Support Gladstone   Contact Us   Pressroom
Gladstone
Nobel Home    The Postdoc Years    Learn About iPS Cells    Media Resources      
Yamanaka

Stem Cell Science, Frequently Asked Questions

What are induced pluripotent stem cells?
How are iPS cells different from embryonic stem cells?
Why is iPS cell technology so important?
Does iPS technology obviate the need for embryonic stem cell research?
What has happened since Dr. Shinya Yamanaka developed iPS technology?
How can iPS cell technology be used in the future?
Who is Dr. Shinya Yamanaka?
How did Dr. Shinya Yamanaka develop iPS cell technology?
Where does Dr. Shinya Yamanaka work?
What is the Gladstone Institutes doing to build on Dr. Shinya Yamanaka's work?
What is the Gladstone Institutes?

What are induced pluripotent stem cells?
Induced pluripotent stem cells, or iPS cells, are a type of cell that has been reprogrammed from an adult cell, such as a skin or blood cell. iPS cells are pluripotent cells because, like embryonic stem cells, they can develop into virtually any type of cell. iPS cells are distinct from embryonic stem cells, however, because they are derived from adult tissue, rather than from embryos. iPS cells are also distinct from adult stem cells, which naturally occur—in small numbers—in the human body.

In 2006, Dr. Shinya Yamanaka developed the method for inducing skin cells from mice into becoming like pluripotent stem cells and called them iPS cells. In 2007, Dr. Yamanaka did the same with adult human skin cells.

Dr. Yamanaka's experiments revealed that adult skin cells, when treated with four pieces of DNA (now called the Yamanaka factors), can induce skin cells to revert back to their pluripotent state. His discovery has since led to a variety of methods for reprogramming adult cells into stem cells that can become virtually any cell type—such as a beating heart cell or a neuron that can transmit chemical signals. This allows researchers to create patient-specific cell lines that can be studied and used for drug discovery and possibly someday for regenerative medicine.

Back to top   

How are iPS cells different from embryonic stem cells?
iPS cells are a promising addition to embryonic stem cells for tackling human disease in the future. Embryonic stem cells hold tremendous potential for regenerative medicine, in which damaged organs and tissues could be replaced or repaired. But the use of embryonic stem cells has long been controversial. iPS cells hold the same sort of promise and can be made in a patient-specific manner. iPS cells are similar to embryonic stem cells, but some differences remain. Ongoing research, which compares iPS cells to embryonic stem cells, is addressing these differences.

Back to top   

Why is iPS cell technology so important?
iPS cell technology represents an entirely new platform for fundamental studies of human disease. Rather than using models made in yeast, flies or mice for disease research, iPS cell technology allows human stem cells to be created from patients with a specific disease. As a result, the iPS cells contain a complete set of the genes that resulted in that disease—and thus represent the potential of a far—superior model for studying disease and testing new drugs and treatments. In the future, iPS cells could be used in a Petri dish to test both drug safety and efficacy for an individual patient.

Back to top   

Does iPS technology obviate the need for embryonic stem cell research?
Because iPS technology is so new, it is still critical to fund and conduct human embryonic stem cell research. Knowledge gained from research with embryonic stem cells, in part, helped Dr. Yamanaka discover iPS technology. Researchers are still learning many important things about the safest and most efficient ways to create iPS cells for drug discovery, personalized medicine and tissue regeneration. To further refine iPS technology for such promising purposes, scientists still need to measure iPS cells against the "gold standard" of actual human embryonic stem cells.

Back to top   

What has happened since Dr. Shinya Yamanaka developed iPS technology?
There have been several advancements in the field since Dr. Yamanaka first developed iPS cell technology. The most recent advancement is called direct reprogramming, which offers a host of advantages when adult cells are reprogrammed into another type of cell without having to revert back to the pluripotent state. Deepak Srivastava, MD, who directs cardiovascular research at the Gladstone Institutes, earlier this year announced the direct reprogramming of cardiac fibroblasts—the heart's connective tissue—directly into beating cardiac-muscle cells in animal hearts. Also this year, Associate Investigator Yadong Huang, MD, PhD, announced the use of a single genetic factor to reprogram skin cells into cells that develop on their own into an interconnected, functional network of brain cells.

Back to top   

How can iPS cell technology be used in the future?

