Cell membrane disruption take place in different cell systems under physiological and pathological conditions. We tested the hypothesis that disruption of acinar cell membranes take place in the onset of acute pancreatitis.

A population of ventral neural tube cells has recently been shown to migrate out of the hind brain neural tube via the vagus nerve and contribute to the developing gastrointestinal tract. Since liver is also innervated by the vagus nerve, we sought to determine if these cells also migrate into the liver. Ventral neural tube cells in the caudal hindbrain of chick embryos were tagged with a replication-deficient retroviral vector containing the LacZ gene on embryonic day 2. Embryos were processed for detection of labeled cells on embryonic day 5 and 11. Labeled cells were seen in the liver on both days and identified as hepatocytes. Previously, it was believed that all hepatocytes develop from the gut endoderm. Results of the present study show an additional source for the formation of liver cells.

We tested the hypothesis that membrane wounding of acinar cells is one of the earliest changes during the induction of acute pancreatitis. Wounding of cell membranes was detected by the penetration of the animals own albumin into cells. The pancreatitis was induced by the intraperitoneal injection of supramaximal doses of caerulein. The controls received saline. Fifteen to 180 min. after the injection the animals were perfused with buffer followed by fixative. Frozen sections of pancreas were processed identically for immunocytological localization of albumin. The intensity of staining was quantified by image analysis. Animals receiving caerulein consistently display significantly greater (p < 0.001) anti-albumin immunostaining in the cytoplasm of acinar cells than controls. The penetration of albumin into acinar cells indicates that wounding of their plasma membrane occurs during the onset of acute pancreatitis. Wounding of membranes may allow the exit of molecules such as enzymes from the acinar cells during this period.

BACKGROUND & AIMS:Smooth muscle cells in the walls of the gastrointestinal tract are thought to derive solely from mesoderm surrounding the primitive gut. A population of neuroepithelial cells has recently been shown to migrate from the ventral part of the neural tube in the region joined by the vagus nerve. We sought to determine if these cells contributed to the development of the stomach and intestine.METHODS:Cells of the ventral hindbrain of chick embryos were tagged by replication-deficient retroviral vectors containing the lacZ gene, providing a permanent label that is transmitted without dilution as the cells divide. Embryos were processed for detection of labeled cells. Specific markers were used to determine differentiation of progeny in the gastrointestinal tract.RESULTS:Cells labeled in the ventral neural tube migrate in association with the vagus nerve. Labeled cells are found in the intestine and stomach after time for further migration and differentiation. Using a specific marker, they were clearly identified as smooth muscle cells.CONCLUSIONS:Some of the smooth muscle cells of the gastrointestinal tract are derived from precursor cells that originate in the ventral part of the hindbrain neural tube. Their developmental importance and functional significance remain to be determined.

Pathomorphological features of chronic pancreatitis become evident in a number of ways. Some are revealed by methods used for diagnosis of the disease. Dilation of the ductal system, strictures, and pseudocysts may be detected during endoscopic retrograde pancreatography (Malfertheiner et al. 1987). Enlargement of the pancreas becomes obvious during investigation by ultrasound or computed tomography.

Proper development of the thymus is critical for an individual to acquire full immune capability. A full complement of the components that participate in thymic development, interacting with each other at the correct time, is required for maturation. In order to establish the microenvironment necessary for T-cell differentiation, the epithelial primordium of the thymus must expand from pharyngeal endoderm with the aid of contributions from the ectoderm. Experimental studies have established the importance of mesenchymal derivatives from the neural crest in functional development of the epithelial primordium. Interfering with this process inhibits thymic development in a manner similar to that observed in congenital conditions such as the DiGeorge syndrome and the fetal alcohol syndrome. These observations provide clues to understanding the origin of defects in thymus-dependent immunity, and point the way to studies that will expand our understanding of the controls that are involved in genetic and environmental factors impacting on this process. (C) 1997 Wiley-Liss, Inc.

