1 1.Excretory system 2.Reproductive system F19_05 2 oExcretion of metabolites via filtration oRegulation of electrolyte amounts in body oWater reabsorption oRenin production by juxtaglomerulac cells – regulation of blood pressure oProduction of erytropoetin by kidney intersticial fibroblasts – regulation of erytrocytes number GH_19_14 3 odevelopment of excretory system tightly connected with development of reproductive system (intermediate mesoderm) oExcretory system developes earlier than reproductive oExcretory system is composed of: okidney oureter obladder ourethra somatopleura Neural tube Paraxial mesoderm Intermediate mesoderm amnion notochord splanchnopleura ectoderm endoderm Dorsal aorta kidney ureter bladder urethra 4 omesoderm localized intermediary – between paraxial mesoderm and lateral plate mesoderm oepiblast cells invaginate to space between newly formed endoderm (originally hypoblast) and forming ectoderm (originally epiblast) omigration of mesodermal cells cranialy, caudaly, lateraly oThree mesodermal zones: oParaxial mesoderm – closest to developing neural tube oLateral plate mesoderm – mesoderm localized on sides oIntermediate mesoderm – between paraxial m. and lateral plate m. somatopleura Neural tube Paraxial mesoderm Intermediate mesoderm amnion notochord splanchnopleura ectoderm endoderm Dorsal aorta 5 ofrom intermediate mesoderm differentiate pairs of nephrotomes – nephrogenic cords oCords formed by migration of cells from mesoderm lateraly from developing dorsal aorta opronephric region - cranially omesonephric region - caudally from pronephric region ometanephric region - caudally oThree paired basis of „kidney“ developmental stages Duke embryology Dorsal aorta Splanchnic mesoderm Somatic mesoderm Intermediate mesoderm Paraxial mesoderm oCells of nephrogenic cords migrate and form three nephrogenic segments along craniocaudal body axis: Pronephric region Mesonephric region Metanephric region Cranial part Caudal part somites cloaca 6 oKidney develop in two transitional stages, third stage is definitive: oTransitional – pronephros a mesonephros oDefinitive - metanephros oPronephros (pre-kidney) – first kidney tissue, gradual degradation oMesonephros (primary kidney) – second developmental stage, partial degradation, part is transformed oMetanephros (definitive kidney) – last stage, definitive kidney pronephros Degenerating pronephros mesonephros Degenerating mesonephros mesonephros developing metanephros Teach Me Anatomy cranial caudal 7 oRudimentary, non-functional kidney oformed ventraly from developing cranial somites oMesodermal cells form pronephric duct (tube) lateraly oCells of ducts migrate caudaly, cranial part of ducts induce formation of pronephric tubules from surrounding nephrogenic mesenchyme oPronephric tubules functional only in fish and larva of amphibians, non-functional in reptiles, birds and mammals oCranial part of ducts and tubules degenerate cranial caudal pronephros Pronephric duct Nephrogenic mesenchyme Edited: McGeady et al. Veterinary Embryology. 2009 dorsal ventral somites Pronephric tubule Pronephric duct Wolffian duct degeneration ocaudal part of pronephric ducts preserve excretory function during development - formation of Wolffian duct from caudal part of pronephric duct 8 Edited: McGeady et al. Veterinary Embryology. 2009 Dorsal aorta Inner glomerulus Outer glomerulus Pronephric duct Pronephric tubule oPronephric tubules formed on level of each cranial somite coelom oEach developing tubule is connected with nephrocoel cavity which opens to coelomic cavity through nephrostome obranching of capillary loops (glomerulus) from dorsal aorta, invaginate to: oEpithelium of coelom – outer glomeruli, filtration from coelom oWalls of tubule – inner glomeruli, separated from coelom oepithelium forming around loop of capillaries forms Bowmans capsule oOuter glomeruli oFormation in lower vertebrates, less effective filtration oFiltration of fluid is allowed thanks to activity of ciliated cells from coelomic cavity to pronephric tubules close to nephrostome 9 odegeneration of pronephros cranialy oWolffian duct induces development of tubules from adjacent nephrogenic mesenchyme oFormation of mesonephros – in some mammals (human) filtration is functional oInduction of tubule formation more caudaly omale – Wolffian duct as basis for epididymis and ductus deferens development cranial caudal Degenerating pronephros mesonephros Nephrogenic mesenchyme cloaca degeneration Wd Teach Me Anatomy 10 olateraly development of mesonephric ducts oInduction of mesonephric tubule formation medialy from nephrogenic mesenchyme omesonephric tubules connect laterally to mesonephric (Wolffian) duct oBowmans capsule enclose developing capillary loops of glomerulus from mesonephric arteries omesonephric arteries develop through branching directly from dorsal aorta otubules grow medialy and start to form Bowmans capsule Edited: McGeady et al. Veterinary Embryology. 