  1. Regenerative medicine. Gladstone scientists are testing the regenerative effects of iPS cells on animal models. For example, Deepak Srivastava, MD, who directs cardiovascular research at Gladstone, is working on ways to use iPS cell technology to re-grow heart muscles in individuals who have suffered heart attacks. Researchers are also testing whether iPS cell technology can help individuals with spinal cord injuries, as well as neurodegenerative diseases such as Alzheimer's, Huntington's and Parkinson's.
  2. Testing drug safety. Many drugs fail because they cause health problems that are not detected until clinical trials begin. Using iPS cell technology, Gladstone Investigator, Bruce Conklin, MD, is developing heart cells from reengineered adult human cells to test toxicity of drug therapies earlier in the drug-development process—with the goal of reducing the cost and time required for expensive animal and human trials.
  3. Personalized medicine. Drugs interact differently with different patients due to each individual's unique genetic makeup. Using a patient's own cells, researchers could leverage iPS technology to create brain, heart, liver and other cells with that patient's DNA. Those cells could then be used to test potential drug interactions for that specific patient, or someday potentially be used for transplantation or regeneration.

Back to top   

Who is Dr. Shinya Yamanaka?
Dr. Yamanaka is a senior investigator and the L.K. Whittier Foundation Investigator in Stem Cell Biology at the Gladstone Institutes. At Gladstone, he conducts research at the Roddenberry Stem Cell Center. Dr. Yamanaka is also a professor of anatomy at the University of California, San Francisco, as well as the director of the Center for iPS Cell Research and Application (CiRA) and a professor at the Institute for Integrated Cell-Material Sciences (iCeMS), both at Kyoto University, Japan. Before joining Gladstone as a postdoctoral fellow in 1993, Dr. Yamanaka was an orthopedic surgeon practicing in Japan. Leading up to his 2012 Nobel Prize in physiology or medicine, Dr. Yamanaka has received a host of other honors recognizing the importance of his iPS discovery, including the Albert Lasker Basic Medical Research Award, the Shaw Prize, the Wolf Prize in Medicine, the Millennium Technology Award Grand Prize and the Kyoto Prize for Advanced Technology. In 2011, Dr. Yamanaka was elected to the U.S. National Academy of Sciences, garnering one of the highest honors available for U.S. scientists and engineers.

Back to top   

How did Dr. Shinya Yamanaka develop iPS cell technology?
Dr. Yamanaka came to Gladstone in 1993 as a postdoctoral fellow, where he studied cholesterol and fat metabolism. However, after his experiments yielded unexpected results, his focus soon evolved into the study of how stem cells transform into various cell types.

Armed with the expertise he gained at Gladstone, Dr. Yamanaka returned to Japan in 1997 where he developed the innovative method of inducing skin cells into becoming pluripotent, just like embryonic stem cells. He first announced this breakthrough in mice in 2006 and the following year reported that he had done the same with human cells.

Back to top   

Where does Dr. Shinya Yamanaka work?
Dr. Yamanaka splits his time between San Francisco and Kyoto, where he is the director of the Center for iPS Cell Research and Application (CiRA) and professor at the Institute for Integrated Cell-Material Sciences (iCeMS) at Kyoto University. In San Francisco he is a senior investigator and L.K. Whittier Foundation Investigator in Stem Cell Biology at the Gladstone Institutes, where he conducts his research at the Roddenberry Stem Cell Center. He is also a professor of anatomy at the University of California, San Francisco (UCSF).

Back to top   

What is the Gladstone Institutes doing to build on Dr. Shinya Yamanaka's work?
The Roddenberry Stem Cell Center at Gladstone, houses several Gladstone scientists who are building upon Dr. Yamanaka's development of iPS cell technology:

And in July, Dr. Yamanaka's Gladstone lab reported that environmental factors critically influence the growth of iPS cells, taking an important step towards understanding how these cells develop—and towards the ability to use stem cell-based therapies to combat disease.

What is the Gladstone Institutes?
Gladstone is an independent and nonprofit biomedical-research organization dedicated to accelerating the pace of scientific discovery and innovation to prevent, treat and cure cardiovascular, viral and neurological diseases. Founded in 1979, Gladstone is affiliated with the University of California, San Francisco.

