1 DEVELOPMENT OF GASTROINTESTINAL SYSTEM FUNCTION OF GASTROINTESTINAL SYSTEM 2 o food intake and processing o absorption of nutrients o excretion of waste products Obsah obrázku interiér, zavřít Popis byl vytvořen automaticky DEVELOPMENT OF GASTROINTESTINAL SYSTEM IN VERTEBRATES 3 osources of precursor cells of gastrointestinal system oEndoderm: opharynx oesophagus ostomach ointestine oEctoderm: ooral cavity oglands oteeth oanus oMesoderm: ovessels omuscles oNeural crest: oteeth omuscles oupper and lower jaws onerves DEVELOPMENT OF ORAL CAVITY 4 oformation of facial prominences – mesenchymal swellings Duke Embryology DEVELOPMENT OF THE PALATE 5 oPalate composes of two parts: oPrimary palate – anterior, frontonasal prominence oSecondary palate – lateral palatal shelves, maxillary prominence omedial nasal prominences pushed medially by maxillary prominences oIntermaxillary segment formation – formation of primary palate, philtrum, parts of nose oMaxillary prominences grow medially ogradual separation of oral and nasal cavivites omedial fusion in some species oanterior - hard palate oposterior – soft palate ointerspecies variability Worley et al. 2018. Clin Perinat DEVELOPMENT OF THE PALATAL SHELVES AND SECONDARY PALATE 6 opalatal shelves medially outgrow from maxillary prominences (mesenchyme from neural crest, stomodeal epithelium from ectoderm) otongue prevents horizontal growth – vertical growth along the tongue overtical head elongation, tongue recedes ventrally, palatal shelves reorient into horizontal plane oconnection of opposite palatal shelves, formation of epithelial seam apoptosis EMT oepithelial cells undergo apoptosis and epithelial-mesenchymal transition → fusion and complete palate formation Schoen et al. 2017. Front Physiol Nakajima et al. 2018. Int J Mol Sci SECONDARY PALATE VARIABILITY 7 Obsah obrázku text Popis byl vytvořen automaticky Obsah obrázku text Popis byl vytvořen automaticky Obsah obrázku text Popis byl vytvořen automaticky Obsah obrázku text Popis byl vytvořen automaticky Obsah obrázku text Popis byl vytvořen automaticky Obsah obrázku text Popis byl vytvořen automaticky fusion of palatal shelves – complete palate (mouse) fusion of palatal shelves – complete palate (alligator) palatal shelves in contact – keratinization, physiological cleft (birds) palatal shelves not in contact, great variability (chameleon) rudimentary palatal protrusions (gecko) palatal shelves not formed (turtle) Abramyan and Richman, 2015. Dev Dyn DEVELOPMENTAL DEFECTS OF LIP AND PALATE 8 oCleft lip and/or palate – the most often developmental defects of head and neck (1:500/700) o3 % of all the developmental defects ocombined and isolated ounilateral and bilateral osyndromic and non-syndromic clefts TOOTH DEVELOPMENT 9 Tucker and Sharpe, 2004. Nat Rev Genet Epithelial thickening (mouse E11.5) (human 6.w) Bud stage (mouse E13) (human 8.w) Cup stage (mouse E14.5) (human 11.w) Bell stage (mouse E15.5) (human 14.w) Erupted tooth ooral epithelium (ectoderm) oameloblasts oenamel omesenchyme (neural crest) oodontoblasts odentin ocement odental pulp 1. EPITHELIAL THICKENING 10 oin the region of future tooth are proliferating oral epithelial cells – epithelial thickening oepithelial thickening – dental placode oplacodal cells proliferate and invaginate into underlying mesenchyme originating in neural crest Cobourne and Sharpe. Tooth development. Pocket dentistry oral aboral 2. BUD STAGE 11 oepithelium invaginates into mesenchyme, formation of dental organ (epithelium) – epithelial cells are proliferating Cobourne and Sharpe. Tooth development. Pocket dentistry omesenchyme starts to condensate around forming epithelial bud – bud stage oral aboral 3. CUP STAGE 12 oepithelial bud growth into mesenchyme, formation of epithelial (enamel) knots Cobourne and Sharpe. Tooth development. Pocket dentistry oenamel organ formed from inner enamel epithelium, dental papilla formed from mesenchyme – cup stage oinner and external epithelial cells distinguished, layer of loose reticular cells (stellate reticulum) form layer between them Dental papilla Inner enamel epithelium Enamel organ External dental epithelium Oral epithelium Stellate reticulum oral aboral omesenchymal cells form Dental follicle around forming tooth Dental follicle 4. BELL STAGE (EARLY BELL) 13 ostellate reticulum cells induce differentiation of inner enamel ep cells – formation of ameloblasts o Cobourne and Sharpe. Tooth development. Pocket dentistry oTooth cup grows further into jaw mesenchyme, connection with oral epithelium preserved via „string“ of epithelial cells – dental stalk odiphyodont and polyphyodont species – outgrow of so called dental lamina (next generation teeth source) from dental stalk omesenchymal cells of dental papilla in contact with differentiating ameloblasts – differentiation into cylindrical cells - odontoblasts o oral aboral oral epithelium dental stalk External enamel epithelium Stellate reticulum Inner enamel epithelium Dental papilla 5. APPOSITION STAGE (LATE BELL) 14 oameloblasts produce enamel into space towards odontoblasts, ameoblasts transfered to the tooth surface oodontoblasts produce dentin into space towards ameloblasts, odontoblasts transfered to the dental cavity External dental epithelium ameloblasts forming enamel forming dentin dental follicle odontoblasts Stellate recitulum dental papilla oral aboral odental crown base formed Cobourne and Sharpe. Tooth development. Pocket dentistry DEVELOPMENT OF TOOTH ROOT 15 ostellate recitulum absence→ epithelial cells do not differentiate into ameloblasts oenamel organ base – crown and root interface oenamel