Chapter 23 Essays B
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1) Explain the study of the neural process in the small intestine.
a. The lining of the small intestine is a single-layered epithelium. This epithelium covers the surfaces of the villi that project ino the lumen and it lines the crypts that descend into the underlying connective tissue. Dividing stem cells lie in a protected position in the depths of the crypts. These generate four types of differentiated progeny: absorptive cells, goblet cells, paneth cells, and enteroendocrine cells
What happens after the progeny of cells are created?
a. The absorptive, goblet, and enteroendoccrine cells travel mainly upward from the stem-cell region, by a sliding movement in the plane of the epithelial sheet, to cover the surfaces of the cilia. The most rapidly proliferating precursor cells int eh crypt are in a transit amplifying stage, already committed to differentiation but undergoing several divisions on their way out of the crypt, before they stop dividing and differentiate terminally. Within 2-5 days, after emerging from the crypts, the cells reach the tips of the villi, where they undergo the initial stages of apoptosis and are finally discarded into the gut lumen.
The paneth cells are produced in much smaller numbers and have a different migration pattern. They live at the bottom of the crypts, where they too are continually replaced, although not so rapidly, persisting for about 20 days before undergoing apoptosis and being phagocytosed by their neighbors. The stem cells too remain at or near the bottoms of the crypts.
1) Explain what mutations in the APC (Adenomatous Polyposis Coli) gene do?
a. They cause adenomas in the lining of the large intestine due to the failure to halt their proliferation in the normal way. T
1) Explain Wnt signaling.
a. Wnt signaling normally keeps crypt cells in a proliferative state, and cessation of exposure to Wnt signaling normally makes them stop dividing as they leave the crypt.
1) What experiment with Wnt in transgenic mice confirmed the importance of Wnt signaling?
a. Using the Cre/lox technique with an indicuble promoter for Cre, Apc was knocked out in gut epithelial cells abrupty. Within a few days, the gut structure transformed: the crypt-like regions of proliferative cells are greatly enlarged, villi are reduced, and the numbers of terminally differentiated cells are drasticall diminished. Conversely, one can make a transgenic mouse in which the gut epithelial cells all secrete a diffusible inhibitor of Wnt signaling. These cells, in which Wnt signaling is blocked, form scarcely any crypts and have hardly any proliferating cells in their gut epithelium. Instead, almost all the gut lining cells are fully differentiated non-dividing absorptive cells; but goblet cells, enteroendocrine cells, and Paneth cells are missing. Thus Wnt signaling not only keeps cells in a proliferative state but is also needed to make them competent to give rise to the full range of ultimate differentiated cell types.
1) What causes cells to diversify as they differentiate?
a. Notch signaling has this function, where it mediates lateral inhibition—a competitive interaction that drives neighboring cells toward different fates. All the essential components of the Notch pathway are expressed in the crypts; it seems that Wnt signaling switches on their expression.
When Notch signaling is abruptly blocked by knocking out one of these essential components, within a few days all the cells in the crypts differentiate as goblet cells and cease dividing; conversely, when otch signaling is artificially activd in all the cells, no goblet cells are produced and the crypt-like regions of cell proliferation are enlarged
1) How do Wnt and Notch signaling pathways combine to control the production of differentiated cells from stem cells in the intestine?
- a. Chapter type: Wnt signaling promotes cell proliferation and confers competence for the full range of modes of differentiation, while preventing differentiation from occurring immediately. In this way, it defines the crypt and maintains the stem cells.
- But Wnt signaling also at the same time activates the expression of Notch pathway components, and Notch signaling, within the crypt population mediates lateral inhibition, which forces the cells to diversify, in such a way that some become singled out to deliver lateral inhibition, while others receive it. Cells of the former class express Notch ligands and activate Notch int heir neighbors, but escape from Notch activation themselves; as a result, they become committed to differentiate as secretory cells. Cells of the later class are kept in the opposite state, with Notch activated and ligand expression inhibited; as a result, they retain compentence to differentiate in any of a variety of ways and to engage in lateral-inhibition competition with their neighbors.
1) What happens to the cells when they remain or leave the crypt?
a. Both classes of cells continue dividing so long as they are in the crypt, under the influence of Wnt. But when cells leave the crypt and lose exposure to Wnt signaling, the compeititin halts, division stops, and the cells differentiate according to their individual states of Notch activation at that time—as absorptive cells if Notch is still activated, as secretory cells if it is not
1) What is one of the most remarkable features of the gut stem-cell system?
a. It is the steady, ordered, selective migration of cells from crypt to villus. Differentiating absorptive, goblet, and enteroendocrine cells stream out of the crypts and up the villi; stem cells remain deep in the crypts; and Paneth cells migrate right down to the crypt bottoms. This pattern of movements depends on another cell-cell signaling pathway: ephrin/eph signaling pathway.
