Replenishing the ranksGrowth and Differentiation: the Case of Hematopoiesis As we have mentioned on several occasions this semester, there is a marked contrast between the genotypes of the cells in our body and their phenotypes. Almost all the cells in our body have an identical genotype - an identical set of genes. Yet the phenotypes of cells in our body are highly variable. The only way to reconcile these two apparently contradictory facts is to assume that the genotype of our cells contains much more information than is used by any one particular cell. In other words, different cells consult the common genomic library in different ways. Differentiation We imagine that during the early development of an embryo, cells in different parts of the embryo decide on which parts of their genome they will use to program their future lifestyles, their future phenotypes. This selective reading of the genome means that each distinct cell type will only consult a subset of the genes that are carried in its genome. The embryologic processes that allow cells to assume distinct phenotypes, phenotypes that distinguish them from other cells coexisting in the same embryo is termed differentiation. We can imagine that as the fertilized egg divides into 2 cells, then 4 then 8 and so forth, the cells in this ever-increasing population decide on what their individual differentiated fates will be. This decision commits the embryonic cell to a distinct differentiation pathway that will affect not only this cell itself, but all of its lineal descendants as well. The line of descendants that leads from this early embryonic cell to its descendants is also called a differentiation lineage. As an example, we might speculate that early in the development of an embryo, one cell decides that it will become the ancestor of all the blood-forming (hematopoietic) cells in the body. Another cell may commit to becoming the ancestor of all the nerve cells in the body; and yet another may become the ancestor of all the connective tissue cells. Importantly, the lineal descendants of these early embryonic cells will continue to respect the decision made by their early embryonic ancestor. Thus, the descendants of the embryonic cell that committed itself to become a blood-forming cell will, many cell generations later, continue to be specialized for the processes of blood formation. This scheme immediately provokes two major questions, neither of which we can answer for the moment. First, how does a given cell in the embryo choose its fate and that of its descendants? An early, still undifferentiated embryonic cell can pick and choose among many distinct differentiation pathways. What factors and what information persuade it to choose one fate rather than another? Second, after an early embryonic cell has decided its own fate, how is this decision remembered by its descendants? How does a particular cell 30 or 40 cell generations later know that its early ancestor was committed to a distinct differentiation pathway? We might speculate that each time a cell commits itself to a particular differentiation lineage, its genome is mutated in a specific way, ensuring that this decision will be perpetuated in the DNA sequences of its genes. But in fact, this does not happen. The nucleated cells in different tissues possess identical genomes. Therefore, we conclude that differentiation decisions are transmitted from one cell generation to the next via mechanisms that do not involve changes in the structure (sequence) of the DNA. Cell Growth and Differentiation 1 7.012 Fall 2004Let's focus for a moment on the first problem. In doing so, we must assume that a complicated series of signals persuades an early embryonic cell to commit itself to take on one or another differentiated state. What kind of information could this cell use? Positional information A cell may use positional information when committing to a particular differentiation lineage. You can imagine that a cell knows or remembers what region of the fertilized egg it arose from. Different regions of the egg may be chemically distinct from one another and this distinctness may be passed on to the cells that descend from these different regions. Alternatively, a cell that is deciding how to differentiate may sense what part of the embryo it is located in. Such positional information may help a cell decide what it and its descendants should become. For example, a cell that finds itself in the outer layers of the embryo might decide to become the ancestor of skin cells while a cell in the middle of the embryo might decide to become ancestor to the cells that will form the gut. How might a cell sense its own position in the embryo? We have a clue to this puzzle. Cells in an embryo concern themselves with the identities of their nearby neighbors. The identities of these neighbors govern its perceptions about its own position in the embryo. Growth factors If position is determined by neighboring cells, how does a cell ascertain the identities of its neighbors? A cell will communicate with its nearby neighbors by releasing and/or receiving the protein molecules that we previously termed growth factors, (GFs). Previously, we discussed GFs in the context of decisions made by cells whether they should grow or not. GFs were depicted as mitogens (agents that induce mitosis), and as such convey a binary signal. When GFs are present, they induce a cell to grow; when they are absent, the cell does not grow. Now we want to add more richness to the information that they carry: maybe some GFs can also carry information that persuades a cell to differentiate in one direction or another. Recall that GFs operate as inter-cellular messengers that convey information from one cell to another through their presence or absence. Several dozen distinct growth factors have been discovered to date*. Each is a protein molecule, usually of relatively small size (100 amino acids or less). A given cell may release several distinct growth factors and respond to a number of others. This means that the positional information received by a cell might be provided by the combinatorial mix of growth factor signals that it receives from its surrounding space, each of these factors having been released by one or more of the neighbors that surround it. *Examples of GFs are platelet-derived growth factor (PDGF), epidermal growth factor
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