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Cellular differentiation

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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.



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.


Here is what the path of fibroblasts to iPSC looks like:



Fibroblasts are cultured in nutrients at 37 degrees Celsius. Retroviruses, which can infect fibroblasts, are used to deliver several transcription factors to the fibroblasts. These transcription factors are Oct3/4, Sox2, Klf4 and c-Myc. They dedifferentiate (revert) the fibroblasts to a stem cell-like state comparable to embryonic stem cells, hence producing iPSC. These can be cultured and used with a yet another different set of transcription factors to differentiate into specialise cells like heart cells.


Oct3/4 and Sox2 are involved in cell self-renewal which is what enables potency as opposed to specialisation, while Klf4 and c-Myc are involved in regulation cell proliferation and death (apoptosis), differentiation and reprogramming. Research is constantly discovering new transcription factors and combinations of these that have roles in various cell activities at different times in development. Therefore transcription factor cocktails can be figured out for different purposes such as differentiating neurones.


Limitations of using stem cells for replacing damaged tissues and organs include delivery, integration into existing tissue, compatibility with host tissue, and sourcing and production.


Using a patient’s own cells gets around the issue of compatibility and rejection, but raises challenges in terms of extracting the cells and growing them and differentiating them for the target tissue type. The balance of transplanted cells versus present tissue in a patient is an issue. Introducing few therapeutic cells causes little disturbance to the tissue, but may overpower the new cells and simply reprogram them into cells similar to the diseased cells. Introducing too many new cells can be traumatic to existing tissue, similar to surgery or implantation of synthetic devices or structures.


Questions around cell proliferation are also important if the tissue or organ seeking replacement is large or spread out, or deep into tissue. Sourcing and production (including scalability) are also limiting because growing and differentiating stem cells for certain tissue types can take a long time (many months for nerve cells), and can use up large amounts of biological materials. Some of these materials (used as food for the cells; no, they do not grow by magic) are sourced from slaughtered animals e.g. blood of calves, various other chemicals and proteins collected as a byproduct of the animal industry.



In terms of using stem cells for organ transplants, the issue is one of the extracellular matrix of organs. This is the solid, shape-giving structures made of collagen for example, that cells grow in. Hearts have had their cells (red) removed, and the scaffold used to populate with new stem cells, which spread throughout the heart successfully. There are many synthetic, bio-compatible materials being tested in combination with stem cells to make muscle, bone or skin tissues, as well as livers, kidneys, hearts, etc.


The issue is one of making the cells adhere to the artificial scaffold and proliferate in a way that leads to the normal development of organ function. 3D printing and other methods are used to create these scaffolds, sometimes at the same time as seeding them with stem cells.





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