organ base – direct contact of inner and external enamel epithelium, proliferation and migration into mesenchyme → epithelial root sheath (root base) osheath induces dental papilla mesenchymal cells to form odontoblasts → connection of crown dentin to root dentin odental follicle inner cells – cementoblasts (cement – root surface) 1994. Curr Top Periodontol enamel dentin odontoblasts dental papilla dental follicle epithelial root sheath crown Oral epithelium odontoblasts cement dentin cementoblasts osteoblasts Alveolar bone epithelial sheath Periodontal cells oouter cells – osteoblasts (alveolar bone) omiddle layer – mesenchymal cells of periodontium, collagen fibers (periodontal ligaments) 6. TOOTH ERUPTION 16 oPre-eruption phase – preparation for tooth eruption, begins in early bell stage, terminates at the begining of the root formation oEruption phase – intensive growth of root, tooth supported by formed alveolar bone, oral epithelium rupture, tooth enters oral cavity oPost-eruption phase – further growth of tooth into oral cavity Bleahid, 2017. Health and Medicine NEXT GENERATION TEETH DEVELOPMENT 17 omonophyodont species (chameleon, mouse, marsupials, whales, moles) – one generation, dental lamina do not develop Obsah obrázku text, lůžkoviny, tkanina Popis byl vytvořen automaticky chameleon Buchtova et al. 2013. Arch Oral Biol Buchtova et al. 2012. JDR oDental lamina is formed in chameleon – next tooth generation is not formed NEXT GENERATION TEETH DEVELOPMENT 18 odiphyodont species (majority of mammals, human) – second teeth generation, secondary or successional dental lamina opolyphyodont species (sharks, snakes) – more than two teeth generations, lifelong teeth replacement, active dental lamina Fraser et al. 2019. Sci Rep DEVELOPMENTAL DEFECTS OF TEETH 19 oHypodontia – missing one or more teeth oHyperdontia – excessive teeth omicrodontia – smaller teeth omalposition – teeth in atypical positions DEVELOPMENTAL DEFECTS OF TEETH 20 oEnamel hypoplasia oinsufficient or abnormal enamel development oAmelogenesis imperfecta – congenital defect, insufficient enamel development oDentin dysplasia oDentin development affected o1. type – crown dentin not disturbed, missing or rudimentary roots o2. type – crown dentin development disturbed, altered crown color DEVELOPMENT OF SALIVARY GLANDS 21 oproliferation → oral epithelium thickening – formation of epithelial placode (pre-bud stage) oinvagination of epithelial cells into mesenchyme of 1. pharyngeal arch (neural crest) – formation of bud and epithelial stalk (ES), condensation of mesenchyme oFollowing branching, cavitation via apoptosis of the inner epithelial cells, luminisation from proximal to distal parts, formation of glandular acini (lobes) – canalicular phase oother buds formed from main by branching, onset of cavitation from oral cavity, mesenchymal capsule – pseudoglandular phase ocavitation ended, differentiation of epithelial cells in ducts (excretory cells) and acini (secretory cells) – terminal phase Tucker, 2007. Sem Cell Dev Biol Epithelial placode Pseudoglandular phase Canalicular phase Terminal phase Bud stage ES Major salivary glands – ectoderm; minor mucuous glands of the tongue – endoderm; palatal glands – mixed origin Major salivary glands – ectoderm; minor mucuous glands of the tongue – endoderm; palatal glants – mixed ectodermal and endodermal origin TONGUE DEVELOPMENT 22 oInteraction of cells from two sources: oconnective tissue from neural crest mesenchyme omuscles from occipital segments (mesoderm) o1. pharyngeal arch – paired lateral and unpaired medial swellings (tubercle), lateral grow and overgrow medial swelling → formation of medial tongue sulcus, covered with epithelium from ectoderm (2/3 anterior part, body of tongue) Gallatz Katallin o2. and 3. pharyngeal arches – formation of ventromedial swelling, called cupola o3. and 4. pharyngeal arch – hypopharyngeal eminence from mesenchyme oFusion of cupola and hypopharyngeal eminence – root of tongue, covered with epithelium from endoderm ofusion of tongue root and body DEVELOPMENTAL DEFECTS OF TONGUE 23 oCleft tongue (bifid tongue) odeffective interaction between medial and lateral swellings oformation of longitudinal cleft osurgery oMostly syndromic Fleming and Flood, 2005. British Dental Journal ENDODERM FORMATION 24 Balinsky, 1975 oEpiblast cells invaginate in primitive streak and Hensen`s node regions oFirst epiblast cells invaginating through Hensens node – migrate cranially, forming future pharyngeal cells of the primitive gut ohypoblast cells replaced by endoderm cells oAttachment of digestive tube – formation of dorsal and ventral mesentery (hinge) from splanchnic mesoderm FORMATION AND DEVELOPMENT OF PRIMITIVE GUT 25 oblindly terminated tube of primitive gut connects cranial and caudal parts of the developing individual oGut endoderm connected with ectoderm on both sides, formation of two membranes: oPrimitive gut divided into three parts: oforegut – pharynx, esophagus, stomach, cranial part of duodenum omidgut – from liver bud to transversal colon oHindgut – from transversal colon to cloacal membrane Hindgut ocranial – connection with primitive oral cavity (stomodeum) – oropharyngeal membrane ocaudal – connection with primitive anal opening (proctodeum) – cloacal membrane DEVELOPMENT OF ESOPHAGUS 26 oSeparation of laryngotracheal tube in pharynx region, dorsaly basis of esophagus, ventraly basis of trachea and lung Tracheoesophageal groove Laryngotracheal tube foregut Laryngotracheal groove oPrimitive esophagus – multilayered cylindrical epithelium, prolongation, number of layers lovered → proliferation