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1) How can one determine what range of cells a single hemapoietic stem cell can generate?
a. We can mark individual stem cells genetically so that their progeny can be identified even after they have been released into the bloodstream. A specially engineered retrovirus serves the purpose by inserting its own genome into the chromosomes of the cell it infects, but the genes that would enable it to generate new infectious virus particles have been removed. The marker is confied to the progeny of the cells that were orignalyl infected, and the progeny of one cell can be distinguished from the progeny of another because the chromosomal sites of insertion of the virus are different.
What must be done to analyze hemopoietic cells?
a. To analyze hemopoietic cell lineages, bone marrow cells are first infected with the retroviral vector in vitro and then are transferred into a lethall irradiated recipient; DNA probes can then be used to trace the progeny of individual infected cells int eharious hemopoietic and lymphoid tissues of the host. These experiments show that the individual hemopoietic stem cell is multipotent and can give rise to the complete range of blood cell types, both myeloid and lymphoid, as well as new stem cells like itself.
1) How do hemopoietic stem cells undergo differentiation?
a. It is not a direct jump, but rather a series of progressive restrictions. The first step is commitment ot either a myeloid or lymphoid fate. This gives rise to two kinds of progenitor cells, one capable of generating large numbers of all the different types of myeloid cells, or perhaps of myeloid cells plus B lymphocytes, and the other giving rise to alrge numbers of all the different types of lymphoid cells, or at least T lymphocytes. Further steps give rise to progenitors committed to the production of just one cell type. The steps of commitment correlate with changes in the expression of specific gene regulatory proteins, needed for the production of different subsets of blood cells.
1) Hemopoietic progenitor cells become committed to a particular pathway of differentiation long before they cease proliferating and terminally differentiate. What do the committed progenitors go through?
a. They go through many roudns of cell division to amplify the ultimate number of cells is such a small fraction of the total population of hemopoietic cells. For the same reason, a high rate of blood cell production can be maintained even though the stem-cell division is low.
1) Infrequent division is a common feature of stem cells in several tissues. What can be achieved by reducing the number of division cycles that stem cells have to undergo in the course of a lifetime?
It lowers the risk of generating stem-cell mutations, which would give rise to persistent mutant clones of cells in the body.
It also has another effect: it reduces the rate of replicative senescence. In fact, hemopoietic stem cells that are forced to keep dividing fail to sustain heopoiesis for a full normal lifespan.
1) What does the stepwise nature of commitment mean?
- a. It means that the hemopoietic system can be viewed as a hierarchical family tree of cells.
- -Multipotent stem cells give rise to committed progenitor cells, which are speicified to give rise to only one or a few blood cell types.
- -The committed progenitors divide rapidly, but only a limited number of times, before they erminalyl differentiate into cells that divide no further and die after several days or weeks. Many cells normally die at the earlier steps in the pathway as well.
1) What must be maintained for long-term maintenance of hemopoietic cells?
- a. Contact with appropriate supporting cells, as well as specific signal proteins.
- b. In the bone marrow, where they normally live, the heomopoietic stem cells are mostly located in close contact with the osteoblasts that line the bony surfaces of the marrow cavity. Osteoblasts provide the signals that the hemopoietic stem cells need to keep them in their uncommitted stem-cell state.
c. Stem cells are normally confined to a particular niche, and when they leave this niche, they lose their stem-cell potential. Hemopoietic stem cells in the bone marrow and elsewhere are often associated with a specialized class of endothelial cells.
1) What is a key feature of the stem-cell niche in bone marrow?
- a. It provides stimulation of the Wnt signaling pathway. Artifical activation of this pathway helps them to survive, proliferate, and keep their character as stem cells, while blocking Wnt signaling does the opposite.
- b. Another important interaction for maintaining hemopoiesis was revealed through mice with mutations in either the Kit gene, which codes for a receptor tyrosine kinase, or its ligand. The cell types affected by the mutations all derive from migratory precursors, and it seems that these precursors must express the receptor and be provided with the ligand by their environment if they are to survive and produce progeny in normal numbers. The Kit ligand must be membrane-bound to be fully effective, implying that normal hemopoiesis requires direct cell-cell contact between the hemopoietic cell that express Kit receptor protein, and stromal cells that express Kit ligand.
1) How can cells that respond to erythropoietin be ID’ed?
a. They can be identified by culturing bone marrow cells in a semisolid matrix in the presence of erythropoietin. IN a few days, colonies of about 60 erythrocytes appear, each founded by a single committed erythroid progenitor cell, which depends on erythropoietin for its survival and proliferation.
a. At least seven distinct CSFs that stimulate neutrophil and macrophage colony formation in culture are defined and some or all act in different combos that regulate the selective production of these cells in vivo.
They are synthesized by various cell types and the concentration in the blood increases rapidly in response to bacterial infection in a tissue, thereby increasing the number of phagocytic cells released from the blone marrow into the blood stream.
What are all of the CSFs?
- a. glycoproteins that act at low concentrations by binding to specific cell-surface receptors.
- b. transmembrane tyrosine kinases or large cytokine receptor family (composed of two or more subunits, one of which is frequently shared among several receptor types)
What do CSFs not only operate on?
The CSFs not only operate on the precursor cells to promote the production of differentiated progeny, they also activate the specialized functions of the terminally differentatited cells.
1) What are the possible effects of a CSF?
- a. It can control the rate of cell division or number of division cycles that the progenitor cell undergoes before differentiating;
- b. It might act late in the hemopoietic lineage to facilitate differentiation or early to influence commitment; it might increase the probability of cell survival.
