CURS 1: MEDICINA DEZVOLTARII UMANE
INTRODUCERE IN EMBRIOLOGIE, CELULE
GERMINALE PRIMORDIALE
Conf. Dr. B. A. Voiculescu
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DE AICI INCEPE TOTUL… FIECARE DINTRE NOI A
FOST CANDVA UN… OU
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PRIMA SAPTAMANA
Zigot- diviziuni mitotice- rezulta blastomere
Embrionul cu 32 de blastomere= morula
Prin compactare si cavitatie, din morula se
formeaza blastocistul sau blastula
Blastocistul ajunge in cavitatea uterina si
elimina zona pellucida
Incepe implantarea pe peretele posterior al
uterului
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PRIMA SAPTAMANA
BLASTOCISTUL
O masa interna de celule= embrioblast, din
care se va forma embrionul
O masa externa de celule= trofoblast, ce va
forma anexele embrionare
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INITIEREA IMPLANTARII
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1 zona pellucida
2 trofoblast
3 hipoblast
4 blastocel
5 epiblast
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SAPTAMANA A 2- A
Trofoblastul se diferentiaza in:
sincitiotrofoblast (extern)
citotrofoblast (intern)
Embrioblastul:
Se subdivide in hipoblast si epiblast, formand discul bilaminar
Hipoblastul- celulele migreaza de-a lungul citotrofoblastului, formand sacul yolk primar
Epiblastul formeaza cavitatea amniotica
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SAPTAMANA A 2-A
Mezodermul extraembrionar
Origine controversata- din citotrofoblast/ epiblast/
citotrofoblast + epiblast
Migreaza intre citotrofoblast si sacul yolk/ cav
amniotica
Caviteaza, fomand:
Cavitatea corionica
Mezodermul somatic (sub CT)
Mezodermul visceral ( in jurul embrionului)
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SAPTAMANA A 2- A
La sfarsitul saptamanii implantatia se termina,
embrionul e alcatuit din:
2 cavitati emisferice
- Amniotica (dorsala)
- Yolk= vezicula ombilicala (ventrala)
Hipoblast + epiblast= disc embrionar didermic
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DISCUL BILAMINAR
Epiblast= strat germinal dorsal
Hipoblast= strat germinal ventral
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SAPTAMANA A 3-A
Formarea liniei primitive- mediana, de-a lungul
axei cranio- caudale- prin proliferarea si
migrarea celulelor epiblastice
Capatul anterior al liniei primitive- incepe sa se
adanceasca si formeaza santul primitiv, ce are
la extremitatea craniala nodul primitiv
(extremitate cefalica)
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SAPTAMANA A 3-A
Are loc formarea discului trilaminar prin
aparitia celei de-a treia foite embrionare-
mezoblastul
Procesul= gastrulatie, dar noul termen preferat
este tranzitie epitelio- mezenchimala
Mezoblastul se formeaza din celulele
epiblastice, care migreaza prin linia primitiva
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MIGRAREA CELULELOR EPIBLASTICE
Primele care migreaza, inlocuiesc celulele hipoblastice si formeaza endoblastul definitiv
Alte celule migreaza in directie craniala prin nodul primitiv si formeaza:
Placa precordala
Procesul notocordal
Cea mai mare parte dintre celule migreaza intre hipoblast si epiblast si formeaza mezoblastul intraembrionar
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DISCUL TRILAMINAR
STRATUL GERMINAL DORSAL= ECTOBLAST/
ECTODERM
STRATUL MIJLOCIU (AL TREILEA IN ORDINEA
FORMARII)= MEZOBLAST/ MEZODERM
STRATUL VENTRAL= ENDOBLAST/ ENDODERM
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RETINETI
EPIBLASTUL ESTE PRECURSOR PENTRU:
- ECTOBLAST/ ECTODERM
- MEZOBLAST/ MEZODERM intraembrionar +/ - extraembrionar
- ENDOBLAST DEFINITIV/ ENDODERM intraembrionar (visceral)
HIPOBLASTUL ESTE PRECURSOR PENTRU:
- ENDODERM EXTRAEMBRIONAR (VEZICULA OMBILICALA SI ALANTOIDA)
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CELULE GERMINALE PRIMORDIALE
celula progenitoare care va forma gametii la
ambele sexe
la toate speciile de vertebrate, morfologia si
proprietatile histochimice sunt asemanatoare
CGP- celule mari, rotunde, cu un nucleu mare,
heterocromatic
citoplasma bogata in ribozomi si mitocondrii
(activitate metabolica intensa- sinteza proteica),
aparatul Golgi si RER slab reprezentate.