leads to narrowing of esophagus (no temporary encloser) in region of tracheal biffurcation → recanalization oEmbryo grows along cranio-caudal axis – separation of head and neck from thoracic cavity – prolongation of esophagus oEpithelial cells start to form cilia → gradual replacement with multilayered squamous epithelium, ciliary epithelium preserved only in cranial region of esophagus ofinally – cylindrical epithelium only in initial and final regions of esophagus Sahar Hafeez Veterian Key pharynx Dorsal mesentery Dorsal mesogastrium Ventral mesogastrium Esophagus basis stomach pharynx stomach Esophagus prolongation DEVELOPMENT OF CROP IN BIRDS 27 oFormation of bag-like extension from ventral side of esophagus in neck region oExtended part of esophagus for food storage omorfology based on species according to type of food DEVELOPMENTAL DEFECTS OF ESOPHAGUS 28 oEsophageal atresia oBlindly ended termination of esophagus oOften connected with tracheoesophageal fistula oTracheoesophageal fistula oImproper division of basis of trachea and esophagus oPersistent communication between them oCongenital esophageal stenosis oNarrowing of esophagus oInsufficient recanalization of esophagus oProblems in movement of food to stomach https://www.healthline.com/health/tracheoesophageal-fistula#types DEVELOPMENT OF STOMACH 29 oDevelops from front region of primitive gut oExpansion of primitive gut endoderm, formation of larger cavity oleft cranial side grow faster than the right side → basis for greater curvature on left side, lesser curvature on right side Thomson, 2017. Embryology of the Stomach oRotation around longitudinal axis: oleft side displaced ventraly oright side displaced dorsaly oFurther growth results in displacement of former cranial part to the left and caudal to the right oproliferation of smooth muscle cells precursors (mesoderm) on the interface of stomach and small gut – pyloric sphincter duodenum Lesser curvature Craniocaudal axis FORMATION OF GASTRIC GLANDS 30 oInvagination and proliferation of epithelial cells at the bottom of depressions → basis of glands oFormation of depressions in epithelium (invagination) – basis of gastric depressions, 3 layered epithelium oEpithelium further invaginates (grow) into underlying mesenchyme, formation of cavities in depressions, concurrent growth of mesenchyme to epithelium oRearrangement of cells, from 3 to 1 layered epithelium 3 layered epithelium invagination depression cavitation growing of mesenchyme to epithelium 1 layered epithelium depression gland DEVELOPMENT OF TWO TYPES OF STOMACH IN BIRDS 31 oTwo types of stomach: ocranialy – proventricle (glandular) ocaudaly – muscular stomach oGlandular stomach – invagination of epithelial cells into underlying mesenchyme, onset of glands developemnt, epithelium divided into glandular and covering, production of digestive enzymes oMuscular stomach – formation of thick smooth muscle layer from underlying mesenchyme, epithelial cells differentiate and keratinize oDetermining role of mesenchyme – stomach epithelium specifically differentiate based on factors produced in underlying mesenchyme Takiguchi-Hayashi and Yasugi, 1986 – 1996, experiments DEVELOPMENT OF STOMACHS IN RUMINANTS 32 oThree parts of prestomach, one main stomach: orumen, reticulum, omasum oabomasum (stomach glands) oFormation of spindle-shaped dilatation of the caudal region of foregut, dorsaly greater curvature, ventraly lesser curvature ogreater curvature – basis for rumen and reticulum olesser curvature – basis for omasum oRotation around longitudinal axis: oDorsal side displaced to the left oventral side displaced to the right oright and caudaly basis of abomasum liver Small intestine Reticulum basis Rumen basis Omasum basis Abomasum basis oright formation of omasum basis oleft and cranialy – formation of rumen and reticulum basis Edited: McGeady et al. Veterinary Embryology. 2009 esophagus liver rumino-reticular basis Omasum basis DEVELOPMENT OF STOMACHS IN RUMINANTS 33 oGrowth of rumen and reticulum in cranial direction and to the left, stomach lining formed of cylindrical epithelium ogroove divides rumen into two parts and undergo dorsocaudal rotation oformer dorsocranial direction, now caudal and left direction orotation of rumen causes displacement of other parts of stomach and gut to the right oaccelerated growth of abomasum, other parts grow slowly → doubling the volume compared to other parts olining: orumen, reticulum, omasum – replaced with multilayered squamous epithelium oabomasum – cylindrical epithelium preserved, formation of glands rumen abomasum omasum liver reticulum Edited: McGeady et al. Veterinary Embryology. 2009 rumen abomasum omasum Dorsal rumen liver omasum Ventral rumen abomasum gut reticulum DEVELOPMENTAL DEFECTS OF STOMACH 34 oHypertrophic pyloric stenosis oPartial pyloric blocking of stomach oHypertrophy of the pyloric sphincter muscle oBlockade of digested food transition from stomach to duodenum Mayo Clinic FORMATION AND DEVELOPMENT OF PRIMITIVE GUT BI6140 EMBRYOLOGY 35 oblindly terminated tube of primitive gut connects cranial and caudal parts of the developing individual oGut endoderm connected with ectoderm on both sides, formation of two membranes: oPrimitive gut divided into three parts: oforegut – pharynx, esophagus, stomach, cranial part of duodenum omidgut – from liver bud to transversal colon oHindgut – from transversal colon to cloacal membrane Hindgut ocranial – connection with primitive oral cavity (stomodeum) – oropharyngeal membrane ocaudal – connection with primitive anal opening (proctodeum) – cloacal membrane INTESTINE DEVELOPMENT 36 oDevelops from caudal foregut, midgut and hindgut oProlongation of midgut – midgut loop formation ventraly (remnants of viteline-intestinal duct in the loop) oascending loop – distal ileum, caecum, ascending colon, part of transverse colon Edited: McGeady et al. Veterinary Embryology. 