The amazing potential of induced pluripotent stem cells (iPSC)

My interest in stem cells was heightened, even re-inspired, by a talk I saw recently at The Royal Society. Dr. Ian Wilmut, the man who created Dolly the sheep, the very first cloned animal, gave a brilliant and thought provoking talk about induced pluripotent stem cells (iPSC). I have read about iPSC but was not familiar with their incredible potential in investigating the biochemical basis of disease, in drug discovery, and for the treatment of many diseases and injuries.

Dr Wilmut started the talk with the question that has intrigued researchers for many years: “How does the single cell of the embryo become all of the tissues of the adult?” A cell with this ability is known as pluripotent, and the embryo is the perfect example of a pluripotent cell -in the course of embryogenesis it divides and differentiates into the 200 tissues present in the body. A similar point can be made about stem cells: they are not all created equal: some can become anything (i.e., are pluripotent), and some, such as adult stem cells, can only become certain types of cells (i.e., mulitpotent).1

In contrast to adult stem cells, the therapeutic potential of pluripotent cells seems limitless. You could use your pluripotent cells to replace any damaged or defective tissue in the body. Inject your pluripotent cells into a heart to replace cells damaged in a heart attack. Stimulate your pluripotent cells to become cartilage and repair a joint. And a myriad of other applications. However, until recently, the only source of pluripotent cell lines were embryos (embryonic pluripotent stem cell lines). Embryonic stem cells are pluripotent and grow for a very, very long time in tissue culture (essentially forever), making them ideal tools for research. As long as the embryos were from mice, rats or fruit flies, there were no problems. Human embryonic cell lines (hESC) are derived from human embryos, specifically from viable embryos that remained unused after in-vitro fertilisation and were destined to be destroyed. The use of a viable human embryo in this manner is seen as a violation of a life and as a consequence there are many who object to the use of human embryonic stem cells in research or at all. The controversy concerning the ethics of using cells derived from human embryos is not likely to go away.2

Fortunately there are alternatives to hESC lines, which are the induced pluripotent stem cells (iPSC) that Dr. Wilmut spoke of in his talk. iPSC are created from cells (usually adult skin cells) that have been induced to revert to their pluripotent state (no embryos destroyed!). iPSC lines share many of the desirable characteristics of hESC  in that they are pluripotent and grow for a very, very long time in tissue culture.

iPSC are made by reprogramming differentiated cells. The first iPSC were created by introducing four transcription factors into differentiated cells using retrovirus vectors. The process is inefficient, slow, and may make the cells cancerous, a danger of any therapy using retroviruses. Fortunately progress has been made overcoming these problems, and a new way to make iPSC was recently published. Dr Wilmut mentioned the work done by Derrick Rossi’s laboratory using synthetic messenger RNA was to reprogram the cells. The synthetic RNA method is faster and more efficient than the use of retroviruses, and had the added advantage that the DNA of the cells is left unaltered.

Another issue with hESC lines is that they represent an unknown genetic quantity. Dr. Wilmut observed that there is no knowledge of the genetic history of the embryo. Although many genetic defects can be tested for, one cannot predict what hidden defects the hESC lines may contain. In contrast iPSC are made from tissue donated by a person with a known medical history. This also allows for the possibility to make iPSC from people with specific diseases: with enormous potential for research and drug discover. For example Dr. Wilmut’s, laboratory is interested in the cause and cures for motor neuron disease. They have created an iPSC line from cells from a motor neuron patient and are using this iPSC to investigate the biochemical basis of the disease, and potential drug therapies.

Additionally, Dr. Wilmut envisioned making approximately 16 iPSC lines which would be compatible to most people (covering the major histocompatibility families). These cell lines could be used in the therapies outlined below negating the need, expense and time of creating individual iPSC lines for each patient, at least until making iPSC lines becomes as fast and easy as collecting the donor cells!

Below are some therapeutic areas where the uses of hESC lines are actively being investigated. iPSC lines could easily be used in place of the hESC in any of these treatments.