Using iPS Technology in Biomedical Research

iPS Technology

BRAIN

Scientists have used iPS cell technology to create nerve cells, allowing them to study a range of neurological disorders, including Alzheimer's, Parkinson's, and Huntington's disease, and develop better models for evaluating potential treatments. 1,2,3,4,5,6,7,8,9

  1. Ring KL, Tong LM, Balestra ME, Javier R, Andrews-Zwilling Y, Li G, Walker D, Zhang WR, Kreitzer AC, Huang Y. Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor. Cell Stem Cell. 2012, 11:100–109, Epub 2012 Jun 7.
  2. Almeida S, Zhang Z, Coppola G, Mao W, Futai K, Karydas A, Geschwind MD, Tartaglia MC, Gao F, Gianni D, Sena-Esteves M, Geschwind DH, Miller BL, Farese RV Jr, Gao FB. Induced pluripotent stem cell models of progranulin-deficient frontotemporal dementia uncover specific reversible neuronal defects. Cell Rep. 2012, 2:789–798, Epub 2012 Oct 11.
  3. Dimos J, Rodolfa K, Niakan K, Weisenthal L, Mitsumoto H, Chung W, Croft G, Saphier G, Leibel R, Goland R, Wichterle H, Henderson C, Eggan K. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science, 2008, 321:1218–1221, Epub 2008 Jul 31.
  4. Soldner F, Hockemeyer D, Beard C, Gao Q, Bell GW, Cook EG, Hargus G, Blak A, Cooper O, Mitalipova M, Isacson O, Jaenisch R. Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell. 2009 136:964–977.
  5. Wernig M, Zhao JP, Pruszak J, Hedlund E, Fu D, Soldner F, Broccoli V, Constantine-Paton M, Isacson O, Jaenisch R. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease. Proc Natl Acad Sci U S A. 2008, 105:5856–5861. Epub 2008 Apr 7.
  6. HD iPSC Consortium. Induced pluripotent stem cells from patients with Huntington's disease show CAG-repeat-expansion-associated phenotypes. Cell Stem Cell, 2012, 11:264–278.
  7. Ebert AD, Yu J, Rose FF Jr, Mattis VB, Lorson CL, Thomson JA, Svendsen CN. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature. 2009, 457:277–280. Epub 2008 Dec 21.
  8. Polentes J, Jendelova P, Cailleret M, Braun H, Romanyuk N, Tropel P, Brenot M, Itier V, Seminatore C, Baldauf K, Turnovcova K, Jirak D, Teletin M, Côme J, Tournois J, Reymann K, Sykova E, Viville S, Onteniente B. Human induced pluripotent stem cells improve stroke outcome and reduce secondary degeneration in the recipient brain. Cell Transplant. 2012 Aug 10. In press.
  9. Chang DJ, Lee N, Park IH, Choi C, Jeon I, Kwon J, Oh SH, Shin DA, Do JT, Lee DR, Lee H, Moon H, Hong KS, Daley GQ, Song J. Therapeutic potential of human induced pluripotent stem cells in experimental stroke. Cell Transplant. 2012 Oct 3. In press.

EYE

Scientists have generated iPS-based retinal cells, allowing them to study the causes and potential treatments of a range of diseases that can cause blindness, such as glaucoma and age-related macular degeneration.10,11

  1. Parameswaran S, Balasubramanian S, Babai N, Qiu F, Eudy JD, Thoreson WB, Ahmad I. Induced pluripotent stem cells generate both retinal ganglion cells and photoreceptors: therapeutic implications in degenerative changes in glaucoma and age-related macular degeneration. Stem Cells. 2010, 28:695–703.
  2. Jin Z, Okamoto S, Osakada F, Homma K, Assawachananont J, Hirami Y, Iwata T, Takahashi M. Modeling retinal degeneration using patient-specific induced pluripotent stem cells. PLoS On. 2011 Feb 10;6(2):e17084.

SPINAL CORD

In animal models of spinal cord injuries, scientists implanted iPS cells that then differentiated into functional nerve cells, suggesting a promising cell-replacement therapy that may one day be used to treat spinal cord injuries in people.12

  1. Tsuji O, Miura K, Okada Y, Fujiyoshi K, Mukaino M, Nagoshi N, Kitamura K, Kumagai G, Nishino M, Tomisato S, Higashi H, Nagai T, Katoh H, Kohda K, Matsuzaki Y, Yuzaki M, Ikeda E, Toyama Y, Nakamura M, Yamanaka S, Okano H. Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury. Proc Natl Acad Sci. USA, 2010, 107:12704–12709, Epub 6 Jul 2010