2009 ventral Viteline-intestinal duct oProlongation of loop – temporary leave of abdominal cavity, located in extraembryonic cavity – physiological umbilical hernia oOnset of dorso-ventral rotation cranial caudal INTESTINE DEVELOPMENT 37 oDorso-ventral rotation –180O transfer of structures odescending loop structures→ caudal oascending loop structures→ cranial Edited: McGeady et al. Veterinary Embryology. 2009 oProlongation of descending part – formation of coiled loops –small intestine basis oascending part, basis of colon and caecum, slower growth oFurther growth– not enough space in extraembryonic cavity – return of descending and ascending parts to abdominal cavity DEVELOPMENT OF INTESTINE 38 oreturn of intestine to cavity causes further rotations Edited: McGeady et al. Veterinary Embryology. 2009 oFurther prolongation of coiled loops in forming small intestine and colon oStructures movement: ooriginally descending moved left ooriginally ascending moved right obasis of descending colon left Video: https://www.news-medical.net/health/Malrotation-of-the-Gastrointestinal-Tract.aspx INTESTINE TWISTING 39 oBowl of spaghetti look? oWhat molecule is responsible for this twisting? oconnective tissue molecule hyaluronan odecorated with amino acids chains – only on right side of the gut oaccumulation of modified hyaluronan on right side oright side expansion otilting the intestine leftward otriggering rotation WT embryo Embyro mut Kurpios et al. 2018. Nature INTESTINE DEVELOPMENT BI6140 EMBRYOLOGY 40 oendoderm – intestine lining omesoderm – vessels, muscular layer, connective layer oendodermal cells differentiate → growth, thickening and diffentiation of mesoderm to smooth muscle cells oFormation of specific intestinal mucosa – crypts and villi Teach me Physiology SMALL INTESTINE DEVELOPMENT 41 oFirst villi formed in duodenum – proliferation and infiltration of mesenchymal cells into multilayered epithelium, villi start to form in duodenum and follow to ileum oEpithelium transformed from multilayered into single layered oformation of intervillar zone –intensively proliferating cells ointensive proliferation leads to partial or complete blocking of intestinal lumen– recanalization via vacuoli formation and their fusion oEpithelium of villus – differentiation to enterocytes, Goblet cells, enteroendocrine cells Multilayered epithelium Cylindrical single layer Intervillar zone Zhang et al. 2019. MDPI Animals Enterocyt – nejhojnější buněčný typ tenkého střeva, absorpční funkce Pohárková buňka – žlázová buňka tvořicí mucin Enteroendokrynní buňka – chemosenzorické buňky, v závislosti na senzorické funkci detekují stav ve střevě a regulují tvorbu trávicích enzymů CRYPT FORMATION 42 oIntervillar zone – onset of invagination, so called apical constriction ocells proliferate and invaginate into underlying mesenchyme oFormation of crypts – progenitor cells supply oThree cell types: oStem cells – source of immature progenitors oTransit-amplifying cells oPaneth cells Zhang et al. 2019. MDPI Animals Sumigray et al. 2018. Dev Biol mesenchyme mesenchyme invagination Panethovy buňky – tvorba a sekrece antimikrobiálních peptidů, tvorba imunomodulačních proteinů Přechodně se dělicí buňky - DEVELOPMENT OF COLON 43 ovilli and crypts form at the same time (compared to small intestine) from endoderm, migration of mesenchymal cells to forming villi oThickening of apical parts of villi during development oflattening and transformation of villi in width – villi specific for small intestine disappear oEnterocytes oEnteroendocrine cell oGoblet cells oSpaces between villi spaces develop into permanent crypts oStem cell oPaneth cells Kostorous et al. 2020. Int J Mol Med villus crypt oDevelops from mid and hindgut DEVELOPMENTAL DEFECTS OF INTESTINE 44 oIntestinal atresia oInsufficient growth or recanalization oOften in duodenum oResults in vomiting, intestinal obstruction oSurgery Obsah obrázku text Popis byl vytvořen automaticky oAltered intestinal rotation with volvulus ooften connected with missing mesentery oCaused by mislocalization of intestine during migration back to abdominal cavity and altered rotation oKnotting of intestinal mesentery and obstruction osurgery DEVELOPMENT OF RECTUM AND ANAL CANAL 45 oterminal part of digestive tube oPartly from endoderm of hindgut oPartly from ectoderm, so called proctodeum (primitive anal opening) oConnection between endoderm and ectoderm – cloacal membrane, rupture and formation of opening between digestive system and external environment hindgut proctodeum Anal canal rectum oAnal sphincters develop from mesoderm Cloacal membrane DEVELOPMENTAL DEFECTS OF RECTUM AND ANAL CANAL 46 oDisplaced development of anus oInsufficient development and blindly terminated rectum oFormation of fistula to other developing structures (urethra, bladder, penis, vagina) oAnus developed ectopically oNarrowing of anal canal oCloacal membrane is not perfored UCSF. Dep Surgery http://www.biologymad.com Blood Bile LIVER – STRUCTURE OVERVIEW LIVER LOCATION INDUCED BY CARDIAC MESODERM K.S. Zaret, Nature Reviews Genetics 3, 499-512, 2002 [USEMAP] The ventral foregut endoderm gains the competence to develop into various tissues as a result of the expression of transcription factors in the endoderm. These include Foxa proteins, as well as signals that affect the