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Induced Pluripotent Stem Cells Generated from Patients with ALS Can Be Differentiated into Motor Neurons

John T. Dimos,1* Kit T. Rodolfa,1,2* Kathy K. Niakan,1 Laurin M. Weisenthal,1 Hiroshi Mitsumoto,3,4 Wendy Chung,4,5 Gist F. Croft,4,6 Genevieve Saphier,1 Rudy Leibel,5 Robin Goland,7 Hynek Wichterle,4,6 Christopher E. Henderson,4,6 Kevin Eggan1

The generation of pluripotent stem cells from an individual patient would enable the large-scale production of the cell types affected by that patient's disease. These cells could in turn be used for disease modeling, drug discovery, and eventually autologous cell replacement therapies. Although recent studies have demonstrated the reprogramming of human fibroblasts to a pluripotent state, it remains unclear whether these induced pluripotent stem (iPS) cells can be produced directly from elderly patients with chronic disease. We have generated iPS cells from an 82-year-old woman diagnosed with a familial form of amyotrophic lateral sclerosis (ALS). These patient-specific iPS cells possess properties of embryonic stem cells and were successfully directed to differentiate into motor neurons, the cell type destroyed in ALS.

1 Harvard Stem Cell Institute, Stowers Medical Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.

2 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.

3 Eleanor and Lou Gehrig MDA-ALS Research Center, Neurological Institute, Columbia University Medical Center, New York, NY 10032, USA.

4 Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032, USA.

5 Division of Molecular Genetics and Naomi Berrie Diabetes Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

6 Departments of Pathology, Neurology and Neuroscience, Columbia University Medical Center, New York, NY 10032, USA.

7 Department of Medicine and Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, NY 10032, USA.

* These authors contributed equally to this work.

Originally published in Science Express on 31 July 2008

Science 29 August 2008:

Vol. 321. no. 5893, pp. 1218 - 1221

DOI: 10.1126/science.1158799



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Researchers Report Stem Cell Advance

By Jeffrey Perkel

HealthDay Reporter

September 25, 2008

Researchers report that they have sidestepped a major technical hurdle in the generation of pluripotent stem cells from adult cells.

A team of Boston scientists developed a way to generate induced pluripotent stem cells (iPS) -- which are functionally similar to embryonic stem cells, but which can be produced from adult cells, rather than via the creation or destruction of an embryo -- more safely than ever.

Should the findings, which involved mouse cells, be repeated with humans, they could pave the way for using iPS to delve into the biology of a wide range of genetic diseases. Longer term, they could lead to patient-specific stem-cell therapies.


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In the "second generation" embryonic stem cell technology, they take an adult skin cell, and introduce a small number of genes which direct the "committed" adult skin cell to revert all the way back to an embryonic stem cell.

All cells from a single individual have the same DNA. It's only a matter of controlling which part of the total DNA is active. There is no reason a cell cannot be reprogrammed to return to precisely the state it was in which it was a primitive embryonic stem cell or the original stem cell (the fertilized egg itself).

This technology would have the same genetic material and the same capabilities as the "first generation" embryonic stem cell technology. It would be the same cell as it was at the time it was a newly fertilized egg. It would genetically be an identical twin, a clone of the original fertilized egg, in every sense of the word.

In terms of them being 100% identical, save for four extraneous genes introduced to turn the non-pluripotent skin (somatic) cell back into a true embryonic stem cell, these genes would either silence themselves spontaneously or could be silenced using already available technology (e.g. RNA interference).

RNA interference uses small molecules that are an important regulatory component in the machinery of living cells. It allows scientists to "silence" certain genes. In RNA interference, certain molecules trigger the destruction of RNA from a particular gene, so that no protein is produced. Thus, the gene is effectively silenced.

While adult stem cells can be reprogrammed into embryonic stem cells by the introduction of four specific genes, direct reprogramming carries a theoretical risk of cancer for the recipients of tissue from these cells.

Normally, the four genes are delivered using retroviruses, which integrate their viral DNA into the cells' chromosomes. It seems like they've circumvented this problem by delivering the genes using adenoviruses instead, which do not insert their viral DNA into a cell's chromosomes. The cells then become pluripotent stem cells (iPS cells).

Making induced pluripotent stem cells (iPS cells) without using retroviruses (changing the DNA of their host cells, which can trigger cancer) is a safer way to make iPS cells. Pluripotent means they can become any type of cell.

Scientists used adenoviruses to insert the four genes needed to cause an adult cell to transform into an iPS cell. Adenoviruses do not change the DNA of their host. They go into the nucleus of the host and work directly on the proteins and leave the chromosomes alone (you don't need integration of the virus into the genome to produce iPS cells).

Researchers have also been looking at using chemicals instead of viruses as ways to introduce the four genes needed to make normal cells into iPS cells.

Human iPS cells have many potential uses. In research they could be used to find out how genes trigger diseases like cancer and Parkinson's, and one day there may be drugs tailored to individual patients that cause their own bodies to prevent genetic diseases from being triggered, or even to regenerate damaged tissue (e.g. brain cells damaged by neurodegenerative diseases).

"Induced Pluripotent Stem Cells Generated Without Viral Integration." Matthias Stadtfeld, Masaki Nagaya, Jochen Utikal, Gordon Weir, and Konrad Hochedlinger Science, Published Online September 25, 2008 DOI: 10.1126/science.1162494


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Researchers find easier way to make stem cells

Sun Oct 12, 2008

By Maggie Fox, Health and Science Editor

WASHINGTON (Reuters) - Researchers trying to find ways to transform ordinary skin cells into powerful stem cells said on Sunday they found a shortcut by "sprinkling" a chemical onto the cells.

