Hipokanpoko Zelula Ama Neuralak: Garapenetik Patologiara Hipokanpoko zelula ama neural helduen jaio ondorengo tokiko sorrera eta hazkuntza faktore epidermal hartzailearen blokeoa lobulu tenporaleko epilepsian neurogenesia babesteko
44 bisita jaso dira
Autoretza:
Oier Pastor Alonso
Zuzendaria:
José Ramón Pineda Martí, Juan Manuel Encinas Pérez
Unibertsitatea:
Euskal Herriko Unibertsitatea
Fakultatea:
Medikuntza eta Erizaintza Fakultatea
Saila:
Neurozientziak
Jakintza-arloa:
Medikuntza
Urtea:
2020
Hizkuntza:
Ingelesa
|Ugaztun gehienen burmuina neurona berriak sortzeko gai da bizitza osoan zehar, jaio ondorengo aroa eta helduaroa barne, neurogenesi heldua bezala ezagutzen den prozesu baten bitartez. Gaur egun ongi jakina da prozesu neurogeniko heldu osoa zelula ama neural (ingelesetik neural stem cell; NSC) helduetan oinarritzen dela. Zelula hauetatik jaiotzen dira aurretiaz ezarritako zirkuituetan integratuko diren neurona berriak, behintzat burmuinaren bi zonaldetan; bentrikulu lateraletan aurkitzen den gune azpibentrikularrean (ingelesetik subventricular zone; SVZ) eta hipokanpoko formazioko (ingelesetik hippocampal formation; HPF) horzdun zirkunboluzioan (ingelesetik dentate gyrus; DG) aurkitzen den gune azpigranularrean (ingelesetik subgranular zone, SGZ). Azken honetan jazotzen dena hipokanpoko neurogenesi heldu (ingelesetik adult hippocampal neurogenesis, AHN) bezala ezagutzen da, tesi honetan jorratuko duguna.
Saguetan, SGZko ahalmen neurogenikoa denborarekin murriztu egiten dela deskribatu da. Adinarekin erlazionaturik dagoen AHNaren murrizketa hau NSCen agortzeagatik jazotzen dela proposatu da, neurona aurrekariak sortzeko ziklo zelularrean barneratzen diren (bestela esanda, aktibatuak izaten diren) NSCek prozesuaren ostean pairatzen duten diferentziazio astrozitiko edo neuronalaren ondorioz. Gainera, nahiz eta SGZ helduan NSCen auto-errepikapena posiblea dela deskribatu den ez da NSC populazioaren agorpen progresiboari aurre egiteko gai. Honela, norbanakoaren ahalmen neurogenikoa hasierako NSC kopuruak baldintzatzen du. Honen harira, NSCen jatorria ondo ezagutzen ez den arren, hauek zein AHNa jaio aurreko hipokanpoaren garapeneko hondakin bat direla da zabalduen dagoen ikuspegia.
Gizakietan, AHNaren benetako jazoera eta hedadura historikoki debate beroak sorrarazi dituen gaia izan da. Duela gutxi, debatea berpiztua izan zen umezarotik aurrera AHNaren gabezia argitaratu zuen ikerlan baten ondorioz. Hala ere, beste autore batzuek doblekortina (ingelesetik doublecortin, DCX) espresatzen duten zelulen presentzia adierazi izan dute DG helduko SGZan, AHNaren izatea ondorioztatuz. Gaurdaino, bi ikuspegi kontrajarriek eztabaidapean diraute.
Tesi honen lehengo zatian, NSC helduen garapeneko jatorriari helduko diogu. Honetarako, DGaren jaio ondorengo garapena ziklina D2rik (ingelesetik cyclin D2, cD2) gabeko sagu transgeniko lerro batean ikertu genuen, zeina NSCak behar bezala Hipokanpoko NSCak: Garapenetik Patologiara ikusaraztea ahalbidetzen duen Nestin-proteina fluoreszente berde (ingelesetik green fluorescente protein, GFP) sagu transgeniko batekin gurutzatua izan zen. Jaio ondorengo burmuineko eremu ezberdinetan ugaritzen zeuden zelulak markatu eta haien leinuaren jarraipena egiteko, eremu espezifikoetara zuzenduriko infekzio retrobiralak erabili genituen. Emaitzek adierazten dutenez, NSC helduen populazioa tokian sortzen da DGan jaio ondorengo lehen 2-7 egunen artean eta cD2ren menpeko prozesu baten bitartez. Aurkikuntza honek NSC helduek garapeneko sortzaileengandik ezberdina den populazio bat osatzen dutela iradokitzen du, jaio ondoren sortuak izanda era independente batean. Hala, jaio ondorengo eta helduaroan zehar ematen den AHNa ez da jaio aurreko garapenaren hondakin soil bat. Emaitza hauek babestuz, garapeneko NSCek aurkezten ez duten biomarkatzaile baten espresio diferentziala aurkitu genuen. Azido lisofosfatidiko 1 hartzailea (ingelesetik lysophosphatidic acid receptor 1, LPA 1 )-areagoturiko proteina fluoreszente berdea (ingelesetik enhanced green fluorescent protein, EGFP) sagu transgenikoa erabiliz, LPA 1 NSCetan jaio ondorengo 10-14 egunetatik (ingelesetik postnatal, P10-P14) aurrera espresatua izaten hasten dela ikusi genuen, hortik aurrera bere espresioak hipokanpoko NSCetan dirauelarik.
