Development of liver and pancreas

1. Development of liver and pancreas Semmelweis University, Department of Anatomy, Histology and Embryology Dr. Kocsis Katalin 2019.04.04.

2. Development of the foregut

4. mellső végtag caudális határa atlas

5. Hox gene expression boundaries in the endoderm and mesoderm during early chick gut development. Specific combinations of homeobox gene expression can be mapped to specific regions of the gastrointestinal tract, with some combinations demarcating the position of sphincters and organs. The regional expression patterns of mouse homologs are similar.

7. Figure 14-5 Signals and transcription factors important in establishing regional differences in the early developing gastrointestinal tract. The top drawing represents an early mammalian embryo shortly after the initiation of embryonic folding, with areas enlarged below showing some of the signaling events involved in liver, pancreas, and hindgut specification. After initiation of cranial body folding, the endoderm of the ventral foregut is situated adjacent to the caudal cardiogenic mesoderm and septum transversum. Tissue-tissue interactions between the cardiogenic mesoderm and the endoderm, mediated by Fgf and Bmp signals, induce hepatocytic markers within the endoderm (e.g., Albumin and Alpha fetoprotein) while suppressing pancreatic development by upregulating Shh expression. The homeoprotein pancreatic/duodenal marker, Pdx1, promotes pancreatic development. However, in the presence of Shh, pancreatic development is repressed. Much of the endoderm expresses Shh, but it is repressed by notochordal release of Fgfs and Activin B in the future pancreatic region. Shh expression within the hindgut endoderm induces Bmp4 and Hoxd13 expression within the caudal mesoderm. Shh/Bmp4 are only capable of inducing Hoxd13 expression in the caudal gut, possibly due to the caudal restriction of Cdx2 expression established during gastrulation. Hoxd13 instills a caudal identity to the hindgut. Alb, Albumin, Afp, Alpha fetoprotein; Ipf1, insulin promoter factor 1.

8. aorta a. vitellina entoderm 20 D yolk sac foregut midgut a. umbi-licalis hindgut foregut szik-hólyag hindgut aortic arch ductus omphalo-entericus 24 D yolk sac allantois ductus omphalo-entericus yolk sac 26 D 26 D

12. flexura duodenojejunalis cecum flexura coli sinistra pharyngeal gut membrana buccopharyngea ductus thyreoglossus yolk sac esophagus cardiogenic area lung foregut ductus omphalo-entericus stomach body stalk midgut membrana cloacalis allantois cloaca hindgut

14. Liver development

15. Figure 14-9 Development of the liver, gallbladder, pancreas, and their duct systems from endodermal diverticula of the duodenum. The liver bud sprouts during the 4th week and expands in the ventral (anterior) mesentery. The cystic diverticulum and ventral pancreatic bud also grow into the ventral mesentery, whereas the dorsal pancreatic bud grows into the dorsal mesentery. During the 5th week, the ventral pancreatic bud migrates around the posterior side (former right side) of the duodenum to fuse with the dorsal pancreatic bud. The main duct of the ventral bud ultimately becomes the major pancreatic duct, which drains the entire pancreas.

16. Figure 14-14 Formation of the liver and associated membranes. As the liver bud grows into the ventral mesentery, its expanding crown makes direct contact with the developing diaphragm. The ventral mesentery that encloses the growing liver bud differentiates into the visceral peritoneum of the liver, which is reflected onto the diaphragm. This zone of reflection, which encircles the area where the liver directly contacts the diaphragm (the bare area), becomes the coronary ligament. The remnant of ventral mesentery connecting the liver with the anterior body wall becomes the falciform ligament, whereas the ventral mesentery between the liver and lesser curvature of the stomach forms the lesser omentum.

18. induction (SHH, cardiogenic mesoderm): BMP (2, 4, 7), FGF (1, 2, 8), Wnt, GATA4, Hnf3, C/EBP Hex (hematopoietically expressed homeobox) essential for the hepatocyte differentiation cell differentiation, mesoderm, endothel migration: Notched / Jagged1,(Alagille syndrome) Vegf, BMP, FGF adult liver functions (albumin, alfa fetoprotein synthesis): Hnf (hepatic nuclear factor family) C/EBP, Egf, Hgf, Tgf Tissue-tissue interactions between the cardiogenic mesoderm and the endoderm, mediated by Fgf and Bmp signals, induce hepatocytic markers within the endoderm (e.g., Albumin and Alpha fetoprotein) while suppressing pancreatic development by upregulating Shh expression.

19. Sites of hematopoiesis in the human embryo. The graph highlights the relative importance of the various sites of hematopoiesis. AGM, aorta/genital ridge/mesonephros region. (Based on Carlson B: Patten's foundations of embryology, ed 6, New York, 1996, McGraw-Hill).

21. regeneration capacity of the liver cells Figure 18.29. Kinetics of DNA synthesis in the four major cell types of the mammalian liver. It is possible that, since the hepatocytes respond fastest, they are secreting paracrine factors that induce DNA replication in the other cells.

22. Pancreas development

24. Figure 14-9 Development of the liver, gallbladder, pancreas, and their duct systems from endodermal diverticula of the duodenum. The liver bud sprouts during the 4th week and expands in the ventral (anterior) mesentery. The cystic diverticulum and ventral pancreatic bud also grow into the ventral mesentery, whereas the dorsal pancreatic bud grows into the dorsal mesentery. During the 5th week, the ventral pancreatic bud migrates around the posterior side (former right side) of the duodenum to fuse with the dorsal pancreatic bud. The main duct of the ventral bud ultimately becomes the major pancreatic duct, which drains the entire pancreas.

25. dorsal pancreas bud (corpus és cauda pancreatis) duodenum pancreas ventrale sinister (regrediated) pancreas ventrale dexter (: caput pancreatis és proc. uncinatus) liver bud

26. Pancreas buds induction: aorta, Pdx1 homeobox genes • Pancreas / blood vessel

29. Figure 14-10 Initiation of pancreatic development in a day 10 mouse embryo. Pancreatic development begins with the formation of endodermal buds projecting into the splanchnic mesoderm near the stomach-duodenal border. Pdx1 is expressed (seen here by immunostaining in green) in both the dorsal and ventral pancreatic bud endoderm. Glucagon-positive cells are also detected at this early stage (cells in red) within the pancreatic endodermal buds.

30. Tissue-tissue interactions between the cardiogenic mesoderm and the endoderm, mediated by Fgf and Bmp signals, induce hepatocytic markers within the endoderm (e.g., Albumin and Alpha fetoprotein) while suppressing pancreatic development by upregulating Shh expression. The homeoprotein pancreatic/duodenal marker, Pdx1, promotes pancreatic development. However, in the presence of Shh, pancreatic development is repressed.

33. Fig.8. Model of beta-cell development. In beta-cell precursors, Ngn3 induces the expression of Pax4; these cells also express Nkx2.2 and Nkx6.1, and shortly thereafter, they express Islet1 and Pax6. The parallel activities of Pax4 and Nkx2.2 enable the program of beta-cell differentiation, and as a result, the level of Pdx1 increases; the expression of HB9 is induced; and the synthesis of insulin ensues. In fully mature betacells, the activity of Pax4 is no longer required.

34. Irodalom • Scott F. Gilbert: Developmental Biology (7th edition, Sinauer Associates, 2003) • Gary Schoenwolf: Larsen's: Human Embryology (4th edition, Elsevier, 2009) • Thomas W. Sadler: Langman's Medical Embryology (10th edition, Lippincott Williams and Wilkins,Philadelphia,2006) • Carlson BM. Human Embryology and Developmental Biology (Mosby, Philadelphia, 2004)