1) Explain the EPhrin-Eph signaling pathway.
a. Wnt signaling stimulates the expression of cell-surface receptors of the EphB family in the cells in the crypt; however, as cells differneitiate, they switch off expression of these receptors, and switch on instead expression of the ligands, cell-surface proteins of the ephrinB family. There is one exception: the Panet cells retain expression of the EphB proteins. Thus EphB expression is characteristic of cells that stay in the crypts, while ephrinB expression is characteristic of cells moving out onto the villi.
1) What happens in other tissues concering Eph and Ephrin?
a. Eph proteins are repelled by contacts with cells expressing ephrins. In EphB knockout mutatns, the populations become mixed so that Paneth cells wander out onto the villi.
1) What is essential for maintenance of an organ, such as the liver? How it it maintained?
- a. It is important that the rate of cell production and the rate of cell death are the same
1) What else does the balance between cell births and deaths depend on besides regulation of cell proliferation?
a. Cell survival is also important. If the number of hepatocytes rises above a standard number, hepatocyte death will bring the number back down.
1) Explain the lining of the blood vessels.
- a. The largest BVs are arteries and veins, which have a thick, tough wall of connective tissue eand many layers of smooth muscle cells. The wall ins lined by a single thin sheet of endothelial cells, the endothelium, separated from the surrounding outer layers by a basal lamina. The amounts of connective tissue and smooth muscle in the vessel wall vary according to the vessel’s dimater and function, but the endothelial lining is always present.
- b. In capillaries and sinusoids, the walls consist of nothing but endothelial cells and a basal lamina, together with a few scatterd preicytes, which are cells of the connective-tissue family, related to vascular smooth muscle cells, that wrap themselves around smallvessels.
1) Where do endothelial cells originate?
a. They originate at specific sites in the early embryo from precursors that also give rise to blood cells. From tehse sites the early embryonic endothelial cells migrate, proliferate, and differentiate to form the first rudiments of blood vessels—a process called vasculogenesis. Subsequent growth and branching of the vessels throughout the body is mainly by proliferation and movement of the endothelial cells of these first vessels, in a process called angiogenesis
a. Paragraph notes: each new vessel originates as a capillary sprout from the side of an existing capillary or small venule. At the tip of the sprout, leading the way, is an endothelial cell with a distinctive character. This tip cell has a pattern of gene expression someone different from that of the endothelial stalk cells following behind it, and while they divide, it does not; but the tip cell’s most striking feature is that it puts out many long filopodia, resembling those of a neuronal growth cone. The stak cells meanwhile become hollowed out to form a lumen.
1) How do endothelial tip cells respond to signals int eh environment?
guidance molecules are involved along with their corresponding receptors. The most important of the guidance molecules of rendothelial cells is vascular endothelial growth factor, or VEGF.
1) How is a circuit to blood flow created?
a. A vascular sprout must continue to grow out until it encounters another sprout or vessel with which it can connect. The rules of connection have to be selective, to prevent the formation of undersirable short circuits and to keep the blood and lymphatic systems properly segregated. In fact, endothelial cells of developing arterial, venous, and lymphatic vessels express different genes and have different surface properties. These differences evidently help guide the various types of vessels along different aths, control the selective formation of connections, and govern the development of different types of wall as the vessel enlarges.
1) What do invading endothelial cells respond to?
a. Thy respond to signals produced by the tissue that they invade. The signals are complex, but VEGF plays a key role. The regulation of blood vessel growth to match the needs of the tissue depends on the control of VEGF production, through changes in the stability of is mRNA and in its rate of transcription.
1) Explain control of VEGF production via the rate of transcription.
a. A shortage of oxygen causes an increase in the intracellular concentration of a gene regulatory protein called hypoxia-inducible factor Ialpha (HIFIalpha). HIFIalpha stimulates transcription of VEGF. The VEGF protein is secreted, diffuses through the tissue (with different isoforms diffusing to different extents) and acts on nearby endothelial cells, stimulating them to proliferate, to produce proteases to help them digest their way through the basal lamina of the parent capillary or venule, and to form sprouts. The tip cells of the sprouts detect the VEGF gradient and move toward its source.
1) What happens to HIFIalpha as new vessels form?
- a. The oxygen concentration rises; HIFIalpha activity declines, VEGF production is shut off and angiogenesis comes to a halt. As in all signaling systems, it is as important to switch the signal off correctly as it is to swtich it on.