endoderm, including bone morphogenetic proteins (Bmps) that emanate from the adjacent cells of septum transversum mesenchyme (STM). b | During tissue specification, fibroblast growth factor (Fgf) signals from the cardiogenic mesoderm, perhaps in conjunction with Bmp signals from the STM, initiate the liver gene programme in proximal endoderm, as well as blocking that for pancreas. Ventral endoderm cells sufficiently distal to the cardiogenic mesoderm escape the latter inhibitory effect and initiate the pancreatic gene programme. Ventral foregut explants were found to initiate liver gene expression, if exposed to cardiogenic mesoderm or Fgfs, or initiate pancreatic gene expression in the absence of such effectors70. The ventral endoderm explant studies therefore indicate that the pancreatic programme is the default state for this domain of endoderm. After the hepatic endoderm has been specified, it begins to extend towards the midgut. This process is abetted by turning of the embryo from the 'gut out' position (see figure in Box 1) to the inward curve shown by the typical fetus. At the same time, the hepatic endoderm cells become columnar in shape. These transitions seem to be elicited by signals that specify the endoderm (Fig. 2). Cells such as septum transversum mesenchyme (STM) cells and primitive endothelial cells, signalling molecules (such as Bmp, Hgf and Vegfr2) and transcription factors (such as Hex, Prox1, Hlx and c-Met) are essential to promote the morphogenesis of the liver bud itself (see b). b | Liver-bud morphogenesis is marked by the formation of the rostral diverticulum of the gut, remodelling of the extracellular matrix around the hepatoblasts and of E-cadherin-based connections between the cells, and proliferation and migration into the surrounding STM (beige). So, the hepatic endoderm (green) makes a transition from an epithelium to a non-polarized cell type during this period. Primitive endothelial cells, or angioblasts, appear near the hepatoblasts (a) and also promote outgrowth of the latter into the STM. During the outgrowth, the endothelial cells coalesce around spaces in the loose STM and create vesicles that fuse to form blood vessels (not shown). Haematopoietic cells then invade the growing liver and the organ becomes distinct from the gut epithelium. Bmp, bone morphogenetic protein; c-Met, HGF receptor; Hgf, hepatocyte growth factor; Vegfr2, vascular endothelial growth factor receptor 2. DEVELOPMENT OF LIVER 49 oInterface between foregut and midgut oYolk sac detaches from intestine otransversal septum region (basis for diphragma) oInteraction between endoderm of primitive gut and mesenchyme from splanchnic mesoderm oventral side of caudal area of foregut – formation of liver diverticle → basis for liver and gallbladder oBasis for liver – pars hepatica (larger part cranialy) oBasis for gallbladder – pars cystica (smaller part caudally) Edited: McGeady et al. Veterinary Embryology. 2009 dorsal mesogastrium (splanchnic mesoderm) dorsal ventral Gallbladder bud Liver bud DEVELOPMENT OF LIVER BI6140 EMBRYOLOGY 50 oendodermal liver basis grow cranio-ventraly into ventral mesogastrium (splanch. mesoderm) and reaches the transversal septum oEpithelial cells proliferate (endoderm) – differentiate into hepatoblasts (liver cells) – furter growth into mesenchyme of transversal septum oFormation of liver sinusoids (capillaries) from mesoderm oPart of former diverticle between basis of liver and primitive gut – main bile duct ohepatoblasts form liver beams oFrom septum mesenchyme capsule is formed Edited: McGeady et al. Veterinary Embryology. 2009 Stomach basis Transversal septum Liver beams Ventral mesogastrium Stomach basis Liver beams diaphragma Forming capsule Main bile duct DEVELOPMENT OF LIVER BI6140 EMBRYOLOGY 51 oLining of bud formed from endodermal cells - hepatoblasts oTransformation from cylindrical cells to pseudostratified epithelium oEpithelio-mesenchymal transition (EMT) – hepatoblasts leave liver beams, migrate and settle mesenchyme of transversal septum oendothelial cells intercalate to migrating hepatoblasts – formation of liver sinusoids (exchange of metabolites between capilaries and hepatoblasts) oCondensation of endothelial cells – vessels formation Lemaigre, 2009. Rev Basic Clinic Gastroenter Pseudostratified epithelium Endothelial cells EMT DEVELOPMENTAL DEFECTS OF LIVER BI6140 EMBRYOLOGY 52 oLiver agenesis oComplete liver absence olethal oAbsence or liver lobes hypoplasia oOne or more parts of liver do not develop oInsufficient development of liver oOften connected with free gallbladder oMain bile duct agenesis oExcretion directly to gallbladder oExcretion through gallbladder to duodenum oVery rare Obsah obrázku text Popis byl vytvořen automaticky DEVELOPMENT OF GALLBLADDER 53 oventral of the caudal foregut – formation of liver diverticle → basis for liver and gallbladder oEmbryonic atrophy of gallbladder – horse, rat, whale oGallbladder basis is getting bigger and prolonged, formation of gallbladder duct (stalk) oGallbladder duct first hollow tube – proliferation leads to solid structure– recanalization by formation of vacuoles in endodermal cells Cardinale et al. 2012. Nat Rev Gastroenterol Hepatol Liver part gallbladder stomach Gallbladder duct gallbladder Main bile duct gallbladder stalk (Gallbladder duct) DEVELOPMENTAL DEFECTS OF GALLBLADDER BI6140 EMBRYOLOGY 54 oGallbladder agenesis oComplete absence of gallbladder oGallbladder does not outgrow from liver diverticle (pars cystica) oGallbladder hypoplasia oInsufficient growth of gallbladder oOnly small basis of gallbladder oGallbladder cleft