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CGP
La om, citoplasma contine numeroase granule
de glicogen si lipide.
Prezinta o intensa activitate fosfataz- alcalina
pozitiva.
Nu se cunoaste rolul acestei enzime in celuele
germinale, insa este importanta pentru
identificarea lor.
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ORIGINE EMBRIONARA
Originea lor este in epiblastul proximal in
saptamana a 2- a.
Aparitia este conditionata de prezenta unor
factori de crestere secretati de ectoderm
extraembrionar si endoderm visceral
De la origine migreaza catre crestele genitale
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BMP
Bone morphogenic protein
grup de factori de crestere ai marii familii TGF-b
- transforming growth factor
BMP1 nu face parte din aceastã familie
20 de proteine- GM= 10 si 30 kDa
Se fixeaza de un receptor heteromeric (BMP-R),
aflat pe membrana celulei tinta- douã
subunitãti tip I si douã subunitãti tip II.
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BMP
Subunitãtile tip II sunt kinaze ce pot fosforila un rest serinic sau treoninic de pe subunitatea tip I adiacentã
In citoplasma celulei tinta
SARA- proteina adaptoareo nouã fosforilare a unui grup de proteine
R-smad- proteina aflata in stare nefosforilata, inactiva
Prin intermediul SARA, R- Smad se fosforileaza
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BMP
R-smad fosforilate formeazã complexe cu
proteine adiacente numite Co- smad.
Complexul se deplaseazã în nucleu, unde se
leagã de secvente specifice din ADN (elemente
de rãspuns ale BMP) si activeazã anumite
gene, ce determina sinteza unor proteine
specifice- initiaza diferentierea celulelor
epiblastice in CGP
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IMPORTANTA BMP SI A CAII SALE
Cãile de semnal ce implicã BMP, BMP-R si
Smad sunt importante în :
diferentierea CGP,
dezvoltarea cordului,
dezvoltarea SNC,
dezvoltarea cartilajului,
sistemului nervos enteric,
dezvoltarea osoasã postnatalã.
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CALE DE SEMNALIZARE BMP
Receptorii reglati de
Smad sau R-Smad se
asociazã cu receptorul
de tip 1, printr-o proteinã
adaptoare numitã SARA
(Smad Anchor for
Receptor Activation).
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INDUCTIE CGP
Factori secretati de ectoderm si endoderm sunt
decizionali in diferentierea celulei epiblastice in
CGP
Celulele epiblastului proximal nu sunt
restrictionate la linia germinala primordiala,
dand nastere si unor celule somatice de la
nivelul alantoida si s-ar parea ca si al
mezodermului extraembrionar
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INDUCTIE CGP
Ectodermul secreta
BMP4, semnalul inductor primar- interactiune
Smad 5
Apoi BMP4 si BMP8b- Smad 1, -5- diferentiere si
localizare- doar 40 de celule epiblastice se vor
diferentia in CGP
Endodermul secreta
BMP2- diferentiere
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INITIEREA MIGRARII
Sub actiunea factorilor BMP, celulele
precursoare CGP exprima proteina fragilis
(IFITM), care:
marcheaza initierea diferentierii ca celule
germinale primordiale
are rol de adeziune intercelulara
Odata cu formarea celulelor fragilis + incepe
separarea de celule somatice, formandu-se o
aglomerare de precursori CGP
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INDUCTIE CGP
Apoi, o parte din celulele fragilis + exprima
proteina stella, detectata exclusiv la linia
germinala primordiala
La nivelul celulelor fragilis, stella + nu sunt
exprimate proteinele Hox 1, specifice celulelor
somatice
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INDUCTIE CGP- BLIMP 1
In afara de factorii mai sus amintiti, care induc diferentierea cel epiblastice in CGP, exista un represor transcriptional numit Blimp1 (Prdm1)
Inhiba sinteza factorilor somatici la nivelul precursorilor CGP
Soarecii mutanti Blimp1 negativi- se formeaza in jur de 20 de celule primordiale (in loc de 40), asemanatoare CGP, dar care nu au proprietatile acestora: migrare, proliferare si represia genelor somatice (Hox1)
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MIGRARE
In saptamana a 3- a, CGP migreaza din ectodermul primar in peretele sacului vitelin, prin miscari ameoboidale.