HEART

iPS cell technology provides an entirely new platform for understanding the causes of heart disease from congenital heart defects in babies to heart failure in the elderly. This technology offers new tools for evaluating drug treatments and the possibility of restoring heart muscle damaged by heart attack.13,14,15

  1. Lahti AL, Kujala VJ, Chapman H, Koivisto AP, Pekkanen-Mattila M, Kerkelä E, Hyttinen J, Kontula K, Swan H, Conklin BR, Yamanaka S, Silvennoinen O, Aalto-Setälä K. Modeling for long QT syndrome type 2 using human iPS cells demonstrates arrythmogenic characteristics in culture. Dis Model Mech. 2012, 5:220–230.
  2. Efe JA, Hilcove S, Kim J, Zhou H, Ouyang K, Wang G, Chen J, Ding S. Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy. Nature 2012, 485, 593–598
  3. Qian L, Huang Y, Spencer CI, Foley A, Vedantham V, Liu L, Conway SJ, Fu JD, Srivastava D. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature. 2012, 485:593–598.

KIDNEY

Kidney cells created from human iPS cells are helping scientists to better understand kidney disease and to evaluate potential alternative treatments in the hopes of one day eliminating the need for dialysis or transplants.16

  1. Song B, Smink A, Jones C, Callaghan J, Firth S, Bernard C, Laslett A, Kerr P, Ricardo S. The directed differentiation of human iPS cells into kidney podocytes. PLoS ONE 7(9): e46453.

LIVER

Scientists have generated iPS cell-derived liver cells from patients with liver disease to study its underlying causes and evaluate potential drugs to treat the disease.17

  1. Rashid ST, Corbineau S, Hannan N, Marciniak S, Miranda E, Alexander G, Huang-Doran I, Griffin J, Ahrlund-Richter L, Skepper J, Semple R, Weber A, Lomas DA, Vallier L. Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J Clin Invest. 2010, 120: 3127–3136, Epub: 25 Aug 2010.

PANCREAS

Researchers have transformed human iPS cells into insulin-producing cells that, when transplanted into mice with Type I diabetes, secrete insulin and normalize blood sugar levels. Such therapies may one day replace insulin injections for people with diabetes. 18

  1. Jeon K, Lim H, Kim J, Thuan NV, Park SH, Lim Y, Choi H, Lee E, Kim J, Lee M, Cho S. Differentiation and transplantation of functional pancreatic beta cells generated from induced pluripotent stem cells derived from a type 1 diabetes mouse model. Stem Cells and Development. 2012, 21:2642–2655

BLOOD

Scientists have converted human skin cells into blood cells through direct reprogramming, bypassing the iPS cell stage altogether. This approach represents the new frontier of cellular reprogramming for disease research.19

  1. Szabo E, Rampalli S, Risueno R, Schnerch A, Mitchell R, Fiebig-Comyn A, Levadoux-Martin M, Bhatia M. Direct conversion of human fibroblasts to multilineage blood progenitors. Nature 2010. 468:521–526.

BONE/CARTILAGE

Scientists have reprogrammed human iPS cells into bone and cartilage cells that may one day be used to treat diseases, such as osteoporosis, and replace damaged or injured cartilage.20,21,22

  1. Jin G, Kim T, Kim J, Won J, Yoo S, Choi S, Kim H. Bone tissue engineering of induced pluripotent stem cells cultured with macrochanneled polymer scaffold. J Biomed Mater Res Part A, 10.1002/jbm.a.34425
  2. Hiramatsu K, Sasagawa S, Outani H, Nakagawa K, Yoshikawa H, Tsumaki N. Generation of hyaline cartilaginous tissue from mouse adult dermal fibroblast culture by defined factors. J Clin Invest. 2011 121: 640–657, Epub: 10 Jan 2011.
  3. Medvedev SP, Grigor'eva EV, Shevchenko AI, Malakhova AA, Dementyeva EV, Shilov AA, Pokushalov EA, Zaidman AM, Aleksandrova MA, Plotnikov EY, Sukhikh GT, Zakian SM. Human induced pluripotent stem cells derived from fetal neural stem cells successfully undergo directed differentiation into cartilage. Stem Cells Devel. 2011, 20: 1099–1112, Epub 17 Oct 2010.