oGallbladder basis split into two basis during development (diverticulum) DEVELOPMENT OF PANCREAS 55 Gorelick et al. 2003. Gastrointestinal Teaching Project oTwo basis from foregut endoderm: odorsal – develops earlier oventral – later from liver diverticle orotation of stomach and intestine – ventral part moves and contacts dorsal part o ventral part duct – main pancreatic duct conects to main bile duct, together form larger duodenal papilla (LDP) odorsal part duct – additional pancreatic duct, forms smaller duodenal papilla (SDP) Formation of basis stomach Dorsal part Ventral part rotation Main bile duct fusion Dorsal part duct Ventral part duct SDP LDP ofusion of parts – formation of one structure DEVELOPMENT OF PANCREAS BI6140 EMBRYOLOGY 56 O´Dowd and Stocker, 2013. Front Physiol oinvagination of epithelial (endoderm) bud into surrounding mesenchyme (splanchnic mesoderm) oEpithelial cells proliferate, branching to mesenchyme oOnset of differentiation of cells oCells of ducts – form excretory canals oacinar cells – exocrine pancreas oCells of islets – endocrine pancreas oacinar cells – formation of secretory parts connected to ducts leading to duodenum, exocrine cells oCells of islets – epithelial-mesenchymal transition, migration into mesenchyme, differentiation to endocrine cells, vesseles formation Epithelial bud branching differentiation Acinar precursors Islet precursors maturation Forming islets Secretory parts ducts ZEBRAFISH DIFFUSE PANKREAS BI6140 EMBRYOLOGIE 57 https://embryology.med.unsw.edu.au/embryology/index.php/Endocrine_-_Pancreas_Development#Developing _Pancreatic_Islets Zonula occludens1 – polarita buněk, tvorba lumen polarizované https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2990215 Non-polarized cells Polarized cells [USEMAP] DEVELOPMENTAL DEFECTS OF PANCREAS 59 oPancreas divisum oDorsal duct do not fuse with bile duct oLarger dorsal part drain pancreatic products through smaller duct osmaller ventral part drain to main bile duct oInsufficient drainage – inflammation of pancreas o4 – 14 % population oAnular pancreas oThe most often congenital defect of pancreas oDefect in rotation of ventral part oFormation of ring of panreatic tissue around duodenum oIn majority of patients leads to partial or complete blockade of duodenum GIT IN DANIO RERIO - Swimbladder - Functions – buoyanc (in teleosts), secretion of ions - Dorsal outgrowth of foregut - pneumatic duct degenerates in teleosts (inflating by oxygen from the circulation) Typical features of GIT: - cannot distinguish esophagus and pharynx - doesn´t have stomach and acidification of chyme - has anterior intestinal bulb, midle intesine, posterior intestine. 60 Swimbladder in a typical cyprinid fish. A: Schematic diagram showing... | Download Scientific Diagram https://www.sciencedirect.com/science/article/pii/S1566070210001840?via%3Dihub DEVELOPMENT OF RESPIRATORY SYSTEM 61 FUNCTIONS OF RESPIRATORY SYSTEM BI6140 EMBRYOLOGY 62 ogas exchange between individual and external environment osounds creation breathing talking lung diaphragm VARIOUS RESPIRATORY SYSTEMS 63 odifussion – gas exchange not dependent on specialized organ, through cuticle or skin oTracheal system – system of piping leading to terminal tissues ogills – gas exchange in aquatic environment olung – system of bronchi, bronchioles and alveoli, gas exchange in terrestrial and aquatic environments Obsah obrázku ryba, máloostné ryby, tmavé Popis byl vytvořen automaticky Obsah obrázku červ Popis byl vytvořen automaticky DEVELOPMENT OF RESPIRATORY SYSTEM IN AQUATIC VERTEBRATES 64 opharynx and gills ooxygenated water enters the pharynx omouth ospiracle omouth or spiracle is closed opharynx pumps water through gills via gill openings outside Comparative Anatomy. University of the Cumberlands pharynx septum (cartilage/bone) partial septum missing septum vessels nerves Gill fibers DEVELOPMENT OF GILLS – PHARYNGEAL ARCHES BI6140 EMBRYOLOGY 65 oNeural crest cells migrating to region of developing head and neck into the space between surface ectoderm and gut endoderm → 6 pairs of pharyngeal arches oPharyngeal clefts osurface depression of ectoderm oPharyngeal pouches oprimitive gut endodermal protrusions oPharyngeal membrane – connection of primitive gut endoderm with surface ectoderm McGeady et al. Veterinary Embryology. 2009 oPharyngeal slits – pharyngeal membrane broken, formation of gills opening FORMATION OF THE GILL (PHARYNGEAL) SLITS 66 oEndodermal cells gradually cover majority of the pharyngeal arches surface endoderm ectoderm rostral caudal oPharyngeal pouches endoderm (pp) reaches the surface ectoderm (arrow), fusion → gill slit oPharygeal arches give rise to: oGill fibers (gf) – contain vessels (mesoderm) for gas exchange, both anterior and posterior sides ocartilage or bone – gill support (neural crest) oInternal gills – majority of fish and cartilaginous fish oExternal gills – some amphibians, larval stages of amphibians, some larval stages of fish Gillis and Tidswell, 2017. Current Biol PARTS OF THE RESPIRATORY SYSTEM 67 oConductive onasal cavity and nasopharynx olarynx, trachea, bronchi oRespiratory obronchioles oalveolar ducts, alveolar sacs, alveoli Harkema, Nikula and Haschek. Respiratory System. Hanbook of Tox and Path DEVELOPMENT OF THE CONDUCTIVE RESPIRATORY SYSTEM BI6140 EMBRYOLOGY 68 oformation of the facial prominences Duke Embryology DEVELOPMENT OF NASAL CAVITY BI6140 EMBRYOLOGY 69 oformation of nasal placodes – ectodermal thickening, epithelium growth and mesenchymal proliferation around placodes oPlacode deepening – formation of nasal pit, lateral nasal processes on sides, medial