1) What is suggested about hemotopoietic behavior?
a. It is by chance. Some CSFs seem to act by regulating probabilities, not dictating directly. Even if cells have been selected to be as homogenous a population as possible, there is variability in sizes and characters. Even if two sister cells are taken after cell division and cultured under the same conditions, they give rise to colonies of different blood cells. Thus, it is random.
1) What is the default behavior of hemopoietic cells in the absence of CSFs?
a. It is death by apoptosis. Thus, in principle, the CSFs could regulate the numbers of the various types of blood cells entirely through selective control of cell survival in this way. The control of cell survival does indeed play a central part in regulating the numbers of blood cells. The amount of apoptosis is enormous. Too little cell death can be as dangerous to the health of a multicellular organism as too much proliferation.
1) Once formed, what can a skeletal muscle fiber do?
a. It grows, matures, and modulates its character. The genome contains multiple variant copies of the genes encoding many of the characteristic proteins of the skeletal muscle cell, and the RNA transcripts of many of these genes can be spliced in several ways, which allows isoforms of proteins to form.
1) What do isoforms of skeletal muscle do?
a. This satisfies the changing demands for speed, strength, and endurance in the fetus, the newborn, and the adult.
1) What are the three ways in which a muscle can grow?
- a. Its fibers can increase in number, in length, or in girth, which occurs by fusion of myoblasts, and the adult number of multinucleated skeletal muscle fibers is attained early.
Once formed, what happens with skeletal muscle fiber?
- Once formed, a skeletal muscle fiber survives for the entire lifetime of the animal. However, individual muscle nuclei can be added or lost. Increase in muscle bulk is achieved by cell enlargement.
- Growth in length depends on recruitment of more myoblasts into the existing multinucleated fibers, which increases the number of nuclei in each cell.
- Growth in girth involves both myoblast recruitment and an increase in size and numbers of the contractile myofibrils that each muscle fiber nucleus supports.
1) What are the mechanisms that control muscle cell numbers and muscle cell size?
a. One part of the answer lies in an EC signal protein called myostain.
1) Even though humans don’t normally generate new skeletal muscle fibers in adult life, what can they do?
a. They have the capacity to do so, and existing muscle fibers can resume growth when the need arises. Cells capable of serving as myoblasts are retained as small, flattened, and inactive cells lying in close contact with the mature muscle cell and contained within its sheath of basal lamina. If the muscle is damaged or stimulated to grow, these satellite cells are activated to proliferate, and their progeny can fuse to repair the damaged muscle or to allow muscle growth. Like myoblasts, they are regulated by myostatin
1) Explain the process of muscle repair.
a. It is limited in what it can achieve. Satellite cells proliferate to repair the damaged muscle fibers. This regenerative response is unable to keep pace with the damage, and connective tissue eventually replaces the muscle cells, blocing any further possibility of regeneration.
1) Explain what happens in muscular dystrophy?
a. The satellite cells are constantly called upon to proliferate and their capacity to divide may become exhausted as a result of progressive shortening of their telomeres in the course of each cell cycle.
a. They are the least specialized cells in the connective-tissue family. They are dispersed in connective tissue throughout the body, where they secrete a nonrigid extracellular matrix that is rich in type I or III collagen, or both.
When a tissue is injured, what do fibroblasts do?
When a tissue is injured, the fibroblasts nearby proliferate, migrate into the wound, and produce large amounts of collagenous matrix, which helps to isolate and repair the damaged tissue.
1) What is a good example of connective tissue versatility?
- a. Stromal cells of bone marrow are because they can be regarded as a kind of fibroblasts, can be isolated from the bone marrow and propagated in culture. Large clones of progeny can be generated in this way from single ancestral stromal cells. Signal proteins can produce more cells of the same type, or can differentiate as fat cells, cartilage cells, or bone cells. Because of the self-renewing, multipotent character, they are referred to as mesenchymal stem cells.
- b. Fibroblasts from the dermal layer of the skin are different. When placed in the same cultural conditions, they do not show the same plasticity, but they can change their charater.
1) What does bone matrix contain?
a. It contains high concentrations of several signal proteins that can affect the behavior of connective-tissue cells. These factors regulate growth, differentiation, and matrix synthesis by connective-tissue cells, exerting a variety of actions depending on the target cell type and the combination of other factors and matrix components that are present. When injected into a living animal, they induce formation of cartilate, bone, or fibrous matrix.
a. It may influence the differentiated state of connective tissue cells through physical as well as chemical effects.
1) What does the biochemical change seem to be induced by?
a. It is induced by the change in cell shape and attachment. Cartilage cells that have made the transition to a fibroblast-like character can be gently detached from the culture dish and transferred to a dish of agarose. By forming a gel around them, the agarose holds the cells suspended without any attachment to a substratum, forcing them to adopt a rounded shape. In these circumstances, the cells promptly revert to the character of chondrocytes and start making type II collagen again.
1) For many types of cells, what does anchorage and attachment depend on?
a. It depends on the surrounding matrix, made by the cell itself. Thus, a cell can create an environment that then acts back on the cell to reinforce its differentiated state. Furtehrmore, the extracellular matrix that a cell secretes forms part of the environment for its neighbors as well as for the cell itself, and thus tends ot make neighboring cells differentiate in the same way.
1) Explain the cartilage matrix?
a. It is derformable, and the tissue grows by expanding as the chondrocytes divide and secrete more matrix.