Adult neural stem cells: intrinsic and extrinsic factors that regulate their self-renewal and differentiation
Research summary:
The principal investigator (Dr. Eva Porlan) is a beneficiary of the Ramón y Cajal program, and has established a novel and independent line of research in the CBMSO, since 2016. This line focuses on the study of intrinsic and extrinsic factors that regulate the quiescence-proliferation switch and the mode of division of mammalian adult neural stem cells (NSC), and how these factors contribute to the maintenance of NSCs in their natural dwelling reservoirs, the neurogenic niches. The subependymal zone (also known as the subventricular zone) is the most prolific neurogenic niche in adult rodents, where residing stem cells generate large numbers of immature neurons that migrate into the olfactory bulb, where they differentiate into different types of interneurons. In a society of demographic change like is our own, a research challenge is the search for druggable targets to mobilize NSCs at their endogenous niches in order to activate stem cells that are mainly quiescent to divide and generate differentiated and functional progeny. This strategy holds promise to promote regenerative responses in physiological ageing, brain lesions or similar pathological situations, and appears as a very attractive venue for the future of cell replacement therapies. We are currently exploring the potential of targets whose biological activity are susceptible of pharmacological modulation for enhancing NSC transition into proliferation and neurogenic output, both during homeostasis and in damage-regeneration paradigms in the adult brain.
A representative confocal microphotograph of murine neural stem cells at the subependymal niche. Shown are ependymal cells (big polygonal cells, outlined by membrane beta-catenin staining –blue-, displaying multiple motile cilia, revealed by gamma-tubulin staining –red-. Neural stem cells are stained with the glial marker GFAP –green-, and univocally identified by the simultaneous immunoreactivity for gamma-tubulin to show one unique basal body revealing the presence of a primary cilium –red-. The combined structure of the ependymal cell wall and the stem cells at their center has been termed ‘pinwheel’.
| Last name | Name | Laboratory | Ext.* | Professional category | |
|---|---|---|---|---|---|
| Porlan Alonso | Eva | 306 | 4629 | eva.porlan(at)cbm.csic.es | Profesor Contratado Doctor Universidad, GA |
Publicaciones relevantes:
- Puerto, A. d., B. Martí-Prado, A. L. Barrios-Muñoz, C. López-Fonseca, J. Pose-Utrilla, B. Alcover-Sanchez, F. Cesca, G. Schiavo, M. R. Campanero, I. Fariñas, T. Iglesias and E. Porlan (2023). "Kidins220 sets the threshold for survival of neural stem cells and progenitors to sustain adult neurogenesis." bioRxiv: 2023.2001.2010.523252.
- Domingo-Muelas, A., J. M. Morante-Redolat, V. Moncho-Amor, A. Jordan-Pla, A. Perez-Villalba, P. Carrillo-Barbera, G. Belenguer, E. Porlan, M. Kirstein, O. Bachs, S. R. Ferron, R. Lovell-Badge and I. Farinas (2023). "The rates of adult neurogenesis and oligodendrogenesis are linked to cell cycle regulation through p27-dependent gene repression of SOX2." Cell Mol Life Sci 80(1): 36.
- Gonzalez-Martinez, J., A. W. Cwetsch, J. Gilabert-Juan, J. Gomez, G. Garaulet, P. Schneider, G. de Carcer, F. Mulero, E. Caleiras, D. Megias, E. Porlan and M. Malumbres (2022). "Genetic interaction between PLK1 and downstream MCPH proteins in the control of centrosome asymmetry and cell fate during neural progenitor division." Cell Death Differ 29(8): 1474-1485.
- del Puerto, A., J. Pose-Utrilla, A. Simón-García, C. López-Menéndez, A. J. Jiménez, E. Porlan, L. S. M. Pajuelo, G. Cano-García, B. Martí-Prado, Á. Sebastián-Serrano, M. P. Sánchez-Carralero, F. Cesca, G. Schiavo, I. Ferrer, I. Fariñas, M. R. Campanero and T. Iglesias (2021). "Kidins220 deficiency causes ventriculomegaly via SNX27-retromer-dependent AQP4 degradation." Molecular Psychiatry 26(11): 6411-6426.
- Morante-Redolat, J.M., and Porlan, E. (2019). Neural Stem Cell Regulation by Adhesion Molecules Within the Subependymal Niche. Front Cell Dev Biol 7, 102.
- Piniella, D., Martinez-Blanco, E., Ibanez, I., Bartolome-Martin, D., Porlan, E., Diez-Guerra, J., Gimenez, C., and Zafra, F. (2018). Identification of novel regulatory partners of the glutamate transporter GLT-1. Glia 66, 2737-2755.
- Porlan, E., Marti-Prado, B., Consiglio, A., and Farinas, I. (2016). Stable and Efficient Genetic Modification of Cells in the Adult Mouse V-SVZ for the Analysis of Neural Stem Cell Autonomous and Non-autonomous Effects. J Vis Exp, 53282.
- Quereda, V., Porlan, E., Canamero, M., Dubus, P., and Malumbres, M. (2016). An essential role for Ink4 and Cip/Kip cell-cycle inhibitors in preventing replicative stress. Cell Death Differ 23, 430-441.
- Porlan, E., Marti-Prado, B., Morante-Redolat, J.M., Consiglio, A., Delgado, A.C., Kypta, R., Lopez-Otin, C., Kirstein, M., and Farinas, I. (2014). MT5-MMP regulates adult neural stem cell functional quiescence through the cleavage of N-cadherin. Nat Cell Biol 16, 629-638.
- Delgado, A.C., Ferron, S.R., Vicente, D., Porlan, E., Perez-Villalba, A., Trujillo, C.M., D'Ocon, P., and Farinas, I. (2014). Endothelial NT-3 delivered by vasculature and CSF promotes quiescence of subependymal neural stem cells through nitric oxide induction. Neuron 83, 572-585.
- Marques-Torrejon, M.A., Porlan, E., Banito, A., Gomez-Ibarlucea, E., Lopez-Contreras, A.J., Fernandez-Capetillo, O., Vidal, A., Gil, J., Torres, J., and Farinas, I. (2013). Cyclin-dependent kinase inhibitor p21 controls adult neural stem cell expansion by regulating Sox2 gene expression. Cell Stem Cell 12, 88-100.
- Porlan, E., Morante-Redolat, J.M., Marques-Torrejon, M.A., Andreu-Agullo, C., Carneiro, C., Gomez-Ibarlucea, E., Soto, A., Vidal, A., Ferron, S.R., and Farinas, I. (2013). Transcriptional repression of Bmp2 by p21(Waf1/Cip1) links quiescence to neural stem cell maintenance. Nature neuroscience 16, 1567-1575.
- Porlan, E., Perez-Villalba, A., Delgado, A.C., and Ferron, S.R. (2013). Paracrine regulation of neural stem cells in the subependymal zone. Arch Biochem Biophys 534, 11-19.
Doctoral Theses:
- Ana Laura Barrios Muñoz. “Plk1, un nuevo regulador de la neurogénesis adulta”. Directora: Eva Porlan. Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 28-09-2021
- Beatriz Martí Prado. Estudio de la quiescencia y activación de las células madre neurales adultas por uniones adherentes: papel de la N-cadherina”. Directores: Eva Porlan e Isabel Fariñas. Facultad de Ciencias Biológicas, Departamento de Biología Celular, Biología Funcional y Antropología Física de la Universidad de Valencia. 19/07/2017
