. In contrast, BrdU studies in the olfactory bulb of adult animals show more labeled cells in adm-null mice that in wild-types, suggesting that a compensatory mechanism exists that guarantees the sufficient production of neural cells in this organ. In NSPC differentiation tests, lack of adm results in significantly lower proportions of neurons and astrocytes and higher proportions of oligodendrocytes. The oligodendrocytes produced from adm-null neurospheres present an immature phenotype with fewer and shorter processes than adm-containing oligodendrocytes. Thus, AM is an important factor in regulating the proliferation and differentiation of adult NSPC and might be used to modulate stem cell renewal and fate in protocols destined to produce neural cells for regenerative therapies.

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Acknowledgements

The authors are grateful to Mr. M. Berrocal, Ms. B. Lázaro, and Ms. R. Varillas for excellent technical assistance and to Ms. V. Nieto-Estévez for help with cell cycle analysis.

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Authors and Affiliations

  1. Department of Cellular, Molecular, and Developmental Neurobiology, Cajal Institute, Consejo Superior de Investigaciones Científicas, 28002, Madrid, Spain

    Eva Vergaño-Vera, Ana P. Fernández, Anahí Hurtado-Chong & Carlos Vicario-Abejón

  2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, CIBERNED, ISCIII, Madrid, Spain

    Eva Vergaño-Vera & Carlos Vicario-Abejón

  3. Angiogenesis Study Group, Centro de Investigación Biomédica de La Rioja (CIBIR), C/ Piqueras 98, 26006, Logroño, Spain

    Alfredo Martínez

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  1. Eva Vergaño-Vera
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  2. Ana P. Fernández
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  3. Anahí Hurtado-Chong
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  4. Carlos Vicario-Abejón
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  5. Alfredo Martínez
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Correspondence to Alfredo Martínez.

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Carlos Vicario-Abejón and Alfredo Martínez contributed equally to this study.

This work was supported by grants from the Spanish Ministry of Science and Innovation (SAF2007-60010, BFU2007-61230, SAF2009-13240) and from the Instituto de Salud Carlos III (RETICS, RD06/0026/1001 and CIBERNED, CB06/05/0065).

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Vergaño-Vera, E., Fernández, A.P., Hurtado-Chong, A. et al. Lack of adrenomedullin affects growth and differentiation of adult neural stem/progenitor cells. Cell Tissue Res 340, 1–11 (2010). https://doi.org/10.1007/s00441-010-0934-3

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