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ScienceWeek
2004 11 June A6 MEDICAL BIOLOGY: ON THE REGENERATION OF PANCREATIC BETA-CELLS
The following points are made by Ken Zaret (Nature 2004 429:30):
1) After we eat a meal, we must store excess sugars so that energy reserves will be available later on. Excess glucose is sensed by beta-cells in the pancreas, which respond by secreting the hormone insulin into the bloodstream. Insulin, in turn, causes various cells in the body to store glucose. In people with type I diabetes, the immune system destroys beta-cells, resulting in a lifelong dependency on insulin treatments. Recently, marked advances have been made in transplanting clusters, or "islets", of beta-cells from human cadavers into type I diabetics, making insulin treatments unnecessary(1). But that source of beta-cells is limited, so the science of producing new beta-cells has become a red-hot topic, sparking a flurry of studies into how the adult body itself generates insulin-producing cells.
2) Analysis of human pancreatic tissue has shown that insulin-producing cells can first appear in and around the walls of the pancreatic ducts, in addition to the beta-cell islets(3). For this reason, and because of their high proliferative rates in experimental models of pancreas regeneration(4), pancreatic-duct cells have long been thought to be a source of beta-cells. Various stem-cell types have also been correlated with the appearance of new beta-cells(2). This fits with the situation in the skin and intestine: cell-lineage studies have shown that unspecialized stem cells generate the specialized cells of these tissues.
3) Correlative studies, however, assess cell position, expressed genes, and proliferative states, which can change so rapidly that they do not definitively track cell fates. The pancreatic field of research has been misled by this before: the appearance of early embryonic cells expressing both insulin and glucagon suggested that they later give rise to cells that express only one or the other hormone. But a genetic method to mark cell lineages showed that mature insulin-secreting beta-cells and glucagon-producing cells derive from a different embryonic precursor(5).
4) Dor et al(2) have used this genetic method to indelibly mark the DNA of adult mouse beta-cells, so that they could definitively track the cells and their descendants during normal and stimulated cell turnover. The authors inserted into mice a hybrid gene containing the regulatory DNA sequence (the promoter) of the insulin gene, linked to a gene for a recombinase -- an enzyme that can rearrange specific DNA sequences in a cell. The insulin regulatory sequence causes the recombinase to be expressed only in beta-cells, not in duct cells or other cell types. An additional twist is that the recombinase is inactive unless the animal is treated with a synthetic hormone. The finding is that beta-cells arise mostly from pre-existing beta-cells, and not from pancreatic-duct or stem cells, which counters prevailing hypotheses in the field.
References (abridged):
1. Shapiro, A. M. N. Engl. J. Med. 343, 230-238 (2000)
2. Dor, Y., Brown, J., Martinez, O. I. & Melton, D. A. Nature 429, 41-46 (2004)
3. Butler, A. E. et al. Diabetes 52, 102-110 (2003)
4. Bonner-Weir, S., Baxter, L. A., Schuppin, G. T. & Smith, F. E. Diabetes 42, 1715-1720 (1993)
5. Herrera, P. L. Development 127, 2317-2322 (2000)
Nature http://www.nature.com/nature
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DEVELOPMENTAL BIOLOGY: ON DEVELOPMENT OF THE PANCREAS
The pancreas is a compound gland found in all vertebrates, functioning both as a duct-gland (exocrine gland) discharging digestive enzymes into the upper portion of the small intestine (into the duodenum), and as a ductless-gland (endocrine gland) secreting hormones that include insulin and glucagon into the bloodstream. Many invertebrates have a gland involved in the secretion of digestive enzymes, and sometimes such a gland is also called "pancreas".
As an organ, the human pancreas is oblong, approximately 12.5 centimeters long and 2.5 centimeters thick. It lies posterior to the great curvature of the stomach and is connected, usually by two ducts, to the duodenum. These two ducts carry the exocrine secretions, called "pancreatic juice", directly into the intestine. Each day, the pancreas produces 1.2 to 1.5 liters of pancreatic juice, which is a clear and colorless liquid consisting mostly of water, some salts, sodium bicarbonate (which neutralizes the acid draining from the stomach), and several digestive enzymes.
The cells in the pancreas that produce the digestive enzymes are called "acinar cells" [from Latin _acinus_, grape], so named because they are found in grape-like clusters. Between these clusters are islands of another type of secreting tissue, collectively known as the islets (or islands) of Langerhans. There are approximately 1 to 2 million islets of Langerhans in the human pancreas, and it is these groups of cells that are responsible for secreting hormones that include insulin and glucagon.
Four types of hormone-secreting cells compose the pancreatic islets: a) alpha cells secrete glucagon; b) beta cells secrete insulin; c) delta cells secrete the growth-hormone-inhibiting hormone called "somatostatin", which acts locally to inhibit the secretion of insulin and glucagon; d) F-cells secrete a pancreatic polypeptide which regulates release of pancreatic digestive enzymes. The islets are infiltrated by blood capillaries into which their secretions diffuse.
The principal physiological activity of glucagon is to increase blood glucose level when it falls below normal; the chief physiological action of insulin is opposite to that of glucagon: insulin helps adjust blood glucose level by decreasing the blood glucose level if necessary.
The main target tissue of glucagon is the liver, and the hormone has a number of actions: a) glucagon accelerates the conversion of glycogen into glucose (glycogenolysis); b) glucagon promotes formation of glucose from lactic acid and certain amino acids (gluconeogenesis; c) as a result, glucagon enhances release of glucose into the blood and blood glucose level rises.