- b. In normal well-oxygenated tissue, continual degradation of the HIFIalpha protein keeps its concentration low; in the presence of oxygen, an oxygen-recquiring enzyme modifies HIFIalpha so as to target it for degradation. Degradation in turn requires the product of another gene, codign for an E3 ubiquitin ligase subunit.
1) Aside from VEGF and related factors stimulating and guiding angiogenesis, what else has a critical role in angiogenesis?
a. Interactions between one endothelial cell and another play an imrtant role. These interactions control which cells will be singled out to beave as tip cells,e xtending filopodia and crawling forward to create new vascular sprouts, and they are required to bring this motile behavior to a halt when it is time to stop. Thus, when endothelial sprouts meet and join up to form a vascular circuit, they normally switch off to reduce their sprouting activities. The effect depends on a specific Notch ligand, called Delta4, which is expressed in tip cells and activates Notch in their neighbors; oNotch activation leads to reduced expression of VEGF receptors, making the neighbors of the tip cell unresponsive to VEGF.
1) Explain recruitment and proliferation of pericytes and smooth muscle cells to form a vessel wall.
a. It depends on PDGF-D secreted by the enodothelial cells and on PDGF receptors in the pericytes and smooth muscle cells. In mutants lacking this signal protein or its recetor, these vessel wall cells in many regions are missing. As a result, the embryonic blood vessels develop microanuerysms that eventually rupture, as well as other abnormalities.
1) What happens once a vessel has matured?
regulation from signals by surrounding connective and smooth muscle tissue
a. Blood have cells, some of which stay within the vascular system, while others use the vascular system only to transport and perform their function elsewhere.
1) What are the similarities in blood cells?
- They all have limited life spans and are produced throughout the life of the animal.
- they are all generated ultimately from a common stem cell in the bone marrow; this hematopoietic stem cell is multipotent, giving rise to all the types of terminally differentiated blood cells as well as some other types of cells.
1) What does the imflammatory response do?
- a. Aftera local infection or injury attracts WBCs for the inflammatory response, it has signal molecules that act on nearby capillaries, causing the endothelial cells to adhere less tightly to one another but making their surfaces adhesive to passing WBCs. The WBCs are caught and escape from the vessels by squeezing between the endothelial cells and using digestive enzymes to crawl across the basal lamina.
- b. Homing receptors called selectins mediate the initial binding to endothelial cells, while integrins mediate the stronger binding required for the white blood cells to crawl out of the blood vessel. Damaged or inflamed tissues and local endothelial cells secrete other molecules called chemokines, which act as chemoattractants for specific types of WBCs, causing them to become polarized and crawl toward the source of the attractant. As a result, large numbers of WBCs enter the affected tissue.
- c. Other single molecules produced during an inflammatory response escape into the blood and stimulate the bone marrow to produce more leucocytes and release them into the bloodstream. The bone marrow is the key target for such regulation because, with the exception of lymphocytes and some macrophages, most types of blood cells in adult mammals are generated only in the bone marrow. The regulation is cell-ype-specific
- d. In other circumstances, erythrocyte production is selectively increased (such as living at higher altitudes)
1) What experiment was done on animals to test identify in ordinary tissue sections the immediate precursors of mature blood cells?
- a. Animals were exposed to large doses of x-rays, which destroyed the hemopoietic cells. This would kill the animal but transfusion of cells taken from the bone marrow of a healthy, compatible donor can save it. The new cells can reequip the host with hemopoietic tissue. This experiment proves that the marrow contains hemopoietic stem cells and show how we can assay for the presence of hemopoietic stem cells nad discover the molecular features for them.
- b. They were then able to sort the cells accrding to surface antigens that they display, and then transfuse the different fractions back into mice. If a rfraction rescues the mouse, it contains hemopoietic stem cells. By doing this, it is possible to show that the stem cells are characterized by a specific combo of cell-srface prtoteins.
35) How is the stem cell niche created and maintained?
a. The mechanism depends on a complex interplay of signals between the epithelium and the underlying connective tissue. Exchange of Wnt, Hedgehog, and PDGF signals between the two tissues, and between different regions of the crypt-villus axis, leads to a restriction of Wnt signaling to the neighborhood of the crypts. The epithelial cells in the crypts produce both Wnt proteins and the receptors that respond to them, creating a positive feedback loop that presumably helps to make Wnt pathway activation in this region self-sustaining. At the same time, signals exchanged with the connective tissue lead to expression of BMP proteins in the connective-tissue cells forming the core of the villi. These cells signal to the adjacent villus epithelium to inhibit the development of misplaced crypts: blocking BMP signaling disrupts the whole organization and causes misplaced crypts to form as invaginations of proliferating epithelium along the sides of the villi
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