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The developing cell: cell division and cell differentiation

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The cytoskeleton

 

Cell division requires the active remodelling of the cell’s cytoskeleton. The cytoskeleton is made of multiple kinds of protein that offer it the right structure and aid during the process of division.

 

The centriole is a tubey spaghetti thing that aids in cell division when the duplicated chromosomes need to move into their subsequent new offspring cells from the parent cell (during mitosis).

 

 

They’re made of a special protein called tubulin because they’re tubeeeeeeeeeeeees. Why didn’t they call it spaghettulin? I guess spaghetti aren’t hollow but…

 

Microtubules also play a key part in how cell organelles are moved and placed within the cell. Two associated centrioles form the centrosome. The microtubules are also where spindle fibres extend from when they separate chromosomes during cell division.

 

Cell cycle and mitosis

 

Cell cycle

 

The cell cycle refers to the distinct stages through which a cell goes, from the moment it becomes a cell to the moment it divides to result in 2 separate cells. Bear in mind that some cells cease to divide any longer after a certain period of time, depending on cell type. If that’s the case, they are said to be in resting phase termed G0.

 

A decrease in the cell cycle beyond appropriate levels would lead to degenerative disease, while too high an increase would cause tumours. Therefore, a balanced cell cycle is key to the good functioning of the body.

 

Within the dividing cell, it starts with gap 1, G1, continues into the S phase (S is for Synthesis) where DNA replicates, followed by gap 2, G2, and ending with mitosis.

 

G1 and G2 may sound like codes for some complex enzymes, but they are mere notations for gaps 1 and 2, which are just that: gaps between mitosis and DNA replication (in the S phase) respectively. G1 through to G2 – that’s G1, S phase and G2 – are all stages which collectively are known as interphase. Inter = between; phase = …phase, so interphase is just the stage between a cell’s creation and that cell’s division by mitosis.

 

Interphase is by far the stage in which most cells are in most of the time. The other stage, the small one, is called the mitotic phase and it encompasses mitosis (prophase, metaphase, anaphase and telophase) plus cytokinesis.

 

 

Overview of Mitosis

 

Mitosis is the process by which cells divide to achieve growth and repair by simply increasing cell number. For unicellular organisms, cell division is actually their reproduction itself (asexual reproduction). The dividing cell is called the parent cell, and the resulting two cells have inappropriately been called daughter cells by scientists so far. Now because cells don’t have a damn gender and we are better than accepting silly nonsensical received wisdom about what to call these cells, we will call them offspring cells instead. The offspring cells are genetically identical i.e. clones, as they contain copies of the parent cell’s DNA.

 

Stages of Mitosis

Prophase, metaphase, anaphase, telophase and cytokinesis.

 

 

There’s no easy way around these stages, so just bloody learn them. Actually there is an easy way. Awesome video time!

 

 

Prophase

1. Chromosomes begin to appear visible under a microscope due to chromatin (the coiled and yet-again coiled DNA fibre) condensing. Before this the DNA is not specifically distinguishable in the shape of chromosomes. This is a terrible word tangle so this is how it is. From a bowl of spaghetti (the nucleus) put the spaghetti in the shape of several chromosomes. Chromatin is the spaghetti initially, and chromosomes are the spaghetti still, just turned and twisted and distinguishable as individual stick-shaped objects. That is all, that’s all it is. Before this happens though, the DNA must be replicated – that’s the reason behind the X shape of chromosomes; they are two “lines” a.k.a. chromatids joined together at their centres called centromeres.

2. The nuclear envelope breaks down.

3. Organelles known as centrioles migrate towards the poles of the cell. These organelles are involved in the act of pulling the chromosomes apart into the soon-to-be offspring cells. They achieve this by the microtubules that extend out of them and connect to the centromeres. Microtubules are like lassos. Sort of.

 

 

Metaphase

1. Chromosomes are aligned at the cell equator by spindle fibres (made of the aforementioned microtubules) which lengthen and shorten themselves on opposing sides (tug of war) until all chromosomes are lined up about halfway across the cell. This area is called the metaphase plate. It looks like a plate. Who said biology can’t be straightforward?

 

 

Anaphase

1. The chromatids split at their centromeres and are pulled towards opposite poles of the cell by the shortening spindle fibres.

 

 

Telophase

1. Nuclear envelopes reform around the two new nuclei.

2. The chromosomes decondense and become indistinguishable under a microscope yet again, and the spindle fibres spread out.

 

 

Cytokinesis

This is the final step of mitosis when the cytoplasm of the parent cell divides to complete the cell division, resulting in two brand new and individual offspring cells. Actin filaments at the metaphase plate form a ring which contracts. Upon contraction, it splits the cell in two, marking the new state of two cells.

 

 

Plant cells must also build a new cell wall between them rather than just a new plasma membrane. The area where this takes place is the cell plate which contains Golgi vesicles. All the building blocks required for the formation of the cell wall are assembled.

 

 

Cell division regulation and apoptosis

 

Cells have checkpoints throughout the cell cycle that regulate if, and when they divide. These checkpoints are at G1, G2 and metaphase.

 

G1 is about cell growth prior to initiating DNA duplication. Unless the right level of growth has taken place, DNA duplication will not go ahead. Cells that do not proceed through G1 remain in the aforementioned G0 state.