2009 Basis of tubule mesonephric duct coelom Forming paramesonephric duct Dorsal aorta Mesonephric tubule Mesonephric duct glomerulus somite Mesonephric duct Paramesonephric duct Bowmans capsule Glomerular cavity Dorsal aorta Forming paramesonephric duct lateral medial 11 obasis for Müllerian duct development ofemales – basis for development of fallopian tubes, uterus, cervix and upper third of vagina omales - atrophies oDevelop lateraly of Wolffian duct from coelomic epithelium, so called Müllerian ridge oparallel development with Wolffian ducts in cranial region otransition of Müllerian ducts to ventral side in caudal region cranial caudal gonads Mesonephric duct (Wolffian) Paramesonephric duct (Müllerian) Corsoginho et al. 2016. ECR lateral medial 12 oFormation of definitive kidney (metanephros) caudaly from mesonephros oFormed from paired primordial structures – ureteral buds – outgrowths of mesonephric ducts Degenerating mesonephros mesonephros Metanephric nephrogenic mesenchyme Ureteral bud Nephric duct cranial caudal oBuds grow into nephrogenic mesenchyme (caudal region of nephrogenic basis) degeneration bud: orenal pelvis ocollecting tubules mesenchyme: omedulla ocortex ofrom buds are developed: orenal pelvis ocollecting tubules ocollecting tubules induce formation of mesenchymal structures: omedulla ocortex 13 obranching of renal pelvis – formation of collecting tubules ocollecting tubules induce formation of primitive tubules from metanephric mesenchyme oPrimitive tubules connect with collecting tubules and change their shape from straight to S-shaped (basis for proximal, medial and distal segment of nephron) othe other side of tubule forms cup (Bowmans capsule) surrounding capillary loops (glomerulus) – together form renal body Collecting tubule Primitive tubule developing tubule S-shaped tubule Capillary loops (glomerulus) Bowmans capsule straight tubule Edited: McGeady et al. Veterinary Embryology. 2009 14 Edited: McGeady et al. Veterinary Embryology. 2009 otubules develop, U-shaped prolongation – formation of Loop of Henle (passage towards renal pelvis) oTubules withdrawing from Bowmans capsule – proximal convoluted tubules ocollecting tubules connects to distal convoluted tubules orenal body, Loop of Henle, proximal and distal convoluted tubules - nephron ocortex – renal bodies, proximal and distal tubules omedulla – Loops of Henle, collecting tubules Collecting tubule Distal tubule Proximal tubule Loop of Henle Bowmans capsule glomerulus afferent arteriole efferent arteriole Collecting tubule Loop of Henle cortex medulla renal pelvis ureter 15 Trends in Genetics oGlomerular capillaries surrounded by podocytes – formation of glomerular membrane oMesangial myofibroblasts – smooth muscle cells of vessels, induce invagination and thus segmentation of capillary loops oParietal epithelium of Bowmans capsule – epithelial cells form capsule of glomerulus, potential role in regeneration (not clear yet) ofenestrated endothelium – endothelium of glomerular capillaries with pores for filtration of bigger molecules Mesangial myofibroblasts Parietal epithelium Glomerular basal membrane Fenestrated endothelium Podocyte protrusions podocyte 16 ocomma-shaped (straight) tubules – pre-podocytes with cylindrical shape, apical intercellular connections oS-shaped tubules – extension of apical sides of podocytes, intercellular connections moved to basal sides oFormation of capillary loops – induction of apical side expansion of podocytes around capillaries, formation of intercellular connections on basal side omature glumeruli – intercellular connections moved to spaces between podocytes protrusions and basal membrane, fusion of podocytes and endothelial cells basal membranes, formation of one glomerulal basal membrane Schell et al. 2014. Sem Cell Dev Biol Larsen Human embryology 2001 18 oRenal agenesis/dysgenesis oDevelopment of metanephric bud is altered or not developed at all, on one or both sides oPatients can live without one kidney oMissing both kidneys lethal perinataly oMulticystic kidney dysplasia oNephron not developed, ureteral bud is not branched oRenal tubules surrounded by non differentiated cells oOften bifid (cleft) ureter oHydronephrosis onarrowed connection between renal pelvic and ureter (stenosis) – altered drainage oExtension of renal pelvis oHigher preasure in cortex – loss of function osurgery Obsah obrázku text, kolo Popis byl vytvořen automaticky 19 oorigin – hindgut endoderm oLater divided by urorectal septum into: odorsal – part of colon, rectum oventral – urogenital sinus (ureter, bladder) omammals – transitional structure oreptiles, birds – permanent structure oCaudal part connected with external environment by cloacal membrane, ventraly connected to alantois Lewis and Kaplan, 2009. Cambridge University Press alantois Yolk stalk midgut hindgut Urorectal septum cloaca tailgut Cloacal membrane alantois Urorectal septum hindgut mesenchyme Cloacal wall strangulation proctodeum Urorectal septum Cloacal membrane Urorectal septum Urogenital sinus rectum Dev. bladder Urogenital membrane perineum proctodeum uror. septum rectum Anal canal Anal membrane Urogenital sinus Urorectal septum perineum rectum 20 oPersistent cloaca oCloaca is not divided orectum, vagina and urethra connected into one canal oMostly in place of developing urethra osurgery Boston Children`s Hospital 21 oVentral part of cloaca – urogenital sinus – divided into: ovesicular segment – cranial part, development of urinary bladder opelvic segment – middle narrower part omales – main part of urethra ofemales – whole urethra ophallic segment – caudal wider part omales – part of urethra in penis ofemales – vaginal vestible cranial caudal vesicular pelvic phallic rectum 22 oureters form by invagination of wall of Wolffian duct (ureteral bud) towards the nephrogenic mesenchyme (kidney development) oWolffian duct and developing ureter