Spinal cord injuries: The biotech firm Geron has applied to the FDA and received approval to implant neural stem cells derived from hESC into people paralysed by severe injuries to the lower spine. The first treatment was performed in Atlanta, GA this week to a person with a recent spinal cord injury. It is a landmark moment as it is the first time that hESC lines have been used in a human in the USA. Concern over the appearance of cysts in test animals put the clinical trials on hold, but new screening procedures and animal tests reassured the FDA enough to allow the study to proceed.

Eyes: Advanced Cell Technology (ACT) has applied to the FDA for permission to use hESC-derived retinal pigment epithelium cells (RPEs) into the eyes of patients with Stargardt’s Macular Dystrophy. Treatment of age-related macular degeneration will probably follow Stargardt’s Macular Dystrophy as the next use of hESC-derived RPEs in human patients.

Parkinson’s disease: Geron is pressing forward with research into the use of hESC for the treatment of Parkinson’s disease. The hESC are differentiated into dopaminergic neurons3, which would be injected into the brains of patients with Parkinson’s disease. Preclinical trials are still being performed to assess the safety and efficacy of the treatment.

Skin: At the forefront of this field are Dr Christine Baldeschi and colleagues, of  the INSERM and Institute for Stem Cell Therapy and Exploration of Monogenic Diseases (I-STEM, France), who have published an article in Lancet describing the use of hESC to make skin. The hESC were driven towards keratinocyte lineage pharmacologically. The cells were then grown in culture on an artificial matrix, which was then grafted onto mice. Twelve weeks after grafting the skin grafts had a structure similar to human skin. The possibilities these results open up are wonderful. Burn patients could receive larger skin grafts derived from hESC in addition to grafts made from their own skin. hESC-derived skin grafts could be used to rectify horrible skin diseases like epidermolysis bullosa. And hESC could possibly be induced to form palmo-plantar epidermis (PPE) for use on the ends of weight bearing stumps on amputees.

Heart: Biotech firm Geron pops up again. They have made cardiomyocytes4 from mouse embryonic stem cells, which when injected into heart muscle are stably integrated. Their hope is to use hESC-derived cardiomyocytes to treat congestive heart failure and repair damage caused by heart attacks.

Another field where iPSC or hESC would be of great help is in the generation of replacement organs. The major hurdles of figuring out how to engineer replacement organs seem to have been overcome. Dr. Shay Soker at Wake Forest University in North Carolina grew an artificial liver by taking animal livers and removing all of the cells using detergent leaving a collagen support structure. Immature liver cells and blood endothelial cells were added to the structure and incubated in a bioreactor. A week later there was formation of liver tissue and liver-associated function. Success! But the question of where are they going to get the cells for future livers, kidneys or pancreases remains? I think iPSC can be as good a source of cells, if not better, as hESC for these replacement organs.

In conclusion, this is why iPSC are so important: anything for which hESC have been or are being used iPSC can be used instead. They are pluripotent and therefore they have enormous potential to help cure many diseases, they can be used to investigate disease, and they can be used for drug screening. Additionally iPSC have the advantage over hESC in that they are socially acceptable and they are a known quantity genetically.

If you are interested in hearing Sir Ian Wilmut’s talk it will available soon on the following link: http://royalsociety.org/All-our-Web-casts/

For more information about the Centre for Regenerative Medicine and Dr. Wilmut’s current research follow this link: http://www.crm.ed.ac.uk/about

The paper by Derrick Rossi’s laboratory on the use of synthetic mRNA to make iPSC: Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Warren L, Manos PD, Ahfeldt T, Loh YH, Li H, Lau F, Ebina W, Mandal PK, Smith ZD, Meissner A, Daley GQ, Brack AS, Collins JJ, Cowan C, Schlaeger TM, Rossi DJ. Cell Stem Cell. 2010 Nov 5;7(5):618-30.


1 See my previous post “Adult Stem Cells and their changing dogma” for a more complete overview.
2 In 2001 president George W Bush restricted the use of federal funds to just a few hESC lines. The restrictions have since lifted, but the controversy remains.
3 i.e. neurons that make dopamine, which are the neurons that die in Parkinson’s disease.
4 Cardiomyocytes are heart muscle cells.
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