Adding the chemical allowed the team at the Harvard Stem Cell Institute in Massachusetts to use just two genes to transform ordinary human skin cells into more powerful induced pluripotent stem cells or iPS cells.

"This study demonstrates there's a possibility that instead of using genes and viruses to reprogram cells, one can use chemicals," said Dr. Doug Melton, who directed the study published in the journal Nature Biotechnology.

To get these genes into the cells, they have had to use retroviruses, which integrate their own genetic material into the cells they infect. This can be dangerous and can cause tumors and perhaps other effects.

Last month U.S. researchers did the same thing using a harmless virus called an adenovirus, but the method was not efficient. And last week, Shinya Yamanaka of Kyoto University in Japan, who discovered iPS cells in mice, used a loop of genetic material called a plasmid to reformat the cells.

http://www.reuters.com/articlePrint?art ... M320081012

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adult Stem Cell Treatment Ready for Human Testing?

by Marty Graham

Wired Magazine

August 29, 2008

Doctors might soon be able to regrow injured muscles, tendons and bones without invasive surgery, simply by injecting a person's own stem cells into the site of an injury. Veterinarians are already doing it with injured horses, and research into human applications is well under way.

The National Institutes for Health seem to think regenerating human muscle and bone using a person's own adult stem cells is nearly ready for prime time. The NIH announced to its staff that it's creating a bone marrow-stem cell transplant center within the National Institute for Arthritis and Musculoskeletal and Skin Diseases.

http://www.wired.com/medtech/stemcells/ ... generation

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A 30-year old Columbian woman living in Spain whose airway was damaged from tuberculosis is the first person in the world to receive a new airway engineered from tissue that was grown from her own stem cells which means she is likely to have a much better quality of life because she will probably not have to take drugs for the rest of her life to stop her immune system rejecting the tissue.


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In two papers published in the journal Nature, researchers described how they reprogrammed stem cells using an even safer technique called electroporation. This allowed the scientists to do away with viruses and ferry genes into the cells through pores. Once the genes do their job, they are removed, leaving the cells healthy and intact.

Scientists could make stem cells from adult cells but the cells could never be used in patients because the procedure involved injecting viruses that could cause cancer. Electroporation allows the scientists to achieve the same feat without using viruses, making induced pluripotent stem (iPS) cell therapies a realistic prospect for the first time. The development of iPS cells was heavily dependent on the knowledge previously gained from embryonic stem cell research, which told scientists what the properties of a pluripotent stem cell are.

Electroporation (electropermeabilization) is a significant increase in the electrical conductivity and permeability of the cell plasma membrane caused by an externally applied electrical field. It is a way of introducing a piece of coding DNA. Because the cells can be made from a patient's own skin, they carry the same DNA and could be used without the risk of being rejected by the immune system.


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Controversial Cancer Stem Cells Offer New Direction For Treatment

In a review in Science, a University of Rochester Medical Center researcher sorts out the controversy and promise around a dangerous subtype of cancer cells, known as cancer stem cells, which seem capable of resisting many modern treatments.

The article proposes that this subpopulation of malignant cells may one day provide an important avenue for controlling cancer, especially if new treatments that target the cancer stem cell are developed and combined with traditional chemotherapy and/or radiation.


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Stem cells have that infinite ability to renew themselves and produce the many different cell types that make up a human. Cancer's hallmark is its ability to grow infinitely, multiplying into various cells that make up a tumor. Is cancer the result of a normal stem cell turned bad or an ordinary cell that somehow acquires a stem cell's immortality and versatility?

A recent finding that Temodar (temozolomide) increased the number of cancer cells with stem-like characteristics sounds eerily similar to the increase in the number of metabolic activity of mitochondria of the surviving cells from taxane (Taxol) therapy, even in cases where the majority of the cells are being killed by taxanes. It may indeed give clinical response (tumor shrinkage), however, these are mostly short-lived and relapses after a reponse to taxanes are often dramatic.

In stem cell research, anti-cancer treatments often effectively shrink the size of tumors, but some might have the opposite effect, actually expanding the small population of cancer stem cells that then are capable of metastasizing. Using the CellSearch System technique that quantifies circulating tumor cells, scientists had shown that chemotherapy with Taxol causes a massive release of cells into the circulation, while at the same time reducing the size of the tumor, explaining that complete pathologic responses do not correlate well with improvements in survival.

Circulating tumor cells (CTCs) are cancer cells that have detached from solid tumors and entered the blood stream. This can begin the process of metastasis, the most life-threatening aspect of cancer. To metastasize, or spread cancer to other sites in the body, CTCs travel through the blood and can take root in another tissue or organ.

Even before the advent of the CellSearch technique, it had been observed in Cell Function Analysis that there was an increase in the number of metabolic activity of mitochondria of the surviving cells from Taxol therapy, even in cases where the majority of the cells were being killed by Taxol.

This new research hightens the faults of gene amplificaton/mutation studies. Genetic profiling assumes that all drugs within a class will produce precisely the same effect, even though from clinical experience, this is not the case. Nor can genetic profiling tell anything about drug combinations.

Are you sure that you’ve identified every single protein that might influence sensitivity or resistance to drugs? The "cell" is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems' response to drug treatments, not theoretical predispositions.

Cancer is a complex disease and needs to be attacked on many fronts. Cellular profiling holds the key to solving some of the problems confronting the critical task of matching individual patients with the treatments most likely to benefit them.

The fact that cancer stem cells (CSCs) may have unique biological properties more likely to fuel cancer, or unfavorable factors in the neighboring cells surrounding the tumor, such as mutated genes, proteins that encourage cell growth, it is important to look at the "forest" and not just the "trees." There are many pathways to altered cellular (forest) function (hence all the different "trees" which correlate in different situations). Cell functional analysis measures what happens at the end (the effects on the forest), rather than the status of the individual trees.

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