connect to developing bladder from cloaca oKidney migrate cranially, prolongation of developing ureters oUreters connected to cranial regions of bladder omales – Wolffian duct moved caudally, connected to urethra ofemales – Wolffian duct degrades Liaw et al. 2018. Differentiation oformation of bladder trigonum oMuscular tube important for active drainage of filtrate from kidney Mesonephric (Wolffian) duct Ureteral bud Posterior wall of bladder urethra Mesonephric (Wolffian) duct ureter urachus trigonum 23 oorigin – ventral side of hindgut endoderm, so called urogenital sinus oVentral side of cloaca – divided by urorectal septum oUrogenital sinus connected to allantois cranially, later degrades oBladder develops from vesicular segments (cranial part) of urogenital sinus cranially from ureters connection oRest is connected to allantois – bladder - urachus (bladder mesentery on ventral side) vagina clitoris Developing uterus Developing ovary kidney Fallopian tube urachus Urorectal septum rectum ureter bladder metanephros Mesonephric duct mesonephros 24 oregion of connection between ureter and Wolffian duct (future deferens duct in males) oregion of connection – urinary bladder trigonum otrigonum formed of urinary bladder smooth muscles, partly of smooth muscles from ureters obasis for formation of valves preventing return of urine back from bladder through ureters to kidneys – kidney damage ureter trigonum urethra Basis of ductus deferens (mesonephric duct) Prostate sac prostate Urogenital sinus Mesonephric duct residue (Gartners canal) female male 25 oUrinary bladder extrophy oUrinary bladder develops outside the body obladder cant keep urine inside - incontinence osurgery o Mayo Foundation for Medical Education and Research 26 ourethra develops from pelvic and phallic parts of urogenital sinus oorigin – hindgut endoderm, forms together with urinary bladder by division of urogenital sinus from ventral side of cloaca omales – pelvic and phallic regions of sinus, distal part of phallic region formed from ectoderm, connection of Wolffian duct (deferens duct) to urethra, connection of excretory and reproductive systems ofemales – pelvic region of sinus, Wolffian ducts degrade, ducts of excretory and reproductive systems separated cloaca Primitive urogenital sinus Primitive rectum Primitive rectum Primitive urogenital sinus Primitive urogenital sinus Primitive urogenital sinus Vesico-urethral canal Definitive urogenital sinus upper and lower parts of vesico-urethral canal pelvic (males, females) and phallic (males) part of urogenital sinus Urinary bladder urethra 27 oEpispadia oDisplaced opening of urethra oOpening on dorsal side of genitals oMore often in males oHypospadia oDisplaced opening of urethra oOpening on ventral side of genitals oMore often in males hypospadia (caudaly, connection with vagina) epispadia (cranialy) 28 oAdrenal cortex develops from intermediate mesoderm oAdrenal medulla develops from neural crest cells Pansky. Review of Medical Embryology ocortex – develops from epithelium of coelom in urogenital cord region cortex (intermediate mesoderm) medulla (neural crest) dorsal ventral omedulla –neural crest cells migrate to urogenital cord region omedullary cells covered by cortical cells Adrenal cortex precursors Adrenal medulla precursors 29 oAdrenal cortex develops from intermediate mesoderm oAdrenal medulla develops from neural crest cells Pansky. Review of Medical Embryology oNeural crest cells migrate to the region of developing cortex, cortical cells cover medullary cells oCortical cells differentiate and form layers: oZona reticularis (androgens) oZona fasciculata (glucocorticoids – cortisol, corticosterone) oZona glomerulosa (mineralcorticoids - aldosterone) oAdrenal medulla oChromaffin cells (catecholamines – adrenaline, noradrenaline) cortex medulla §Medulla – neuroectoderm §Neural crest cells form sympathetic ganglion in solar plexus = chromafinne cells + primitive sympathetic cells (noduli) §Travel to cortex (7th week iud) and along main vein get to its center § Cortex - intermediate mezoderm §Cluster of cells in urogenital ridge (5th week iud) – primitive cortex §Second wave of differentiation of mesotel cells (6th w iud) – definitive cortex §8th w iud – separaconnective tissue §Zona reticulata appears after 3rd year of life §Proliferation and apopttion from other organs by osis reshape primitive cortex in definitive c. § Human-adrenal gland 01.jpg https://basicmedicalkey.com/wp-content/uploads/2016/12/image06166.jpeg 14 w iud 8 w iud 31 oCongenital adrenal hyperplasia oaltered production of cortisol in zona fasciculata ohigher production of adrenocorticotropic hormone ohyperstimulation of adrenal cortex to produce hormone precursors ohyperplasia caused by storage of more precursors ooverproduction of androgens – formation of male sexual characteristics in females 32 33 oproduction of germ cells (oocytes, sperms) ostorage, maturation and transport of germ cells ofertilization and development of new individuals of a given species https://www.niehs.nih.gov/health/assets/images/reproductive_health2.jpg 34 oReproductive system: ofemale – ovaries, oviducts, uterus, vagina omale – testes, epididymis, ductus deferens, glands, urethra, penis somatopleura Neural tube Paraxial mesoderm Intermediate mesoderm amnion notochord splanchnopleura ectoderm endoderm Dorsal aorta 35 oPrimordial germ cells settle undifferentiated gonads (testes, ovaries) oepiblast cells migrate through primitive streak to yolk sac and alantois region oCells further migrate along the hindgut wall to genital ridge – region of developing gonads omammals – active migration of cells through surrounding tissues obirds – germ cells migrate via bloodstream omaturation in gonads – cells outside gonads die, preserved germ cells outside gonads can form teratomas Neural tube mesonefros Mesonephric duct metanefros Ureteral bud Urogenital sinus cloaca Genital ridge viteline-intestinal duct Primordial germ cells allantois gut gut Genital ridge Edited: McGeady et al. Veterinary Embryology. 