 

If the cell does grow adequately, a number of proteins called cyclins are produced, which bind and activate their respective cyclin-dependent kinase proteins (Cdks). These go on to phosphorylate multiple protein factors that take part in cell division. The amount of phosphorylated proteins determines whether the threshold for sending the cell into the next stage has been met.

 

 

If so, one of the phosphorylated proteins responsible for DNA replication (retinoblastoma/Rb, a transcription factor inhibitor) enables DNA replication to start. This has taken the cell into the S phase.

 

DNA replication is an imperfect process, so DNA damage occurring from it causes certain proteins to be released, such as p53. This can aid towards DNA repair, make the cell cycle come to a halt, or cause cell death.

 

Apoptosis (cell death) signals can come from both outside the cell and inside the cell. They activate previously inactive DNAses and proteinases (a.k.a. caspases) that break down DNA and proteins.

 

 

Outside signals e.g. from lymphocytes, bind cell surface receptors and initiate a protein cascade that results in the production of active caspases. As mentioned before, the p53 DNA damage protein can trigger cell death – in this case, it would be a signal from within the cell.

 

Another scenario where apoptosis would be initiated is in the absence of cell growth factors.

 

Apoptosis involves cell shrinkage, the condensation of the nucleus, known as pyknosis, and bleb formation. Blebs are the plasma membrane protrusions that take place before the cell breaks down.

 

Next, the nucleus breaks down. This is nuclear fragmentation. The term for it is karyorrhexis. Such fun new terms for you today.

 

As apoptosis is underway, key signalling components of the cell plasma membranes signal to macrophages to break down the contents of the dying cell. These components include phosphotidylserines which are phospholipids in the membrane. Normally they face inwards the cell. Apoptosis causes other enzymes to make them face outwards instead. They then become an outer cell signal to macrophages.

 

 

Mitosis together with apoptosis form a mechanism for growth and repair. The patterns and timings of cellular growth and death enable the overall architecture of living tissues. For example, as hands form during foetal development, apoptosis is needed to create the fingers from the rough hand tissue (by removing the tissue between them).

 

Stem cell differentiation

 

Cells in our bodies have the same amount of DNA, and that DNA is completely identical! So how come a muscle cell and a brain cell both have very different structure and function despite that? How can cells be different to one another yet carry the same genetic information which codes for the same proteins? Indeed, how come most of a cell’s DNA is not translated?

 

 

The answer is that only the relevant genes are active in a given cell at a given time. The rest are inhibited because their transcription and/or translation is switched off. So how do cells become specialised?

 

Totipotent Stem Cells

Stem cells, just like tree stems are to branches, are the common source of all different kinds of cells. Cells start out as stem cells, and totipotent (totally-powerful) cells can differentiate into any kind of cell. When they translate only certain parts of their DNA, they become specialised.

 

 

Pluripotent (many-powerful) stem cells can differentiate into a wide variety of tissues, but not quite any whatsoever, like totipotent stem cells.

 

 

Multipotent stem cells are yet another sub-branch, narrower than pluripotent stem cells. End-point specialised cells such as heart cells are therefore unipotent and can only propagate their own type.

 

Stem cells are used in their own right in research to shed light on questions around cell division, differentiation and regulation by testing different culture conditions for different cells at different time points in development to see which transcription factors (which are proteins) are key in that process.

 

Using stem cells for replacing damaged tissues and organs

Alongside gene therapy, another promising approach to maintaining health is stem cell therapy. Gene therapy relies on existing cells carrying out functions differently. Stem cell therapy aims to be able to replace some of these cells altogether.

 

Stem cells are the precursor cells to all the specialised cells: muscle, nervous, skin, etc. Therefore, the cultivation of stem cells can produce specialised cells under specific conditions.

 

Prevalence

The embryos of mammals possess totipotent stem cells which upon differentiation and development into the adult organism do not occur again. The adults only have multipotent stem cells which have a limited range of cells they can change into. Using totipotent cells from embryos poses ethical issues because the embryo is destroyed in the process. Additionally, a source of disposable embryos must exist to provide the source for these cells.

 

Adult plants, on the other hand, retain many totipotent stem cells and that’s how you can actually grow a whole plant in vitro from just a cut fragment of any part of the plant. The conditions can even dictate which organ will develop!

 

Therapeutic Potential

The benefits of being able to grow any kind of cell from a stem cell (totipotent or multipotent) are vast. Replacing damaged tissue in heart failure and cancer is one example (bone marrow transplants are already happening, alongside corneal transplants and skin grafts). Genetic disorders such as Type I diabetes could also be addressed by stem cell therapy in the near future. Deafness, blindness and infertility are also on the list of conditions that could be treated by stem cell therapy.

 

The same signals known as protein transcription factors which enable differentiation in organisms can be used artificially in the lab to grow and differentiate different types of cell.

 

 

The transcription factors dictate which proteins get made from the DNA, which in turn determine the structure and function of the cell. In this manner, already differentiated cells like fibroblast cells (whose function is synthesising the cell extracellular matrix) can be coaxed into reverting to a stem cell-like state and then be used to differentiate again into a different type of cell such as a neurone. The new stem cells made this way are known as induced pluripotent stem cells (iPSC). They do not pose the issues that embryonic stem cells pose, because the source of cells is not an embryo.

 

 

 

 

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