It has been assumed in the past that pancreatic acinar cells represent an irreversible end stage in development. Consequently, when there was an increase in structures that had the morphology of ductules, the interpretation was that they were derived from the proliferation of stem cells and/or pre-existing ductular cells. Pancreatitis, however, is regressive in nature [Bockman (1984) In: Pancreatitis: Concepts and Classification. Gyr, K.E., Singer, M.V., Sarles, H., eds. Elsevier, Amsterdam, pp. 11-15]. That is, it is characterized by parenchymal destruction and loss, rather than by expansion of parenchyma. Furthermore, it was assumed that the organization of the pancreatic parenchyma is like bunches of grapes, with spheroidal acini representing the grapes, and the ductules representing the stems. Given this organization, it would be difficult to understand how regressive changes could lead to clusters of ductular structures. Investigations using three-dimensional reconstruction and retrograde injections have altered our idea of pancreatic organization. In addition to spheroidal acini, there also are other shapes, including tubular acini. Moreover, ductules do not necessarily stop when they encounter an acinus. They may emerge on the other side. Combined ductular and acinar lumina may anastomose with each other. It is now clear that pancreatic acini may undergo redifferentiation, taking on the morphology of ductules and forming tubular complexes during pancreatitis, as well as in response to pancreatic cancer, cystic fibrosis, or blockage of the ductal system. With this understanding of pancreatic architecture and morphological plasticity, it is easier to understand the changes one sees with pancreatic diseases. (C) 1997 Wiley-Liss, Inc.

Factors that regulate cellular migration during embryonic development are essential for tissue and organ morphogenesis. Scatter factor/hepatocyte growth factor (SF/HGF) can stimulate motogenic and morphogenetic activities in cultured epithelial cells expressing the Met tyrosine kinase receptor and is essential for development; however, the precise physiological role of SF/HGF is incompletely understood. Here we provide functional evidence that inappropriate expression of SF/HGF in transgenic mice influences the development of two distinct migratory cell lineages, resulting in ectopic skeletal muscle formation and melanosis in the central nervous system, and patterned hyperpigmentation of the skin. Committed TRP-2 positive melanoblasts were found to be situated aberrantly within defined regions of the transgenic embryo, including the neural tube, which overproduced SF/RGF. Our data strongly suggest that SF/HGF possesses physiologically relevant scatter activity, and functions as a true morphogenetic factor by regulating migration and/or differentiation of select populations of premyogenic and neural crest cells during normal mammalian embryogenesis.

Zusammenfassung Grundlagen  Obwohl chronische Oberbauchschmerzen das Hauptsymptom der chronischen Pankreatitis darstellen, ist ihre Pathophysiologie bisher nur unzureichend verstanden. Methodik  Die gängigen Schmerzhypothesen werden in einer Übersicht dargestellt. Ergebnisse  Beim pankreatitischen Schmerze handelt es sich um ein multifaktorielles Geschehen. Verschiedene Schmerzhypothesen sind geäußert worden, die jedoch allesamt nur einen unbefriedigenden Erklärungsversuch bieten. Hierzu zählen a) die akute Entzündung des Pankreas, b) erhöhter Druck im Pankreasgangsystem und/oder Parenchym oder c) extrapankreatische Ursachen wie Choledochus- und Duodenalstenosen. Schlußfolgerungen  Neuere Studien, welche direkte Veränderungen an den Pankreasnerven und eine Interaktion zwischen Nerven und Entzündungszellen als potentielle Schmerzmechanismen beschreiben, stellen ein neues interessantes Schmerzkonzept bei der chronischen Pankreatitis dar, das allerdings weiterer Abklärung bedarf.

Cells of the neural tube are thought to be committed to form only the central nervous system, whereas the peripheral nervous system is believed to be derived from neural crest cells and from placodes, which are specialized regions of the surface ectoderm. Neural crest cells arise early from the dorsal part of the neural tube. The possibility that after emigration of the neural crest cells, another population of cells arising from the ventral part of the neural tube also emigrates via a different route was examined. Here we report that, after labeling cells of the ventral neural tube in the rostral hindbrain of E3 duck embryos with DiI, they were later found in the trigeminal ganglion of the fifth cranial nerve. A trail of labeled cells could be traced from the ventral part of the neural tube to the peripheral ganglion. Further, expression of the homeobox gene Islet-1 in cells of the neural tube and the ganglion also indicated that some ventral neural tube cells may normally emigrate to the trigeminal ganglion. It is concluded that not all neural tube cells are committed to form the central nervous system; the ventral part of the neural tube also provides cells for the formation of the trigeminal ganglion. These results raise the possibility that the ventral neural tube may serve as an additional source of cells for the formation of various other components of the peripheral nervous system.