2009 36 otumors developed from germ cells oformed from germ cells that did not reach gonads but did not die ooriginates in epiblast → tumor formed of tissues of all germ layers (ectoderm, endoderm, mesoderm) Obsah obrázku bezobratlí, měkkýši Popis byl vytvořen automaticky 21 (SRY gene – TDF) Primary female sexual differentiation is not hormone dependent – it occurs even if the ovaries are absent. ROLE OF SRY GENE Larsen Human embryology 2001 39 odevelopment of undifferentiated stage of gonads from 3 sources:: oIntermediate mesoderm mesenchymal cells oEpithelium of coelom oCells of mesonephric tubules odevelopment – genital ridges – on both sides medially from mesonephros oProtrusions into coelom covered by coelom epithelium oProlongation along craniocaudal axis (from thoracic to lumbar region) oUndifferentiated gonads settled by primordial germ cells ocells of mesonephros and mesonephric tubules – formation of rete tubular system Edited: McGeady et al. Veterinary Embryology. 2009 Mesonephric duct Genital ridge gut Developing paramesonephric duct Primordial germ cells Developing tubular system 40 oTubular rete system divided to 3 parts: oextra-gonadal cords oconnecting cords ointra-gonadal cords oproliferation of inner part of gonads – genital ridge getting rounded oconnection with adjacent mesonephros preserved oFormation of ducts: oWolffian ducts – from mesonephric ducts (male ducts) oMullerian ducts – from paramesonephric ducts (female ducts) Edited: McGeady et al. Veterinary Embryology. 2009 Paramesonephric ducts Mesonephric duct Intra-gonadal cords Extra-gonadal cords Connecting cords Degenerating mesonephric tubules Paramesonephric duct Connecting cords Intra-gonadal cords Extra-gonadal cords Mesonephric duct 41 Mesonephric duct Seminal cords gut Paramesonephric duct Edited: McGeady et al. Veterinary Embryology. 2009 oFormation of seminal cords from mesonephric cells on periphery → incorporation of germ cells oSeminal cords connect with mesonephric cells in center of gonads – onset of convolution of seminal cords – formation of seminiferous tubules oSeminal cords – solid (not hollow) structures formed of 2 cell types: operiphery – precursors of Sertoli cells ocentraly –precursors of sperms (pre-spermatogonial cells) 42 Edited: McGeady et al. Veterinary Embryology. 2009 oSeminiferous parts finally formed of: owall – Sertoli cells (support sperms development) ocenter – development of sperm precursors oIntersticial cells between seminiferous tubules parts: oIntersticial (Leydig) cells – mesodermal cells differentiate under influence of seminiferous tubules, testosterone production omesonephric cells in the center – formation of rete testis canals (web of tubules between seminiferous tubules and efferent ducts) oMesenchymal cells under the epithelium of coelom – formation of connective tissue - tunica albuginea osubsequent septa connected to tunica albuginea from mesenchymal cells between developing canals – lobe formation ocanalization – formation of tubules from seminiferous cords (adolescence) appendix epididymis Efferent ducts septum paradidymis Mesonephric duct rete testis appendix testis Degenerating paramesonephric ducts lobe tunica albuginea Sertoli cells pre-spermatogonial cells intersticial (Leydig) cells 43 pronephros Pronephric duct Nephrogenic mesenchyme Wolffian duct degeneration cranial caudal ocaudal part of pronephric ducts preserve its excretory function during development, formation of Wolffian (mesonephric) duct from caudal part of pronephric duct oPronephros form ventraly from developing cranial somites omesodermal cells form pronephric ducts lateraly ocranial part of ducts and tubules degenerate omales – Wolffian ducts serve for formation of epididymis, ductus deferens, ejaculatory ducts and seminal vesicles dorsal ventral somites Pronephric tubule Pronephric duct Edited: McGeady et al. Veterinary Embryology. 2009 ofemales – Wolffian ducts gradually degrade (no production of testosterone) 44 oIntensive cell proliferation leads to prolongation and formation of loops – onset of convoluting in proximal region, onset of convoluting efferent ducts oWolffian ducts grow towards cloaca, formation of mesonephric tubules from nephrogenic mesenchyme Joseph et al. 2010. Dev Biol oLuminization of Wolffian ducts, development of efferent ducts from mesonephric tubules (MT – connection between rete testis with epididymis) odistal starts to convolute later – formation of loops in whole epididymis oDuctus deferens is not convoluted Efferent ducts proximal distal Ductus deferens 45 oconnection of epididymis (EpD) and ejaculatory ducts (EjD) oprolongation of duct, formation of cells with cilia and development of thick smooth muscle layer – active transport of sperms obasis – middle part of Wolffian duct ofrom distal part of Wolffian