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How to Change A Skin Cell Into A Nerve Cell or Cellular Anarchy & The Great Leap Sideways

Eyeballs just don’t become toenails — even though the same genome sits in the nucleus of every cell. The difference is in the parts of the genome that are expressed — a cell’s identity is determined by the specific genes that are active within that cell. The differentiation of a cell, and a cell’s commitment to become a particular type, have been long considered irreversible processes.

Stem cells (embryonic ES or induced iPS cells) have not yet committed to become any particular cell type, and they exist in an entirely undifferentiated stage. Only stem cells can become any type of cell in a particular organism –- the property of pluripotency. Pluripotent stem cells become the slightly more differentiated, slightly more distinctive, multipotent adult stem or progenitor cells –- neural stem cells can become any type of cell in the nervous system; hematopoietic stem cells can become any type of cell in the blood.

These cells express certain genes specific to their type, and as they move through the process of differentiation, they become increasingly specific types of cells –- ultimately becoming terminally differentiated somatic cells, like astrocytes or red blood cells. These cells cannot specialize any further, and they cannot go backwards towards less differentiated states. Such has been the wisdom of developmental and cellular biology. There are occasional switches between types of less differentiated adult stem cells, cancer cells inexplicably de-differentiate, and scientists have been able to revert cells to an entirely undifferentiated, induced pluripotent stem (iPS) cell state in a lab – but the closer a cell gets to a terminally differentiated stage, the less able it is to change course. And the unlimited potential of pluripotency is exclusive to cells at the start of all lineages – undifferentiated stem cells alone may become any type of cell.

Werniq Lab. Photo: stemcell.stanford.eduOr are they alone? A team at Stanford’s Institute for Stem Cell Biology & Regenerative Medicine (ISCBRM), led by Marcus Wernig and graduate student Thomas Vierbuchen, recently announced that a combination of only three transcription factors that would change a skin cell into a nerve cell — with no intermediate (undifferentiated) steps. A terminally differentiated cell – a skin fibroblast – became another terminally differentiated cell – a neuron – without entering a stem cell phase.

Such a finding defies our understanding of pluripotency: A pluripotent cell can become any fetal or adult cell type. Only stem cells have been known to do this. How did they do it? The answer lies in gene expression.

Werning’s team searched for genes usually active in neurons. These neuron-specific genes served as the template for the transcription factors they designed. A transcription factor is a type of protein that binds to sequence of DNA, and like an on/off switch, can regulate the expression of a gene.

These transcription factors can be placed into delivery systems called vectors (usually made out of gutted viruses), which carry the information to the cell. Ordinary mouse fibroblasts (skin cells), living a culture dish, were (scientifically) drowned in these vectors, which delivered the transcription factors to their host cells.

The transcription factors did their jobs: the target genes were activated. Just one factor (Ascl1) induced immature neurons, but when Brn2 and Mytl1 were added, the three transcription factors made all the difference. The skin cells changed completely — their shape changed, growing rounder, and extending axon-like processes. They began to resemble neurons – forming functional synapses, generating action potentials – even GABAergic cells were found!

Marius Wernig. Photo: stemcell.stanford.eduThis finding is not entirely unique. In 2008, a Japanese team transdifferentiated pancreatic acinar to beta cells in vitro. And as far back as 1988, viruses have been known to convert B-cells to macrophages. These studies are a rising challenge to the permanence of cellular differentiation, and the integrity of lineage commitment. The direct conversion of one terminally differentiated cell to another changes the facts, and shakes our understanding — implying that, just maybe, under the right conditions, all cells are pluripotent: with the proper tools, all types of cells may form all types of cells.

This research is in very early stages, and scientists still struggle to demonstrate it in human cells. But there is much to hope for as we discover this great leap sideways, and much to be learned about transdifferentiation at the end of cell lineage. Regenerative medicine looks to repair the body with its own cells –-and a supply of a patient’s own healthy neurons, for instance, could lead to revolutionary progress in the fight against Parkinson’s, Alzheimer’s, and neurodegenerative disorders. The secrets of cell development are so filled with promise, you might say the field is brimming with pluripotential…

Read More:

Klinken S. Warren A. Adams J. (1988) Hemopoietic lineage switch: v-raf oncogene converts Eμmyc transgenic B cells into macrophages. Cell (53):6, 857-867.
Minami K. Seino S. (2008) Pancreatic acinar-to-beta cell transdifferentiation in vitro. Front Biosci. 1;13:5824-37.
Murre C. (2004) Reprogramming committed

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