Presentación de PowerPoint - Fundacion Conchita Rabago de

Neurogénesis y neurodegeneración:
cuando el desarrollo se encuentra con la
patología
Isabel Fariñas
Isabel.farinas@uv.es
Neural (synaptic) plasticity
Yuste R.
Neuron 71, September 8, 2011
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
Adult neurogenesis
t
Adult neurogenesis in humans
?
Alonso-Nanclares & De Felipe
BrdU
BrdU
Ericksson et al. (Gage), 1999
NeuN
GFAP
Adult neurogenesis in humans
Incorporation of 14C in
new born neurons
Nuclear bomb testderived 14C
14C
Frisen lab: 14C-based neuron birthdating
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
+
Santiago Ramón y Cajal, 1928
Adult
neurogenesis
Neurogenic niches in the adult mammalian brain
Subventricular zone (SVZ)
Subgranular zone (SGZ)
(Dentate gyrus)
Olfactory
bulb
SVZ
Corpus callosum
SGZ
Cerebellum
Neurogenic niches in the adult mammalian brain: GFAP+ NSCs
SVZ
DNA
GFAP
S100β
SGZ
DNA
GFAP
Origin of adult neural stem cells
Neural tube
Neuroepithelium
Origin of adult neural stem cells
t
Radial glial cells as NSCs
Adult NSCs: B1 cells
beta-catenin (membranes)
γ-tubulin (cilial basal bodies)
GFAP
The Stem Cell Niche
O2 &
small ions
Immune/inflammatory
cells
Neurons
Perivascular &
endothelial cells
Neurotransmitters,
ECM
neuropeptides
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, 131:4059-4070 (2004)
Ramírez-Castillejo et al. Nature Neuroscience, 9:331-339 (2006)
Ferrón et al. Nature Protocols, 2:849-859 (2007)
Ferrón et al. J. Neuroscience, 29:14394-14407 (2009)
Andreu-Agulló et al. Nature Neuroscience, 12:1514-1523 (2009)
Mira et al. Cell Stem Cell, 7:79-89 (2010) (in collaboration)
Ferrón et al. Cell Stem Cell, 7:367-379 (2010)
Ferrón et al. Nature, 475:381-385 (2011) (in collaboration)
Marqués-Torrejón et al. Cell Stem Cell, 12:88-100 (2013)
Porlan et al. Nature Neuroscience,16:1567-75 (2013)
Porlan et al. Nature Cell Biology, 16:629-38 (2014)
Delgado-Fumero et al. Neuron, 83:572-85 (2014)
Adult tissue-specific stem cells
PHYSIOLOGICAL
Neoplasic mutations
CANCER
Tumour formation and recurrence
Self-renewal vs differentiation
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
NICHE INTERACTIONS
MOLECULAR REGULATION OF SELF-RENEWAL
PATHOLOGICAL
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.
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 6:326-35 (2007)
Synaptic
marker
TH
GFAP
Neurogenic niches in the adult mammalian brain
OB
Striatum
Frisen lab: 14C-based neuron birthdating
The Stem Cell Niche as a ‘‘Druggable’’ Target for Regenerative Medicine:
“Niche Therapies’’
Neurons
Immune/inflammatory
cells
O2 &
small ions
Neurotransmitters,
neuropeptides, synaptic
regulators
Adhesion & signalling receptors
(integrins, cadherins, GPCRs, Notch,…)
Perivascular &
endothelial cells
ECM
Stem
cell
Soluble factors
(growth factors, hormones,
chemokines,
neurotransmitters,…)
Support cells
(ependyma in the CNS)
Synaptic
plasticity
Adult
neurogenesis
Potential Entry Points for Niche-Directed Stem Cell Therapies
Stem cell expansion
Expand niches
High
engraftment
Stem
cells
Stem
cells
w/ niche
Ex vivo culture
Transplantation
w/o niche
Untreated
Low
engraftment
Alter niches
Stem cell loss
Biased cell type
production
Transplantation
Loss of stem cell niches
Aging/Disease
Rejuvenation
Endogenous targeting
Dysfunction of stem cell niches
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