nasal processes are formed later odeepening and extension of nasal pit – nasal groove odeepening of nasal groove, approaching stomodeum – formation of nasal sac Som and Naidich, 2013. Am J Neurorad Medial nasal processes SEPARATION OF PRIMITIVE NASAL AND ORAL CAVITIES BI6140 EMBRYOLOGY 70 omaxillary prominences grow medially – nasal sacs are pushed medially omedial nasal prominence form intermaxillary segment oclosing space between maxillary and medial nasal prominences – buconasal groove disappears → closing of the nasal sac lower part oprimitive nasal and oral cavities separated Obsah obrázku klipart Popis byl vytvořen automaticky Som and Naidich, 2013. Am J Neurorad FORMATION OF NASAL AND ORAL CAVITIES BI6140 EMBRYOLOGY 71 oprimitive nasal cavity epithelium grows to underlying mesenchyme – formation of oronasal membrane (connection of primitive nasal and oral epithelium) odifferentiation of the olfactory epithelium dorsally ooronasal membrane breakdown ocommunication between oral and nasal cavitites through primitive choana osecondary palate formed from maxillary prominences, definitive choana formed caudally McGraw-Hill, 2006 brain epithelium oral cavity DEVELOPMENT OF NASOPHARYNX (NASAL PART OF PHARYNX) 72 onasopharynx connects nasal cavity with larynx and trachea through oropharynx oformation – breakdown of oronasal membrane and secondary palate formation→ connection between nasal cavity (ectoderm) and pharynx (endoderm) oEustachean tube opening – from the 1. pharyngeal arch pouch oAnterior – extension of the nasal cavity osimilar microscopic anatomy to nasal cavity opseudostratified cylindrical epithelium ovascularized tissue with lymphatic tissue oPosterior – extension of pharynx osimilar microscopic anatomy to oropharynx ostratified squamous epithelium ectoderm endoderm ectoderm endoderm DEVELOPMENT OF OROPHARYNX (ORAL PART OF PHARYNX) BI6140 EMBRYOLOGY 73 oconnects oral cavity with larynx ocaudally from oral cavity oAnterior – extension of the oral cavity oPosterior – extends to larynx oformation – connects oral cavity (ectoderm) with pharynx (endoderm) oregion of oropharyngeal (buccopharyngeal) membrane breakdown – separation of primitive oral cavity (stomodeum) from pharynx Oropharyngeal membrane DEVELOPMENT OF LARYNX 74 oconnection of pharynx and trachea oEpiglottis (laryngeal flap) located in larynx osounds creation – vocal cords (vocal folds, VF) oepithelial lining and glands from endoderm oEndoderm proliferation – transitional closure of larynx (epithelial lamina, EL) → growth and expansion laryngeal walls, epithelial cells apoptosis → recanalization ocartilage and muscles omesenchyme of 4. a 6. pharyngeal arches ocartilage – neural crest/mesoderm (somites) omuscles - somites Lungova et al. 2018. Dev EPIGLOTTIS DEVELOPMENT 75 oseparates respiratory and digestive systems oEpiglottis swelling (basis) develops on ventral laryngeal side: oepithelial lining from cranial endoderm omesenchyme and cartilage from 3. a 4. pharyngeal arches Embryology of the respiratory system laryngeal basis of vocal folds ORIGIN OF LUNG TISSUE BI6140 EMBRYOLOGY 76 oEndoderm obasis for laryngotracheal (respiratory) tube olung epithelial lining oParaxial mesoderm and lateral plate mesoderm omesenchyme of lung buds osmooth muscle cells ofibroblasts ocartilage ovessels olymphatic system o LUNG DEVELOPMENT 77 1. Embryonic – separation from primitive gut 5 stages: 3. Canalicular – onset of pneumocyte differentiation, expansion of vessels 2. Pseudoglandular – branching, onset of differentiation 5. Alveolar – formation of alveoli 4. Sacular – functional pneumocytes, expansion of vessels Obrázek5 1. EMBRYONIC – SEPARATION OF RESPIRATORY ENDODERM FROM FOREGUT ENDODERM 78 odigestive tube goes along the whole body obuds formation – development of liver, gallbladder, pancreas oonset of respiratory system development – outgrowth from the digestive tube in the primitive foregut oplace of separation – caudally from pharynx ohuman: 3. – 7. week LUNG BUD FORMATION 79 oLaryngotracheal groove oventral foregut side o4. pharyngeal arch region oDeepening of groove oformation of tracheoesophageal groove on both sides oseparation from foregut ocranially from tracheoesophageal septum – pharynx develops from foregut Tracheoesophageal groove Laryngotracheal tube Lung diverticle pharynx esophagus Tracheoesophageal groove pharynx Tracheoesophageal septum Lung buds esophagus Veterian Key foregut Laryngotracheal groove odorsally – esophageal base oventrally – basis of laryngotracheal tube ogrowth in caudal direction – formation of basis of laryngotracheal tube 2. PSEUDOGLANDULAR PHASE 80 oall main bronchial branches are formed – epithelial lining originates in endoderm openetration of epithelial organ to mesenchyme reminds exocrine gland formation – pseudoglandular oDifferentiation ociliated epithelial cells (endoderm) ocartilage (mesoderm) osubmucosal glands (endoderm) osmooth muscles (mesoderm) oendothelium – onset of vascularization (mesoderm) olymphatic cells (mesoderm) main left bronchus main right bronchus bronchial buds trachea left secondary bronchus right secondary bronchus Moore and Persaud, 2008. The Developing Human 3. CANALICULAR PHASE 81 ocavities of bronchi and bronchioles enlarged orespiratory bronchioles formed from terminal bronchioles – cubic epithelium ofrom respiratory bronchioles – alveolar tube with terminal sacs – epithelial flattening oaround bronchiolar branching - formation of vessels – close surrounding of epithelial cells oonset of epithelial cells differentiation in respiratory bronchioles: o1. type Pneumocytes o2. type Pneumocytes Rubarth and Quinn, 