Can all cells be stem cells?

We all want to live longer, escape disease, and experience life to its fullest. Our newspapers claim that stem cells will solve our medical problems. Michael J Fox pleads for support. Yet, debate surrounds stem cell research. We fear what we do not understand.

The controversial cells in question are known as embryonic stem cells (ES cells). Human ES cells are found in the very early four to five-day-old embryo. Their promise resides in the fact that they can become any cell type in the body. ES cells can transform into beta cells for a diabetic, neurons for a Parkinson’s patient, or heart muscle for an individual with cardiac trauma.

The majority of ES cells are harvested from unused embryos after fertility treatments. After isolation, ES cells can be maintained indefinitely in culture with good hands and rigorous care. Unfortunately, cellular contamination and naturally occurring mutations can affect the normal behavior of stem cells.

In a hotly disputed move, the Bush administration limited stem cell research to existing ES cell cultures. Researchers around the world began to pump laboratory manpower into finding ES cell alternatives.

In 2006, K. Takahashi and S. Yamanaka found that a mere four genes introduced into a differentiated mouse cell could coax adult cells back into a stem cell-state. Subsequently, other groups followed suit and had similar results with adult mouse liver, stomach, blood, and skin-specific cells.

A mature cell that is “re-programmed” into a stem cell is known as an induced pluripotent stem cell (iPS cell). Like embryonic stem cells, the iPS cells harbor the ability to differentiate into any cell type in the body. To prove that iPS cells are comparable to embryonic stem cells, they must pass a battery of tests. Only one test continuously stumped researchers – the tetraploid complementation test.

In tetraploid complementation, a flawed embryo serves as an empty vessel. Stem cell contribution to the faulty embryo enables the growth of an animal. Imagine a flowerpot. A flower will not grow from a pot of soil without planting a seed. In this test, the stem cells are like seeds. For iPS cells to be equivalent to ES cells, they must have the ability to grow into an entire animal when planted.

In what seems to be a tie finish, three independent groups successfully performed tetraploid complementation with iPS cells. Their work was released online in two prominent journals, Nature and Cell Stem Cell, last week.

The three teams, lead by Michael Boland of The Scripps Research Institute, Lan Kang of the Chinese Academy of Medical Sciences, and Xiao-yang Zhao of the Chinese Academy of Sciences Institute of Zoology, used mouse embryonic fibroblasts to generate iPS cells.

Fibroblasts produce the connective tissue between all cells in the body and have the ability to generate other cell types such as bone and smooth muscle. Because fibroblasts are primed for a transition to multiple cell types and grow beautifully in culture, they are an optimal choice for iPS cell studies.

To induce stem cells, the three groups each used a virus to deliver four genes, including Oct4, Sox2, Klf4, and c-Myc, into the embryonic fibroblasts. After a series of steps to verify the fibroblasts exhibited typical stem cell-like properties, the iPS cells were subjected to tetraploid complementation.

For the first time, each group successfully obtained at least one surviving adult mouse from their experiments. Importantly, the surviving mice were shown to be fertile, a critical requirement for the iPS cells to be considered equal to embryonic stem cells in this experiment.

While this is a major breakthrough in revealing induced pluripotent stem cell biology, it remains to be determined if cells isolated from adult tissue can have the same potency as the embryonic fibroblasts and if this same finding would hold true for humans. Indeed, for iPS cells to become a viable treatment for disease, we will need to understand the biology of re-programmed cells that are isolated from the human adult.

Finally, I want to ask my readers a question. If we can take a single cell that has already differentiated into its tissue specific form, activate a small set of genes, and use the induced stem cell to generate an entire animal, does this warrant a new area of bioethics in stem cell biology? If one considers human life to start with the potential to grow into an adult, then do all cells harbor this potential? Think about it. I’m happy to answer any questions and look forward to your comments on this controversial issue.

The bottom line: Stem cells generated from mouse embryonic fibroblasts are equivalent to embryonic stem cells in their ability to grow into a functioning adult mouse.

References:
Zhao, X.-Y. et al. Nature advance online publication doi:10.1038/nature08267 (2009).
Kang, L. et al. Cell Stem Cell doi:10.1016/j.stem.2009.07.001 (2009).
Boland et al. Nature advance online publication doi: 10.1038/nature08310 (2009).

A helpful site on stem cells for additional reading:
http://stemcells.nih.gov/info/basics/basics10.asp