In general, insulin also has a number of important actions: a) insulin accelerates the transport of glucose from the blood into cells, especially into the muscle fibers involved in voluntary movements (skeletal muscle fibers); b) insulin accelerates the conversion of glucose into glycogen (glycogenesis); c) insulin accelerates the entry of amino acids into cells, and accelerates the synthesis of proteins; d) insulin accelerates the conversion of glucose or other nutrients into fatty acids (lipogenesis); e) insulin decreases the breakdown of glycogen (decreases glycogenolysis); f) insulin decreases the metabolic formation of carbohydrates from non-carbohydrates (decreases gluconeogenesis).
A deficiency of insulin or defects of insulin receptors on target cells produces the disease known as "diabetes mellitus". Hypersecretion of insulin results in the disease called "hyperinsulinism". (See related background material below for history of the discovery of insulin.)
Concerning the digestive enzymes secreted by the acinar cells of the pancreas, these include a) the carbohydrate-digesting enzyme pancreatic amylase; b) several protein-digesting enzymes (trypsin, chymotrypsin, carboxypeptidase); c) pancreatic lipase, the principal triglyceride-digesting enzyme in the adult body; d) the nucleic-acid-digesting enzymes ribonuclease and deoxyribonuclease. In order to prevent digestion of the cells of the pancreas, the digestive enzymes are secreted in an inactive form which become activated in the duodenum. In general, the pancreatic secretions are regulated by both neural and hormonal mechanisms.
The islets of Langerhans are named after Paul Langerhans (1847-1888), who discovered and named the islets in the course of research for his doctoral dissertation, a project during which he prepared the first careful description of the microscopic structure of the pancreas. The research career of Langerhans was soon after terminated when he contracted tuberculosis, and at the age of 27 he abandoned research and moved to the island of Madeira in an attempt to find a cure for his pulmonary disease. He practiced medicine on Madeira and died there at the age of 41.
The pancreas is an unusual gland in that it is bifunctional, containing two types of secreting cells arranged in two different morphologies. The gland is also the site of a number of serious diseases involving acute or chronic infections, tumors, and cysts. The entire gland can be removed surgically and life sustained by the administration of insulin and potent pancreatic extracts. Approximately 80 to 90 percent of the pancreas can be removed surgically without producing an insufficiency of either endocrines (insulin or glucagon) or exocrines (water, bicarbonate, and enzymes).
In this context, the term "anlage" (pl. anlagen or anlages) refers in general to any group of embryonic cells identified as a future organ or body part. Also, in this context, the term "signal" refers to a specific chemical signal or "messenger" which provokes a specific response in cells, usually by interacting with a cell-surface receptor, and the term "signal pathway", in its broadest sense, refers to the biochemical pathway involved in the production of the signal, the interaction of the signal with the cell, and the response of the cell to the signal.
In animals, "epithelial cells" compose the cell layers that form the interface between a tissue and the external environment, for example, the cells of the skin, the lining of the intestinal tract, the lung airway passages, and the lining of various ducts. The term "mesenchyme" refers to an embryonic connective tissue from which all other connective tissue derives. In general, all embryonic organs consist of an epithelium and an associated mesenchyme, and epithelial-mesenchyme interactions are apparently of great importance in development.
In the embryos of higher animals, there occurs the transformation of a spherical single-layer "blastula" into a 3-layered "gastrula" consisting of ectoderm (outermost layer), mesoderm (middle layer), and endoderm (innermost layer) surrounding a cavity with one opening. The 3 layers are called the "germ layer", and these layers, via further cell differentiation and proliferation, determine the development of all the major body systems and organs.
The following points are made by S.K. Kim and M. Hebrok (Genes & Development 2001 15:111):
1) The authors point out that classic studies of dissected and recombined embryonic pancreas tissues published 40 years ago suggested that epithelial-mesenchymal cell interactions regulate growth and cell differentiation in the embryonic pancreas. Modern studies have revealed additional cell interactions involving pancreatic epithelium and mesoderm-derived tissues essential for normal pancreatic development. Recently, many of the signaling pathways likely to govern cell interactions in the developing pancreas have been identified, allowing detailed studies of the genetic, molecular, and cellular basis of intercellular signaling that establishes proper pancreas development and function.
2) During embryogenesis, organs develop in a stereotyped sequence along the respiratory and gastrointestinal tracts. This organization is accomplished through the temporal and spatial regulation of signaling pathways that specify and thereby separate the distinct organ anlagen. Many endoderm-derived organs, including lungs, trachea, thyroid, liver, and gallbladder, develop from a ventral portion of the embryonic gut. In contrast, the first sign of pancreas morphogenesis in birds and mammals is a dorsal evagination of the foregut caudal to the stomach anlage. Subsequently, a ventral bud develops adjacent to a portion of the liver (liver diverticulum). This ventral bud translocates to the dorsal side during gut rotation to form the mature pancreas. In some species, including humans, this is accomplished by fusion of the dorsal and ventral lobes. Pancreas development, therefore, requires specification of the pancreas anlage along both the anterior-posterior and dorsal-ventral axes of the embryo.
3) The authors point out that genetic and biochemical relationships of the signaling pathways involved in pancreas development have been revealed largely from in vitro studies and examination of embryonic axial patterning, organogenesis, and cell fate determination in the fruit fly Drosophila melanogaster, the nematode worm Caenorhabditis elegans, and the toad Xenopus laevis. Given apparent evolutionary conservation of insulin activities, insulin regulation, or insulin signal transduction machinery, studies in these organisms are likely to remain important for understanding the developmental genetics and function of insulin-producing cells. The authors conclude: "The evolutionary conservation of insulin-signaling and the profound impact of pancreatic diseases on human health insure continuing interest and relentless growth in our understanding of the signals governing pancreas development and function."
Genes & Development http://www.genesdev.org
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