Just last week, a paper was published showing that induced pluripotent stem cells, also called iPS cells, could be used to rescue vision in blind rats.
This international collaborative research effort was led by Prof. Dennis Clegg at the University of California, Santa Barbara, and Prof. Pete Coffey at the University College London. Researchers at UCSB were able to make these human iPS cells differentiate, or turn into, retinal cells.
Specifically, they turned them into retinal pigment epithelium (RPE) cells. These are essential for proper vision. Collaborators at UCL then took these cells and transplanted them into rats that were blind due to having inherited dysfunctional RPE cells. The transplanted cells rescued the blind rats’ vision; they could see.
These findings suggest that RPE cells, derived from iPS cells, could be used to treat blindness in humans, such as blindness caused by age-related macular degeneration, a leading cause of blindness in the Western world. This is just one of the many potential therapeutic applications of iPS cells.
First created in 2007, human iPS cells are a very recently created type of stem cell with great potential. iPS cells are virtually identical to human embryonic stem cells (also called hESCs), which this column has discussed previously, except for their origins. Both iPS cells and hESCs are pluripotent, meaning they have the potential to become any cell type in the body. However, while hESCs are created from human embryos, iPS cells are cells that were originally from adult tissues, such as skin from an adult body, but have been “reprogrammed” to a hESC-like state. The reprogramming is done by basically forcing adult cells to produce proteins that are key to the pluripotency of hESCs. The resultant cells look and act nearly identical to hESCs.
Because they are not derived from embryos, iPS cells help alleviate some of the ethical concerns surrounding the use of hESCs. Additionally, iPS cells can theoretically be patient-specific, using any adult cells from the patient to generate them. Consequently, iPS cells hold great potential for use in regenerative therapies.
To understand just how remarkable it is that iPS cells even exist, one must look at early animal development. As an embryo develops, all the cells in the embryo begin to take on different fates: The cells that will become the future organs are determined and are different from the predecessor cells of the skin, and so on. All of the cells in the embryo become more and more defined, and while they establish what future tissues they will be, they also define what tissues they cannot be; skin cells cannot be liver cells and vice versa. By the time the animal is an adult, most cells have very fixed identities. However, researchers have found ways to reprogram these adult cells so their identities are no longer fixed and they can theoretically become any type of cells; these reprogramming techniques led researchers to the creation of iPS cells.
The idea of reprogramming a cell from adult tissue into an embryonic-like cell existed long before the creation of iPS cells. In 1938, Prof. Hans Spemann (of the University of Freiburg-im-Breisgau, Germany) described his theory that any cell from an embryo that had already been developing still had the potential to create an entire adult animal. This theoretical feat involved two key components: (1) a fertilized egg that has had its nucleus removed (what is called “enucleated”), and (2) a nucleus from an older cell. (The nucleus is the part of a cell that contains the genetic material, or DNA.) Spemann conducted his studies in salamander eggs, which are easy to manipulate. He would take a newly fertilized salamander egg, remove its nucleus, and put the nucleus from an older salamander embryo into the enucleated egg. Somehow, the older nucleus could still give rise to an entire adult salamander in this way.
In the early 1950s, Profs. Robert Briggs and Thomas King (at the Fox Chase Cancer Center, Philadelphia, Pennsylvania) repeated Spemann’s experiments using leopard frogs and had success using a nucleus from an even later point in embryonic development.
In essence, these studies suggested that a newly fertilized, enucleated egg has the ability to “reprogram” a much older donor nucleus, making the resultant cell behave as though it were at a very early embryonic state. For years it was unclear whether the nucleus from a completely mature, adult cell could be reprogrammed because conflicting results were published by different research groups.
Although the studies done by Spemann, Briggs, and King used nuclei from embryos, their results formed the basis for somatic cell nuclear transfer (SCNT). SCNT is a technique wherein the nucleus from a somatic cell (an adult cell that is not a sperm or an egg) is implanted into an enucleated egg which can be implanted into, and develop, in a surrogate mother, and potentially become an adult organism. The resultant organism is a clone of the animal that donated the nucleus. The first widely-accepted successful use of SCNT came with the creation of the sheep Dolly in 1997, the first cloned animal from an adult. Since then, several other animals have been cloned, though many problems still remain.
With the living evidence of Dolly, and other animals cloned from adult cells, the idea that an adult somatic cell could become a reprogrammed embryonic-like cell regained a spotlight in the scientific community. The creation of iPS cells began by studying proteins not only uniquely created by embryonic stem cells, but proteins known to be functionally important in creating the unique properties of these cells. In 2006, Shinya Yamanaka’s group at the Institute for Frontier Medical Sciences at Kyoto University made the first iPS cells by applying this knowledge in mouse cells.
They made adult mouse cells become essentially mouse embryonic stem cells, in appearance and function, by forcing the adult cells to produce four key protein factors. The DNA of these factors was introduced into the cells using a retroviral system (a class of viruses similar to HIV in function but not in severity), incorporating them into the cells’ genomes, and consequently being translated into functioning protein by the host cell.
The same principles applied to the creation of human iPS cells, reported only a year later concurrently, though independently, by the laboratories of Yamanaka and Prof. James Thomson (who holds a faculty appointment at the University of Wisconsin and at UCSB). Yamanaka’s group used human adult skin cells and induced them to become iPS cells by having them produce the same protein factors that the mouse iPS cells had.
Thomson’s group created human iPS cells using fetal lung cells and foreskin cells with two of the same factors as Yamanaka, along with two different factors. The two protein factors the groups had in common appear to be quite crucial for the creation of iPS cells. Even though different cell types were used as the initial starting materials, and they were made to produce different sets of proteins, both groups identified and isolated cells nearly identical to human embryonic stem cells, and did so in the same timeframe.
Though iPS cells and hESCs are both pluripotent and virtually infinite in supply, there are distinct advantages and disadvantages associated with each cell type. As they are created from adult cells, iPS cells overcome many ethical concerns associated with hESCs and can be patient-specific-but may have life spans dependent upon donor cell age. Additionally, the originally generated iPS cells contained DNA randomly inserted into the genome from the retrovirus system, although researchers have since made new forms of iPS cells using non-integrating systems and have also improved delivery of the reprogramming factors to the cells.
Clearly, researchers are quickly overcoming the hurdles to using iPS cells in human clinical trials, though issues still remain to be addressed to ensure their safe use in regenerative medicine.
For more on human embryonic stem cells, see Teisha Rowland’s “All Things Stem Cell post on “Induced Pluripotent Stem Cells: A New Stem Cell Line with a Long History,” The National Institute of Health’s Stem Cell FAQs, or, for a visual explanation of terms used, see All Things Stem Cell’s Visual Stem Cell Glossary.
Biology Bytes author Teisha Rowland is a science writer, blogger at All Things Stem Cell, and graduate student in molecular, cellular, and developmental biology at UCSB, where she studies stem cells. Send any ideas for future columns to her at firstname.lastname@example.org.