duct ejaculatory ducts develops - connected to urethra oDuctus deferens – ejaculatory ducts interface region - development of seminal vesicles Bieth et al. 2021. Hum Genet 46 oFormation of paired evaginations (buds) from distal Wolffian duct into surrounding mesenchyme regulated by testosterone production oFurther growth and development – formation of prolonged vesicular structures oSecretory cells porduce supporting components of ejaculate: ofructose, proteins, enzymes, vitamine C osemenogelin – protein forming gell matrix Ductus deferens Ejaculatory duct prostate Seminal vesicles oSeminal vesicles – supporting glands of male reproductive system 47 oDevelops from urogenital sinus – ventral part after splitting cloaca oFormation of prostatic epithelial buds (4 pairs in mouse, compact gland in human) from urogenital sinus oCanalization from proximal part of bud - formation of ductal cavity oUrogenital mesenchyme – stroma formation – smooth muscle and connective tissue cells Kumari and Sinha, 2021. Peng and Joyner, 2015. central peripheral urethra bladder human mouse transitional Luminal cells Basal cells Branching of buds cavitation Solid buds, no lumen Prostatic buds 48 oCryptorchidism (undescended testiscle) oThe most often congenital defect of male reproductive system (25 %) oAbsence of at least one testes in scrotum oTesticle ofeten descend after the born (within 3 months) oSurgery if not oAnorchia oComplete missing of one or both testicles oRare (1:20000) ounknown origin 49 Edited: McGeady et al. Veterinary Embryology. 2009 Developing genital cords Paramesonephric duct Degenerating mesonephric tubules gut ogenital cords form from epithelium of coelom – incorporation of germ cells ogenital cords then degenerate – followed by intensive mitotic activity of germ cells omesonephric tubules start to degenerate and disintegrate 50 Edited: McGeady et al. Veterinary Embryology. 2009 Developing oviducts rete ovarii Primordial follicle Degenerating mesonephric ducts and tubules oogonia Follicular cells Primordial follicles oMitotic activity of oocytes precursor cells terminated (perinataly in mammals) oPrimordial oocytes after the last mitosis – oogonia – surrounded by cells originated in epithelium of coelom – follicular cells oformation of primordial folicles – germ cell enclosed with basal membrane surrounded by follicular cells 51 oParamezonephric duct – future Müllerian duct Tubule vesicle Mesonephric duct coelom Forming paramesonephric ducts Dorsal aorta Mesonephric tubules Nephric duct glomerulus somite Mesonephric duct Paramesonephric duct Bowmans capsule Glomerular cavity Dorsal aorta Forming paramesonephric ducts Edited: McGeady et al. Veterinary Embryology. 2009 oMesonephric ducts formed lateraly, gradual degradation in females oLateraly from mesonephric ducts fortmation of paramesonephric ducts 52 oBasis for Müllerian duct formation ofemales – formation of oviducts, uterus and upper third of vagina oMale – atrophies (Antimüllerian hormone, Sertoli cells) odevelopment lateraly from Wolffian duct, develop from epithelium of coelom, so called Müllerian ridge oIn cranial region, parallel development with Wolffian duct oIn caudal region, transition of Müllerian ducts ventrally cranial caudal gonads Mesonephric duct (Wolffian) Paramesonephric duct (Müllerian) Corsoginho et al. 2016. ECR lateral medial 53 odevelop from Müllerian duct, grow caudaly odevelopment of paired oviducts cranialy, oviducts connected caudaly – basis of uterus (proliferation in cranial region, extension) oConnection of oviducts – formation of uterine septum – degradation of septum results in cavity of uterus oOviducts: cranialy open to peritoneal cavity (contact with ovaries), caudaly connect to uterine horns oDeveloping uterus caudaly connected to endodermal sinovaginal bulbs – part of urogenital sinus close to uterus (originaly ventral side of cloaca) oVentral part of urogenital sinus divided into: oventral - urethra and bladder odorsal - vagina Bradshaw, 2012. 54 o2 sources: oUpper 1/3 – Müllerian duct (mesoderm) oLower 2/3 – Urogenital sinus (endoderm) oSeparation of ventral urogenital sinus: oventral – urethra and bladder odorsal - vagina oConnection between uterus and sinovaginal bulbs (vaginal plate), proliferation and fusion → formation of compact structure (no cavity) olater resorption of vaginal plate and canalization (apoptosis) – formation of vaginal cavity ovaginal cavity separated from urogenital sinus cavity by transversal membrane - hymen Sahar Hafeez oviduct Uterine cavity UG sinus Caudal part of paramesonephric ducts Sinovaginal bulbs (vaginal plate) Uterine vault cervix vagina hymen bladder urethra uterus Vaginal plate vagina Uterine vault Bi6140 Embryology 55 odevelopmental defects of uterus oAltered fusion of Müllerian ducts oDefects caused by insufficient degradation of septum oOften connected with defects of oviducts oCan lead to infertility and problems during pregnancy Obsah obrázku formičky na těsto Popis byl vytvořen automaticky oDevelopmental defects of vagina oOften connected with defects of uterus and cervix oVaginal septum – no fusion, split vagina o 56 obasis – indifferent stage composed of 3 parts: oGenital (phallic) tubercle (penis, clitoris) ourogenital (cloacal) folds (urethra, labia minora) olabioscrotal swelling (scrotum, labia majora) oExternal genitals form from all 3 germinal layers: oLateral plate mesoderm – stroma (clitoris, penis) oendoderm – urethra oectoderm – external cover by skin and its derivatives (hair) Herrera and Cohn, 2014. Sci Rep Genital tubercle Urogenital folds Labioscrotal swelling Genital tubercle Ventral limb bud Dorsal limb bud Development External Genitalia, 2011. 