Transforming growth factor alpha (TGF alpha) evokes diverse responses in transgenic mouse tissues in which it is over-expressed, including the gastric mucosa, which experiences aberrant growth and a coincident repression of hydrochloric acid production. Here we show that ectopically expressed TGF alpha induces an age-dependent cellular reorganization of the transgenic stomach, in which the surface mucous cell population in the gastric pit is greatly expanded at the expense of cells in the glandular base. Immunohistochemical analysis of BrdU incorporation into DNA demonstrated that although mature surface mucous cells were not proliferating, DNA synthesis was enhanced by approximately 67% in the glandular base and isthmus, where progenitor cells reside. RNA blot and in situ hybridization were employed to determine temporal and spatial expression patterns of specific markers representing a variety of exocrine and endocrine gastric cell types. Mature parietal and chief cells were specifically depleted from the glandular mucosa, as judged by a 6- to 7-fold decrease in the expression of genes encoding H+,K(+)-ATPase, which is required for acid secretion, and pepsinogen C, respectively. The reduction of these markers coincided in time with the activation of TGF alpha transgene expression in the neonatal stomach. The rate of cell death in the glandular region was not overtly different. Significantly, the loss of parietal and chief cells occurred without a concomitant loss of their respective cellular precursors. In contrast to exocrine cells, D and G endocrine cells were much less severely affected, based on analysis of somatostatin and gastrin expression. Analysis of these dynamic changes indicates that TGF alpha can induce selective alterations in terminal differentiation and proliferation in the gastric mucosa, and suggests that TGF alpha plays an important physiological role in the normal regulation of epithelial cell renewal.

Background/Aims: Transforming growth factor (TGF) alpha affects the growth of gastric mucosa. Its overexpression alters the mucosa. The aim of this study was to test the possibility that it regulates differentiation of gland cells. Methods: Transgenic mice that overexpress TGF-alpha were used to detect its effect on zymogenic (chief) cells in the stomach. To test for a general regulatory role of TGF-alpha in differentiation of zymogen-producing cells, salivary glands from transgenic mice were studied. Results: In these mice, messenger RNA for pepsinogen C is present in the stomach at normal levels during the neonatal period and then decreases markedly. Zymogenic cells are present in the stomach during the neonatal period but are missing in transgenic adults. The bases of gastric glands, normally rich in zymogenic cells, are occupied by undifferentiated cells and mucous neck cells, the precursors of zymogenic cells. Zymogen granules in submandibular glands of transgenic female mice are reduced in number. Zymogen granule-containing cells in the parotid gland undergo redifferentiation to form tubular complexes, collections of ductularlike structures like those formed in the transgenic pancreas. Conclusions: TGF a is a major participant in the regulation of terminal differentiation of zymogenic cells in the stomach and salivary glands.

Background/Aims: Perineural extension of pancreatic adenocarcinoma has been explained as a mechanical extension along planes of least resistance. This study tests whether the cancer is limited to following these planes and if substances involved in cell signaling are involved in the interaction of cancer cells with nerves. Methods: Samples of tissue from patients undergoing resection of pancreatic cancer were studied by electron microscopy and light microscopy. Transforming growth factor a (TGF-a) and epidermal growth factor receptor (EGFR) were localized in sections. Results: The adenocarcinoma is not confined to the periphery of nerves. It penetrates the perineurium and becomes intimately associated with Schwann cells and axons in the endoneurium. Neural elements are damaged. Neural invasion likely is a factor in associated pain. TGF-a is abundant in nerves in the pancreas. EGFR is prominent in the cells of the adenocarcinoma. Conclusions: The interaction of pancreatic cancer with nerves involves more than the cancer following a perineural space. Interaction of TGF-a in nerves with EGFR on cancer cells constitutes a possible paracrine mechanism that provides a growth advantage for pancreatic adenocarcinoma and serves as an example of potential interactions that might be active in biological interaction of cancer with nerves.

Many heresies of the past have become the orthodox views of later times. In fact, progress in science is made possible through the generation of new and different ideas that are then tested for validity. It is common and natural for these new ideas to be met with resistance. The tension between the established and the new serves at least as an incentive to determine which is the better concept. In some cases, useful understandings emerge from the dialog that results from the opposing ideas. It is also possible, of course, for the new ideas to be wrong. In this case the shortcomings of the proposed new perspective usually become obvious over time, and the pursuit of the new concept becomes merely a temporary diversion.