Apoi ajung la baza alantoidei.
Astfel, au devenit extraembrionare, fiind asezate in endodermul si mezodermul peretelui sacului vitelin.
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MIGRARE
Intre saptamanile 4- 6, ajutate de curbarea
cranio- caudala si laterala a embrionului,
celulele germinale primordiale migreaza din
nou in embrion
Migreaza de-a lungul peretelui alantoidei si a
intestinului primitiv posterior (metenteron)
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MIGRARE
Dupa ce traverseaza mezenterul dorsal, colonizeaza crestele gonadale.
In cursul acestei calatorii, celulele se multiplica mitotic, astfel incat se pare ca ating un numar de zeci de mii in momentul in care populeaza crestele gonadale.
Mecanismele migrarii sunt incomplet intelese
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Migrarea celulelor germinale primordiale
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Pasul 1. CGP la soarece, cu originea in epiblastul proximal, migreaza de la linia
primitiva la endoderm (viitorul intestin dorsal)
Pasul 2. CGP migreaza de-a lungul endodermului
Pasul 3. CGP migreaza bilateral catre peretele posterior al abdomenului
Pasul 4. CGP ajung in crestele genitale
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TIPURI DE MIGARE
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MECANISMELE MIGRARII
Sunt incomplet intelese, dar se realizeaza pe doua cai:
1. adeziune controlata, care implica existenta unui receptor pe CGP si a unei substante cu rol de ligand, secretate de tesuturile caii de migrare
2. prin chemotactism, ce implica secretia unor factori chemotactici de catre tesuturile tinta (ex, creasta gonadala)- CGP se deplaseaza catre concentratia maxima a acestor substante
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INITIEREA MIGRARII
CGP capata motilitate la scurt timp dupa
formare
In momentul initierii migrarii, CGP capata
morfologie caracteristica- devin polarizate si
prezinta pseudopode/ extensii citoplasmatice
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MORFOLOGIE, POLARITATE
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INITIERE
La soarece, migrarea directionata necesita initial o activitate repelenta a factorului IFITM1 (interferon- induced transmembrane protein) exprimat de mezoderm
Are rol de respingere a celulelor din mezoderm in endoderm si implicit in activarea comportamentului migrator (CGP evita tesuturile ce exprima IFITM1)
IFITM= fragilis
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CALEA MIGRATORIE
In intestinul posterior
prin IFITM3 si E- caderina IFITM3- exprimata in CGP, rol necunoscut (insa in mod sigur
are rol in migrare)
E- caderina- molecula de adeziune exprimata in intestin, nu de CGP in acest stadiu- rol in mentinerea CGP in intestin
Supravietuirea si proliferarea CGP- cuplul C-kit/ Steel C- kit- receptor- pe CGP
Steel- ligandul c- kit- pe tesuturile somatice
La soarece, in stadiul E9,5- parasesc intestinul
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PGC SUNT MOBILE, IN INTESTIN; CELULELE
NOTOCORDULUI SE MISCA SPRE POSTERIOR PE
MASURA CE EMBRIONUL CRESTE
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CGP PARASESC INTESTINUL SI MIGREAZA
CATRE CRESTELE GENITALE
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CALEA MIGRATORIE
Catre crestele genitale
Dupa ce parasesc intestinul, se impart in doua
grupuri- pentru fiecare creasta
Migreaza din intestin individual, dar interactioneaza
intre ele prin extensii subtiri citoplasmatice- retea
de celule migratorii
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CALEA MIGRATORIE
SDF1- secretat de mezenchim si de crestele
genitale, reprezinta un factor chemotactic pentru
CGP
CXCR4- receptorul pentru SDF1- pe CGP
Pe langa rolul in migrare, SDF1 are rol si in
supravietuirea celulelor- cele ce parasesc ruta mor
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PGC IMPARTITE IN DOUA GRUPURI MIGREAZA
CATRE CRESTELE GENITALE
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OPRIREA MIGRARII
Se pare ca aceleasi molecule care au ghidat
migrarea, prezente in cantitate mare la nivelul
crestelor gonadale, determina si oprirea lor
Cantitati mari de SDF1 reprezinta un semnal stop
Celulele devin rotunde, isi pierd polaritatea, adera
intre ele, de celulele somatice din jur si de
matricea extracelulara prin molecule de adeziune-
E-caderina si integrina B1, exprimate de CGP
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VA MULTUMESC! 53
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