2015. Neonat Net, Springer. ohuman: 16. – 28. week 4. SACULAR PHASE 82 Rubarth and Quinn, 2015. Neonat Net, Springer. odifferentiating pneumocytes partly functional o1. type pneumocytes – structural alveolar cells, „membrane“ for gas exchange o2. type pneumocytes – formation of lamelar bodies, surfactant production oimmature sacs ogas exchange can tak place (1. type P) osurfactant is slightly produced (2. type P) oweb of blood and lymphatic vessels enlarged ohuman: 24. – 38. week 5. ALVEOLAR PHASE 83 Chao et al., 2016. Mol Cell Pediatr oformation of secondary septae → higher number of alveolar tubes and alveoli oAlveologenesis – alveoli development (36. w. - 3 years in human) omore effective gas exchange by formation of septae (larger surface) oinduced from mesenchyme – septae formation by alveolal myofibroblasts and lipofibroblasts opneumocytes on the surface, vessels and mesenchyme inside oAlveologenesis ohuman – prenatal and postanal development omouse – postnatal development DEVELOPMENT OF RESPIRATORY SYSTEM MUSCLES ointercostal muscles o oproliferation and migration of myotomal cells – muscle progenitor cells formed - myoblasts o oHypaxial muscles: ointercostal muscles – muscle connective tissue originates in somites ointercostal muscles don`t fuse 84 Sefton and Kardon, 2019. Curr Top Dev Biol DEVELOPMENT OF RESPIRATORY SYSTEM MUSCLES 85 odiaphragm omain muscle for inspiration phase, separating thoracal and abdominal cavity odiaphragm: omyoblasts – somites (cervical area) omuscle connective tissue (MCT) – lateral plate mesoderm Sefton and Kardon, 2019. Curr Top Dev Biol omigration of precursor cells from lateral plate mesoderm to pleuroperitoneal fold (PPF) region omyoblasts from somites migrate to pleuroperitoneal region – asociation with MCT ocrural diaphragm – respiration, esophageal sphincter ocostal diaphragm - respiration Pleural cavity – space between the lining on the lung surface and lining of the trunk wall Peritoneal cavity – space between parietal peritoneum (peritoneum surrounding abdominal wall) and visceral peritoneum (peritoneum surrounding the internal organ) FBMS = FETAL BREATHING-LIKE MOVEMENTS • movements resembling the breathing – crucial for lung development • stimulation of production of PDGFs, IGFs, TTF1 • affect development and function of pneumocytes pneumocytes typeI. – no FBMS = non-efective gasses exchange pneumocytes type II. – no FBMS = no surfactant S.F. Gilbert, Developmental biology 2006 Induction of labor Surfaktant je komplexní povrchově aktivní substance, skládající se z lipidů a proteinů, lemující povrch terminálních bronchiolů a alveolů savčích plic. Zajišťuje základní biofyzikální a imunologické funkce umožňující normální funkci plicní tkáně. Při řadě patologických procesů dochází k postižení surfaktantu, a tím i k poruše plicních funkcí. Tento fakt je znám přibližně 50 let a téměř tak dlouho se datuje snaha vědců o výrobu a využití léků na bázi přírodního či syntetického surfaktantu. Indikace podání surfaktantu jsou zatím stanoveny a všeobecně akceptovány pouze u novorozenců. U dospělých pacientů jsou největší zkušenosti s jeho podáním u ARDS (Acute Respiratory Distress Syndrome), nicméně s velmi rozporuplnými výsledky. V poslední době se objevují nové, užší indikace k užití surfaktantu s prvními dílčími úspěchy. DEVELOPMENTAL DEFECTS OF RESPIRATORY SYSTEM 87 odevelopmental defects – specific for developmental stages of lung o1. embryonic oTracheoesophageal fistula oincomplete separation of trachea and esophagus ocommunication between respiratory and digestive systems osurgery soon after delivery oPulmonary agenesis olung development stopped at primitive stage ounilateral or bilateral defects orare defect, often lethal Obsah obrázku text, rentgenový snímek Popis byl vytvořen automaticky Serrado et al. 2016. ECR 2016 DEVELOPMENTAL DEFECTS OF RESPIRATORY SYSTEM 88 o2. pseudoglandular phase oTracheal atresia ocongenital absence of trachea omostly lethal o oCongenital diaphragmatic hernia oinsufficient development of diaphragm oorgans from abdominal cavity move to thoracal cavity odefective lung development – lung hypoplasia, high lethality (50%) oPulmonary hypoplasia oinsufficient development of lung osmall number of bronchopulmonary and alveoli segments ooften secondary phenotype manifestation to other defects Obsah obrázku text Popis byl vytvořen automaticky Texas Children Fetal Center Obsah obrázku text, hračka, pózování, panenka Popis byl vytvořen automaticky St. Louis Fetal Care Institute DEVELOPMENTAL DEFECTS OF RESPIRATORY SYSTEM 89 o3. canalicular phase o4. sacular phase oRespiratory insufficiency oinsufficient gas exchange onot enough bronchioles oinsufficient vascularization of lung oAcute respiratory distress syndrome olung not well developed olung produce not enough surfactant oblue lips, fingers, toes orapid breathing DEVELOPMENTAL DEFECTS OF RESPIRATORY SYSTEM 90 o5. alveolar phase oBronchopulmonary dysplasia oinsufficiently or abnormally developed lung oless alveoli with thicker walls oinsufficient gas exchange omay be caused by premature birth oinsufficient development of lung lymphatic tissue - inflammation DEVELOPMENTAL DEFECTS OF RESPIRATORY SYSTEM 91 oLaryngeal atresia ocomplete or partial blockage of laryngeal tube ocaused by insufficient recanalization odilatation of the lower respiratory truct osurgical removal FUN FACTS 1. How long is the small intestine? 2. How many bacteria live in the colon? 3. What is the area of the whole intestine? 4. How many cells comprises the Langerhanz island in one pankreas? 92 3fold of your lenght 100 Trillion Microbes 250 m2 1 milion ¨