Stem Cells: A timeline

Stem Cell Timeline
 

  1. Gurdon, JB, Elsdale TR, Fischberg M. Sexually mature individuals of Xenopus laevis from the transplantation of single somatic nuclei. Nature 182: 65–65. 1958.
  2. Till J, McCulloch E. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiation Research 14 (2): 213–222, 1961.
  3. Jaenisch R, Mintz B. Simian virus 40 DNA sequences in DNA of healthy adult mice derived from preimplantation blastocysts injected with viral DNA. Proc. Natl. Acad. Sci. USA 71(4): 1250–1254, 1974.
  4. Evans M, Kaufman M. Establishment in culture of pluripotential cells from mouse embryos. Nature 292 (5819): 154–156, 1981.
  5. Martin G. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA 78 (12): 7634–7638, 1981.
  6. Campbell KHS, McWhir J, Ritchie WA, Wilmut I. Sheep cloned by nuclear transfer from a cultured cell line. Nature 380 (6569): 64–66, 1996.
  7. Jones J, Marshall V, Swiergiel J, Waknitz M, Shapiro S, Itskovits-Eldor J, Thomson J. Embryonic stem cell lines derived from human blastocysts. Science 282 (5391): 1145–1147, 1998.
  8. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126: 663–676, 2006.
  9. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131: 861–872, 2007.
  10. Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T, Okita K, Mochiduki Y, Takizawa N, Yamanaka S. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 26: 101–106, 2008, Epub 2007 Nov 30.
  11. Yu J, Vodyanik M, Smuga-Otto K, Antosiewicz-Bourget J, Frane J, Tian S, Nie J, Jonsdottir G, Ruotti V, Stewart R, Slukvin I, Thomson J. Induced pluripotent stem cell lines derived from human somatic cells. Science 318: 1917-1920, 2007. Epub Nov 2007.
  12. Hanna J, Wernig M, Markoulaki S, Sun CW, Meissner A, Cassady CP, Beard C, Brambrink T, Wu LC, Townes TM, Jaenisch R. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318(5858): 1920-1923, 2007.
  13. Wernig M, Zhao JP, Pruszak J, Hedlund E, Fu D, Soldner F, Broccoli V, Constantine-Paton M, Isacson O, Jaenisch R. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of Parkinson’s disease. Proc. Natl. Acad. Sci. USA 105(15): 5856-5861, 2008.
  14. Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S. Generation of mouse induced pluripotent stem cells without viral vectors. Science 322 (5903): 949-953, 2008.
  15. Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Sudhof TC, Wernig M. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463 (7284): 1035-41. Epub 2010 Jan 27.
  16. Ieda M, Fu J, Delgado-Olguin P, Vedantham V, Hayashi Y, Bruneau B, Srivastava D. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142: 375-386, 2010.
  17. Szabo E, Rampalli S, Risueno R, Schnerch A, Mitchell R, Fiebig-Comyn A, Levadoux-Martin M, Bhatia M. Direct conversion of human fibroblasts to multilineage blood progenitors. Nature 468: 521-526, 2010.
  18. Zhu S, Li W, Zhou H, Wei W, Ambasudhan R, Lin T, Kim J, Zhang K, Ding S. Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell 7:651–655, 2010.
  19. Ambasudhan R, Talantova M, Coleman R, Yuan X, Zhu S, Lipton S, Ding S. Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. Cell Stem Cell 9: 113-118, 2011.
  20. Qian L, Huang Y, Spencer CI, Foley A, Vedantham V, Liu L, Conway SJ, Fu JD, Srivastava D. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature 485: 593–8, 2012.
  21. The HD iPSC Consortium. Induced Pluripotent Stem Cells from Patients with Huntington’s Disease Show CAG-Repeat-Expansion-Associated Phenotypes. Cell Stem Cell 11:264-278, 2012.
  22. http://mainichi.jp/english/english/newsselect/news/20120613p2a00m0na005000c.html
  23. Ring KL, Tong LM, Balestra ME, Javier R, Andrews-Zwilling Y, Li G, Walker D, Zhang WR, Kreitzer AC, Huang Y. Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor. Cell Stem Cell 11: 100-9, 2012.
  24. Tomoda K, Takahashi K, Leung K, Okada A, Narita M, Yamada NA, Eilertson KE, Tsang P, Baba S, White MP, Sami S, Srivastava D, Conklin BR, Panning B, Yamanaka S. Derivation conditions impact x-inactivation status in female human induced pluripotent stem cells. Cell Stem Cell 11: 91-9, 2012.