Esan bezala, AHNaren existentzia gizakietan azkenaldian eztabaida beroa sortu duen gaia izan da guztiz kontrajarriak diren emaitzak argitaratu direlarik. Arazoari garapen ikuspegi batetik helduz, giza etaThe brain of most mammals is capable of producing newly born neurons during the whole life, including postnatal and adult periods, throughout a process called adult neurogenesis. It is now well-established that the core cells that fundament the whole adult neurogenic process are adult neural stem cells (NSCs). These cells give birth to neurons that integrate into the existent circuitry in at least two regions of the brain; the subventricular zone (SVZ) of the lateral ventricles (LVs) and the subgranular zone (SGZ) of the dentate gyrus (DG). The DG is part of the hippocampal formation (HPF) and therefore, the neurogenic process here is termed adult hippocampal neurogenesis (AHN).
In mice, it was described that the AHN diminishes over time. Indeed, a dramatic neurogenic decline is associated with aging and it has been proposed to occur mainly because of NSC depletion, due to the ultimate astrocytic or neuronal differentiation of those NSCs that enter the cell cycle (“get activated”) to generate neuronal precursors. Although self-replication of NSCs is possible in the adult SGZ it is not enough to outpower the progressive depletion of the NSC population. Therefore, the total neurogenic capacity of an individual will be determined by the initial number of NSCs. Although the origin of adult NSCs is not well known, the generally accepted view in the field is that they, as well as the process of AHN, are a remnant from the embryonic hippocampal development.
In humans, the actual occurrence and extent of AHN has been historically subject of fierce debate. Recently, the debate got rekindled due to a controversial work reporting the absence of AHN from childhood onwards. However, other authors have reported the presence of doublecortin (DCX)-expressing cells in the SGZ of the adult DG, inferring thus the presence of AHN. The two opposing views remain under debate up to this day.
In the first part of this thesis, we address the developmental origin of adult NSCs. For that, we studied the postnatal development of the DG in a knock-out mouse for cyclin D2 (cD2) crossed with a Nestin-Green fluorescent protein (GFP) transgenic line of mice in which NSCs are readily visualized. We also used region-targeted retroviral infections to permanently label dividing cells and their progeny in different regions of the postnatal brain. The results indicated that the adult population of NSCs is “Hippocampal NSCs: from Origin to Pathology” generated on-site in the DG around postnatal days 2-7 through a cD2 dependent process. This suggests that adult NSCs comprise a separated population from developmental progenitors, being generated postnatally in an independent manner. Therefore, the process of postnatal and AHN is not a mere continuation of the embryonic development. These results are also supported by the differential expression of a biomarker that is not present in developmental NSCs. Using the transgenic lysophosphatidic acid receptor 1 (LPA 1 )-Enhanced green fluorescent protein (EGFP) mouse model, we observed that LPA 1 starts to be expressed in NSCs only from postnatal day 10-14 (P10-P14) onwards, and then its expression remains throughout adulthood in hippocampal NSCs.
As mentioned, the existence of AHN in humans recently became a hot topic in the field with strongly controversial results being reported. Addressing the issue from a developmental point of view, we described that human and mouse developmental processes may follow different temporal dynamics, although sharing similar formation patterns. In contrast to mouse, where the DG develops mainly postnatally, in humans it is almost completely formed by mid-gestation. However, radial glia cell (RGC) populations are still present early after birth. Indeed, the existence of a population of NSCs in the human DG after birth (independent on the temporal extent) could be of great importance in pathological conditions.
The loss, disrupti
