Neurogénesis y neurodegeneración: cuando el desarrollo se encuentra con la patología. Isabel Fariñas Isabel.farinas@uv.es

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Víctor Manuel Pérez Guzmán
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1 Neurogénesis y neurodegeneración: cuando el desarrollo se encuentra con la patología Isabel Fariñas Isabel.farinas@uv.es

2 Neural (synaptic) plasticity Yuste R. Neuron 71, September 8, 2011

3 Cell regeneration in the nervous system: the unforeseen plasticity el aprendizaje hace que las células nerviosas existentes emitan o hagan crecer nuevas prolongaciones para reforzar sus conexiones con otras células nerviosas Preciso es reconocer que, en los centros adultos, las vías nerviosas son algo fijo, acabado, inmutable. Todo puede morir, nada renacer. Santiago Ramón y Cajal, 1928

conexiones con otras células nerviosas Preciso es reconocer que, en los centros adultos, las vías

4 Adult neurogenesis t

5 ? Adult neurogenesis in humans Alonso-Nanclares & De Felipe BrdU BrdU NeuN GFAP Ericksson et al. (Gage), 1999

6 Frisen lab: 14 C-based neuron birthdating Adult neurogenesis in humans Nuclear bomb testderived 14 C Incorporation of 14 C in new born neurons 14 C

7 Cell regeneration in the nervous system: the unforeseen plasticity Preciso es reconocer que, en los centros adultos, las vías nerviosas son algo fijo, acabado, inmutable. Todo puede morir, nada renacer. será tarea de la ciencia del futuro cambiar, si es posible, este duro decreto. Synaptic plasticity + Adult neurogenesis Santiago Ramón y Cajal, 1928

8 Neurogenic niches in the adult mammalian brain Subventricular zone (SVZ) Subgranular zone (SGZ) (Dentate gyrus) Olfactory bulb SVZ Corpus callosum SGZ Cerebellum

9 Neurogenic niches in the adult mammalian brain: GFAP+ NSCs SVZ SGZ DNA GFAP S100β DNA GFAP

10 Origin of adult neural stem cells Neural tube Neuroepithelium

11 Origin of adult neural stem cells t

12 Radial glial cells as NSCs

13 Adult NSCs: B1 cells beta-catenin (membranes) γ-tubulin (cilial basal bodies) GFAP

The Stem Cell Niche O 2 & small ions Immune/inflammatory cells Neurons Neurotransmitters, neuropeptides ECM Perivascular & endothelial cells Adhesion & signalling receptors (integrins, cadherins,

14 The Stem Cell Niche O 2 & small ions Immune/inflammatory cells Neurons Neurotransmitters, neuropeptides ECM Perivascular & endothelial cells Adhesion & signalling receptors (integrins, cadherins, GPCRs, Notch, ) Stem cell Soluble factors (growth factors, hormones, chemokines, neurotransmitters, ) Support cells (ependyma in the CNS) Ferrón et al. Development, 131: (2004) Ramírez-Castillejo et al. Nature Neuroscience, 9: (2006) Ferrón et al. Nature Protocols, 2: (2007) Ferrón et al. J. Neuroscience, 29: (2009) Andreu-Agulló et al. Nature Neuroscience, 12: (2009) Mira et al. Cell Stem Cell, 7:79-89 (2010) (in collaboration) Ferrón et al. Cell Stem Cell, 7: (2010) Ferrón et al. Nature, 475: (2011) (in collaboration) Marqués-Torrejón et al. Cell Stem Cell, 12: (2013) Porlan et al. Nature Neuroscience,16: (2013) Porlan et al. Nature Cell Biology, 16: (2014) Delgado-Fumero et al. Neuron, 83: (2014)

Development, 131:4059-4070 (2004) Ramírez-Castillejo et al. Nature Neuroscience, 9:331-339 (2006) Ferrón et al. Nature Protocols, 2:849-859 (2007) Ferrón et al. J.

MOLECULAR REGULATION OF SELF-RENEWAL NICHE INTERACTIONS Adult tissue-specific stem cells PATHOLOGICAL PHYSIOLOGICAL Neoplasic mutations Self-renewal vs differentiation CANCER Tumour formation and

15 MOLECULAR REGULATION OF SELF-RENEWAL NICHE INTERACTIONS Adult tissue-specific stem cells PATHOLOGICAL PHYSIOLOGICAL Neoplasic mutations Self-renewal vs differentiation CANCER Tumour formation and recurrence TISSUE HOMEOSTASIS Tissue renewal and regeneration Increased cell death or senescence AGEING Age-related deteriorations Age-related disorders Targeting deregulated selfrenewal. TUMOUR TREATMENT Stem cell source: ex vivo expansion & customized differentiation. Endogenous stem cell activation. REGENERATIVE MEDICINE

regeneration Increased cell death or senescence AGEING Age-related deteriorations Age-related disorders Targeting deregulated

16 The Study of Neurogenesis in Neurogenerative Contexts In PD, specific alterations in neurogenic areas parallel some of the early or premotor symptoms that are seen in the early stages of these diseases, such as depression or olfactory dysfunction.

early or premotor symptoms that are seen in the early stages

17 Reported Dopamine Effects on Proliferation/Neurogenesis Dopamine: or proliferation (transient amplifying progenitor TAP- cells) or neurogenesis From: Arias-Carrión O, et al. CNS Neurol Disord Drug Targets 6: (2007) Synaptic marker TH GFAP

TAP- cells) or neurogenesis From: Arias-Carrión O, et al.

18 Neurogenic niches in the adult mammalian brain OB Striatum Frisen lab: 14 C-based neuron birthdating

cells Adhesion & signalling receptors (integrins, cadherins, GPCRs, Notch, ) Stem cell Soluble factors (growth

19 The Stem Cell Niche as a Druggable Target for Regenerative Medicine: Niche Therapies Neurons O 2 & small ions Immune/inflammatory cells Neurotransmitters, neuropeptides, synaptic regulators ECM Perivascular & endothelial cells Adhesion & signalling receptors (integrins, cadherins, GPCRs, Notch, ) Stem cell Soluble factors (growth factors, hormones, chemokines, neurotransmitters, ) Support cells (ependyma in the CNS) Synaptic plasticity Adult neurogenesis

20 Potential Entry Points for Niche-Directed Stem Cell Therapies Stem cell expansion Expand niches High engraftment Stem cells Ex vivo culture w/ niche w/o niche Stem cells Transplantation Untreated Low engraftment Transplantation Stem cell loss Alter niches Biased cell type production Loss of stem cell niches Aging/Disease Rejuvenation Endogenous targeting Dysfunction of stem cell niches

Untreated Low engraftment Transplantation Stem cell loss Alter niches Biased cell type

21 Martina Kirstein Francisco Pérez-Sánchez Sacri R. Ferrón José Manuel Morante Alex Bizy Ana Pérez-Villalba Salomé Sirerol Carmen Ovejero María Pimentel Germán Belenguer Beatriz Martí-Prado Ana Domingo Mª José Palop Fabrice Durupt BIOTECMED ERI de Biotecnologia i Biomedicina Estructura de Recerca Interdisciplinar de la Universitat de València

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