57 Genital tubercle Urogenital folds Labioscrotal swelling Development External Genitalia, 2011. oGenital tubercle oDevelopment of penis oUrogenital folds oFusion along the midline oFormation of enclosed urethra oLabioscrotal swelling oGrow towards the midline oFusion in along the midline oFormation of scrotum glans penis Urethral fold Urethral groove Scrotal swelling anus Glans penis penis Urethra opening Scrotal swelling scrotum anus foreskin 58 oHypospadia/Epispadia oDisplaced opening of urethra oOpening on ventral/dorsal sides oMore often in boys oscrotum bifidum oLabioscrotal swellings not fused along the midline oTesticles placed in two scrota 59 Genital tubercle Urogenital folds Labioscrotal swelling Development External Genitalia, 2011. oGenital tubercle oSlow growth oFormation of clitoris oUrogenital folds oNo fusion in the medial plane oPaired labia minora oLabioscrotal swelling oNo fusion in the medial plane oPaired labia majora glans clitoris Urethral fold Urethral groove Labial swelling anus clitoris Labia majora Opening of urethra Opening of vagina Labia minora anus 60 oLabial fusion oAbnormal labial fusion oVaginal opening is blocked oHypertrophy of labia majora oAbnormally enlarged labia majora oCause – congenital adrenal hyperplasia oClitoral defects oVery rare oBifid or duplex clitoris oHypertrophy – caused by adrenal hyperplasia § §1) Degenerating pronephros 1) §2) Wolffian duct § §3) Degrading mesonephros § §4) Metanephros § §5) Urogenital sinus § §6) Urinal Bladder anlage § §7) Müller´s duct 7 62 osupply tissues with neccesary molecules odisposal of waste products oone of the first functional systems during development: oembryo is growing → oExchange of nutrients and metabolites on long distances is no more effective → odevelopment of heart and vessels 63 §Open cardiovascular system oblood and tissue fluids are not separated - hemolymph oNot involved in gas exchange oenergetically less demanding oinvertebrates 64 Enclosed cardiovascular system oblood and lymph separated in vessels oblood is separated from tissue fluids ogas and nutrients exchange otransport of nutrients and metabolites on long distances overtebrates oDevelop from 3 sources: oLateral plate mesoderm – splanchnic part oParaxial mesoderm - somites oCardial neural crest 65 oDorsal aorta development o oHeart development o oDevelopment of vessels o oLymphatic organs and vessels development Splanchnic mesoderm somites Rothstein et al. 2018. Dev Biol oagregation of endothelial precursor cells from lateral plate mesoderm - endothelium osomites – endothelium, smooth muscle cells 66 opaired basis in cranial part of embryo, lateral from embryonic midline o Sato et al. 2012. Dev Gr Dif omammals, birds, reptiles – paired dorsal aorta basis ofish – single dorsal aorta basis oendothelial cells transit into hematopoietic cells oLateral embryo bending – paired aorta basis approach in the midline and fuse oHeart develops from 2 sources: 67 Neural crest splanchnic mesoderm oLateral plate mesoderm – splanchnic part oCardiac neural crest Santini et al. 2016. Dev Dorsal aorta 68 oProgenitor cells in epiblast – invaginate through primitive streak, formation of two groups of cells in splanchnic lateral plate mesoderm oMigration in cranial and lateral direction → cardiogenic mesoderm olateral cardiogenic mesoderm → primary heart field omedial cardiogenic mesoderm → secondary heart field Cardiogenic mesoderm Primary heart field Secondary heart field Kloesel et al. 2016. Anesthesia and Analgesia 69 cranial caudal oCranial part of secondary heart field opart of right atrium oregion of the receding heart vessels oCaudal part of secondary heart field oatrial myocytes omyocardium between atriums omyocardium of the venous heart side oPrimary heart field opartly ventricles oleft atrium opart of right atrium opaired heart tube basis – formation from cells of the primary heart field mesoderm 70 oLateral embryo bending – paired endocardial primordia approach each other oprimordia fuse in the embryonic midline oformation of left ventricle, parts of atria and parts of right ventricle Scott Gilbert. Developmental Biology 10th edition omyocardium forms from cells of the secondary heart field mesoderm Heart tube 71 McGaedy et al. 2006 opaired heart tube basis – formation from cells of the primary heart field mesoderm oCraniocaudal embryo bending – forming heart tubes (endocardium) translocates from cranial part of embryo to ventral otubes contact dorsal aorta and vitelline veins (from yolk sac) oafter the fusion – segmentation of heart tube oLateral embryo bending – medial approach of paired endocardial primordia, beginning of fusion Dorsal aorta Heart tube primordium oFormation of first segments: osingle chamber heart connects with vitelline veins (blood enters the heart) caudally and aortic sac cranially (blood exits the heart) 72 cranial caudal oTube bending: ooriginally - cranio-caudal direction onow – right-left polarity oSegmentation into two parts: oatrium (blood enters the heart) oventricle (blood exits the heart) oBending completion: ocranially – atria ocaudally - ventricles Pulmonary artery aorta Left ventricle Right ventricle Left