Transgenic mice overexpressing human transforming growth factor alpha (TGF-alpha) predictably develop an enlarged, firm pancreas. The present study investigated the changes that occur in the different components of the pancreas in these animals. The increase in size of the pancreas may be accounted for by increased connective tissue. The added collagen is mainly type I. Thin, elongate fibroblasts are frequently bordered by a basal lamina, a relationship that is normally restricted to the perineurium. Collagen is intimately associated with epithelial cells. Fingers of connective tissue extend close to acinar lumina. Redifferentiation of acinar cells produces tubular complexes. In some cases, acinar cells take on the appearance of ductular cells. In some, there is a transition to mucin-producing cells. Intermediate forms between acinar and mucin-producing cells are present. The growth factor is localized in acinar cells and decreases with redifferentiation. The pancreas of these animals routinely displays characteristics that also are observed in diseases of the exocrine pancreas in humans, including fibrosis and redifferentiation. It is likely that the changes are the result of both direct and indirect effects of TGF-alpha, some of which may parallel altered control mechanisms in human pancreatic disease. Study of this model may provide clues to understanding the initiation of fibrosis and redifferentiation in human pancreas.

Although bisdiamine has been shown to affect the development of mammals, its effect on the nervous system has gone largely unrecognized. In the present study, rats were given bisdiamine by gavage on days 9 and 10 of pregnancy. They were sacrificed at intervals and the fetuses were prepared for study of serial sections stained with hematoxylin and eosin, or by immunohistochemical reaction with HNK-1 monoclonal antibody. HNK-1 reacted strongly with the nervous system, allowing precise analysis of the components and their relationships. Controls receiving no bisdiamine were prepared and studied in parallel with the experimental fetuses. Administration of bisdiamine inhibited development of the petrosal and nodose ganglia, altered associations of the glossopharyngeal, vagus, and hypoglossal nerves, and inhibited contributions of vagal nerve fibers to the developing enteric system. The proximal ganglia of the glossopharyngeal and vagus nerves developed normally. It is concluded that bisdiamine affects, directly or indirectly, the differentiation of nervous components derived from the epibranchial placodes. It seems likely that these placode-derived components serve as pioneer neurons in establishing the pathway for the posteriorly extending trunks of the glossopharyngeal and vagus nerves. The early changes in congenital conditions such as the DiGeorge syndrome may not be limited to alterations in neural crest derivatives. It may be worthwhile to investigate more closely whether there are alterations in the nervous system associated with these syndromes.

Impaired thymic development as a result of ablation of neural crest has been observed in embryos late in development. The present study was initiated to determine what changes are effected early in thymic development by neural crest ablation. The epithelial primordia of the thymus were studied in chick embryos on the sixth day of incubation. Embryos with neural crest ablations were compared with sham-operated and untreated controls. Neural crest ablation inhibited formation of epithelial thymic primordia. Primordia in experimental embryos were fewer in number and were smaller than in shams and untreated controls. When primordia from shams and controls were transplanted to the chorioallantoic membrane of chick hosts, they were able to develop into organs with the typical features of embryonic thymus. Similar transplantation from neural crest-ablated animals, on the other hand, led to small, predominantly epithelial structures with meager lymphoid development. These findings are consistent with the hypothesis that mesenchyme derived from cranial neural crest is critical in initiating and sustaining the development from pharyngeal pouches of epithelial structures competent to attract and support the proliferation and differentiation of lymphoid stem cells.

Annals of the New York Academy of SciencesVolume 588, Issue 1 p. 296-304 Altered Development of Pharyngeal Arch Vessels after Neural Crest Ablationa DALE E. BOCKMAN, DALE E. BOCKMAN Department of Anatomy Medical College of Georgia Augusta, Georgia 30912-2000Search for more papers by this authorMARY E. REDMOND, MARY E. REDMOND Department of Anatomy Medical College of Georgia Augusta, Georgia 30912-2000Search for more papers by this authorMARGARET L. KIRBY, MARGARET L. KIRBY Department of Anatomy Medical College of Georgia Augusta, Georgia 30912-2000Search for more papers by this author DALE E. BOCKMAN, DALE E. BOCKMAN Department of Anatomy Medical College of Georgia Augusta, Georgia 30912-2000Search for more papers by this authorMARY E. REDMOND, MARY E. REDMOND Department of Anatomy Medical College of Georgia Augusta, Georgia 30912-2000Search for more papers by this authorMARGARET L. KIRBY, MARGARET L. KIRBY Department of Anatomy Medical College of Georgia Augusta, Georgia 30912-2000Search for more papers by this author First published: April 1990 https://doi.org/10.1111/j.1749-6632.1990.tb13219.xCitations: 15 a This work was supported by NIH Grant HL36095. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume588, Issue1Embryonic Origins of Defective Heart DevelopmentApril 1990Pages 296-304 RelatedInformation