Saturday, June 4, 2011

It is never to late to change your mind; how to make a neuron from a skin cell

The take home message from Kung Fu panda 2 (the kaboom of doom) is; your history is not important, it is who you choose to be in the present that count.
I have written several posts about the changing of cells in our bodies. The stem cells divides constantly, providing cells to our organs. But the cell need to differentiate, which means that it has to take step by step changes in order to end up as with a specific phenotype (cells as energetic stable states and their malignant counterpart is presented in review below). This specific phenotype, which we scientists like to refer to as lineage commitment, is robust.
I will write more about stem cell therapy in another post, it is a therapeutic possibility that sparks the imagination. The stem cell is tabula rasa. It has the promise to become any cell from a wide spectrum of choices. For every step it takes, it comes more specialized, and thus the range of choice decreases.

Image taken from the nature publication
showing a former
skin cell working as a neuron

In this post I am focusing on dedifferentiation/transdifferentitation. Once the cell has ended up with a specific phenotype, can it go back? If it can change, which programs are available? Can it backtrack and become any other cell in the body? The cloning of Dolly proved once and for all that every cell in the body has the same genetic set up and in theory could be used as a template for any cell type. Or is the cell’s end-phenotype stable and the only differentiation that is available to it is malignant progression? This last interpretation would fit with western linear thinking and perception of time. Previously I did not believe in dedifferentiation, I thought that the amount of energy that went into driving a cell from tabula rasa into an individual was too costly. I compared it with me not being able to go back in time and become 25 again (it hurts doesn’t it? J )
If we could take a cell, any cell from you, and get it to change it’s phenotype (which means it’s characteristics and it’s history), we would be fulfilling all the promise of stem cell therapy and beyond. I would like to write about this in parallel with eastern spiritual teachings. Not as a truth but just to “spice” it up. According to eastern spiritual teachings there is only now, history and the future is interpretation and ideas of the mind in the present. Now what if we can apply this to cells?
Can a skin cell become a say a heart cell or a neuron, does transdifferentation really exist?
The answer is yes. In the past year, researchers have converted connective tissue cells (fibroblasts) found in skin into heart cells, blood cells and liver cells. Transdifferentiation does not occur naturally (luckily or we would all look like we belonged in a H.P lovecraft novel), we need to give the cell a little help.
Now to the science parts; fibroblasts exist in various forms in every organ. By introducing transcription factors Gata4, Mef2c, and Tbx5 into the cells, scientists reprogrammed postnatal cardiac or dermal fibroblasts directly into differentiated cardiomyocyte-like cells. Induced cardiomyocytes expressed cardiac-specific markers, had a global gene expression profile similar to cardiomyocytes, and contracted spontaneously. Thus fibroblasts from skin can be used as a therapeutic pool for mending “a broken heart”. They can also be used to mend “a broken mind”;introducing factors Ascl1, Brn2 (also called Pou3f2) and Myt1l, converted mouse embryonic and postnatal fibroblasts into functional neurons in vitro (this means outside the body).
How cool is that? Lineage commitment (cell differentiation) is not written in stone. It can change. We can change linage commitment by giving it a kick. I like to think that we work in the same way. We take so much for granted and sometimes things happen in our lives and we are forced to reinterpet the meaning of life, relationships, money and love. Some time or another, most of us live through a transdifferentitation.
Pang, Z. P. et al. Nature advance online publication doi:10.1038/nature10202 (2011).
Reveiw; http://www.ncbi.nlm.nih.gov/pubmed?term=ernberg%2C%20kauffman

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