atrium Right atrium Vitelline veins Scott Gilbert. Developmental Biology 10th edition oseptation of atria and ventricles – formation of septa from heart walls oCaudal region of the cranial neural crest olocalized between otic placode and 3. somite oendothelium of the aortic arch arteries oNeural crest cells migrate into 3., 4., 6. pharyngeal arches → migration to region of the developing aortic-pulmonary septum 73 Scott Gilbert. Developmental Biology 10th edition 74 oForamen ovale patens opermanent opening in septum between atria overy often defect, people are mostly not even diagnosed – functional problems are not common oTruncus arteriosus persistens ofailure in division of pulmonary trunk and aorta omixing of oxygenated and deoxygenated blood omanifests as blue skin (insufficient blood oxygenation) and heart failure osurgery is necessary oVessels develop by two different processes: 75 oangiogenesis – „budding“ and development of new vessels from existing vessels oboth embryonic and postnatal development ovasculogenesis – vessels develop from blood islands - splanchnic lateral plate mesoderm oembryonic development only splanchnic mesoderm dorsal aorta oDifferentiation of mesodermal cells into hemangioblast precursors: oblood cells (hematopoietic precursors) ovascular cells (endothelial precursors) 76 ohemangioblasts condensate forming blood islands Splanchnic mesoderm oBlood islands have two parts: oinner – blood cells precursors oouter – angioblasts, vascular cells precursors ointraembryonic and extraembryonic mesoderm Scott Gilbert. Developmental Biology 10th edition Bi6140 Embryology 77 oextraembryonic vasculogenesis oblood islands of the yolk sac oimportant for embryo nourishment oembryonic vessels formation oformation of hematopoietic cells for early embryonic stages Extraembryonic mesoderm Primitive blood cells Endothelial cells ointraembryonic vasculogenesis oformation of dorsal aorta omesoderm of individual organs ovessels form from mesodermal angioblasts in organs Intraembryonic mesoderm Organ-specific mesenchyme DeSesso, 2017. Rep Tox oouter layers of vessels (smooth muscle cells) partly formed from neural crest Bi6140 Embryology 78 oendothelial cells aggregation osmall vacuoles are formed in individual cells osmall vacuoles fuse and form larger vacuoles olarge vacuoles fuse with cellular membrane oformation of lumen Scott Gilbert. Developmental Biology 10th edition Bi6140 Embryology 79 oformation of intracellular vacuoles oformation of cavity/channel within one cell ofusion of cells on their ends owall of vessel is formed by membrane of one cell Scott Gilbert. Developmental Biology 10th edition Bi6140 Embryology 80 oBudding: oformation of tip cell from endothelial cell omigration of tip cell into surrounding mesenchyme oanother endothelial cells follow, cavity of vessel is maintained oLongitudinal splitting: oformation of the intraluminal pillar (walls of vessels invaginate into cavity), migration of the opposite endothelial cells into center of cavity oenlargement and fusion of pillars osplitting vessel into two vessels Tip cell Proliferating and migrating endothelial cells Intraluminal pillar formation DeSesso, 2017. Rep Tox Bi6140 Embryology 81 oprecursors of arteries – endothelium formation dependent on vascular endothelial growth factor (VEGF) ospecification – Ephrin B2 oarteries are formed earlier than veins oprecursors of veins – artery specification is blocked by presence of COUP-TFII receptor ospecification – Ephrin B4 oveins are formed later artery vein lymphatic vessel olymphatic precursors – from venous endothelial cells ospecification – Prox1 o VEGF/ EphB2 COUP-TFII/ EphB4 Prox1 Bi6140 Embryology 82 oDepends on existence of hematopoietic stem cells (HSC) oHSC are able to: oselfrenew (stem cells production) odifferentiate (production of hematopoietic precursors) oWhere and how are hematopoietic stem cells formed? Caocci and La Nasa, 2017. Med J Hem Inf Dis oDifferentiate into myeloid and lymphoid progenitors oproduction of specific blood cell types Bi6140 Embryology 83 oHematopoietic precursors are embryonically formed in: oyolk sac oaorta-gonad-mesonefros ovessels of placenta, umbilical cord, liver, spleen, thymus, bone marrow Bi6140 Embryology 84 oExtraembryonic hematopoiesis phase odevelops from splanchnic lateral plate mesoderm oblood islands are formed in yolk sac wall Yolk sac Bi6140 Embryology 85 ointraembryonic development of hemetopoietic precursors omesoderm surrounding aorta, developing urogenital system and adrenal cortex ohematopoietic precursors differentiate from endothelium of developing vessels Sugimura et al., 2019. Biomed Microdev Bi6140 Embryology 86 oMore than one theory: oHemangioblast theory oHemogenic endothelium theory oMesodermal prehematopoietic precursor theory Bi6140 Embryology 87 Hemogenic endothelium theory Mesodermal prehematopoietic precursor theory ohemangioblast is formed from mesoderm ohemangioblast derivatives: ohematopoietic precursors oendothelial precursors ohemagioblast precursors differentiate in yolk sac oapplicable theory for early hematopoiesis phases Rossmann et al., 2016. Curr Biol Bi6140 Embryology 88 Mesodermal prehematopoietic precursor theory Hemangioblast theory oHemogenic endothelium forms from endothelial cells in aorta-gonad-mesonephros region oMesoderm from regions around developing aorta, urogenital system and adrenal cortex oHemogenic endothelium can differentiate into lymphoid and myeloid precursors oapplicable theory also for definitive phases of hematopoiesis o Rossmann et al., 2016. Curr Biol Primitive erytroid cells Endothelial cells Entothelial progenitors Hemogenic endothelium Bi6140 Embryology 89 Hemangioblast theory oTheory combining previous theories: oboth theories are valid – consecutive parts of hematopoietic and endothelial cells development ohemangioblast derivatives: oendothelial precursors ohematopoietic precursors ohematopoietic precursors develop from endothelial cells Rossmann et al., 2016. Curr Biol Hemogenic endothelium theory oEndothelial-hematopoietic transition: oendothelial cells loose their epithelial character oreleasing from vessel walls omigration to lumen of vessel Bi6140 Embryology 90 oHereditary hemorrhagic telangiectasia oarterial-venous malformation omissing connecting cappilaries between arteries and veins onose bleeding, bloody spots on skin oCerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL) odefects in skin and brain arteries odegeneration of smooth muscle cells in vessels oaccumulation of fibrous tissues around arteries onarrowed artery transit omigrains, dementia, stroke oAlagile syndrome onarrowing of big arteries including aorta oconnected with defects in skeletogenesis and formation of face Bi6140 Embryology 91 oblindly-terminated system of tissue vessels oabsorbtion and drainage of tissue fluid oenters venous system through lymphatic vessels otransporting antigens and antigen-presenting cells to lymphatic nodes → immune response olymphatic vessels develop from veins odevelopment of lymphatic organs: olymphatic nodes ospleen othymus Alderfer et al., 2018. J Biol Eng Bi6140 Embryology 92 oLymph nodes: ovessels in lymphatic sac ostroma and capsule oLymphatic vessels omesenchyme originates in mesoderm – from vascular endothelium ostroma: omesenchyme originates in mesoderm omesenchyme induces migration of LTiC to sac surrounding – basis of node (LTiC originate in hemogenic endothelium) oLTiC induces mesenchyme in developing node – formation of LToC oLToC differentiation – formation of all stromal cell types of node onode induces migration of lymphocytes into node oinitiation: olymphatic vessels branching – lymph sac is produced olymph sac is settled by mesemchymal precursors of stroma mesenchymal cells migration induction Lymphoid tissue inducer cells (LTiC) reverse activation Lymphoid tissue organising cells (LToC) induction Lymphocyte migration Edited. Nosenko et al., 2016. Acta Natur 93 oembryonically – production of hematopoietic cells oImmune organ, erythrocyte degradation oDevelops from splanchnic lateral plate mesoderm (mesenchyme surrounding stomach and pancreas) oSpleen vessels – branching from dorsal aorta ostroma: oventral from aorta – bilateral splanchnic mesodermal plate (cylindrical epithelium), surrounded with splanchnic mesoderm oright – plate replaced by splanchnic mesoderm oleft – plate cells proliferate, growth omesenchymal cells under the plate proliferate and differentiate oFormation of spleen, mesothelial sheath on surface Brendolan et al. 2007. BioEssays 94 Gordon and Manley, 2011. Dev odevelopment of T-lymphocytes odevelops from 3 sources: oForegut endoderm oNeural crest omesoderm - vessels oForegut endoderm – 3. pharyngeal pouch of pharyngeal arch (gut epithelium) oEndodermal evagination – formation of epithelial sac surrounded by mesenchymal capsule oformation of primordial thymus and parathyroid gland oThymus detaches from endoderm and migrate oNeural crest – mesenchymal capsule, partly vessels till 6th week iud – epithelial tissue from 7th week – formation of mesenchymal septa after 9th week – population with blood cells (T cell) Mezoderm Endoderm (pouches) q2c_thymusA http://www.embryology.ch/anglais/qblood/lymphat03.html Mandibular arch Hyoid 3rd pouch 4th pouch Foramen caecum Thyreoid Phrayngeal cleft Thymus (from 3rd pouch) Parathyroid and ultimobrachial body (from 4th pouch) till 6th week iud – epithelial tissue from 7th week – formation of mesenchymal septa after 9th week – population with blood cells (T cell) Ectoderm (neural crest) Neural crest – mezenchyme capsula, partially veins Cytokin TSLP Thymic Stromal Lympho poietin THYMUS - CHILD Maximal aktivity – puberty T lymphocytes fate??? THYMUS - ADULT Functional Involution §24th day of iud the endoderm on the floor of pharynx swells §Formation of bud and its prolongation around the hyoid bone §The anlage migrates toward the base of trachea §Co-migration of superior parathyroid (dorsal part of 3rd pouch) § thymus (ventral part of 3rd pouch) § inferior parathyroid (dorsal part of 4th pouch) § ultimobrachial body (ventral part of 4th pouch) §7th week – definitive location and shape § § 98 https://basicmedicalkey.com/wp-content/uploads/2016/07/C2-FF1-1.gif https://basicmedicalkey.com/embryology-and-developmental-lesions/ Bi6140 Embryology 99 oLymphedema – enlarged lymphatic vessels in tissues results in insufficient lymph drainage oSpleen defects: oLobular spleen – „clefts“ as remnants of defective development, no functional defects oWandering spleen – missing fibrous spleen attachments in the abdominal cavity oCystic hygroma – cystic neck lymphangioma opolycystic oformation of cysts in lymphatic regions, endothelial lining ocontains clear liquid oneck region – causing respiration problems and food intake problems Obsah obrázku osoba, interiér, dítě Popis byl vytvořen automaticky