Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Published Online December 6, 2007
Science DOI: 10.1126/science.1152092

Reports

Submitted on October 23, 2007
Accepted on November 26, 2007

Treatment of Sickle Cell Anemia Mouse Model with iPS Cells Generated from Autologous Skin

Jacob Hanna 1, Marius Wernig 1, Styliani Markoulaki 1, Chiao-Wang Sun 2, Alexander Meissner 1, John P. Cassady 3, Caroline Beard 1, Tobias Brambrink 1, Li-Chen Wu 2, Tim M. Townes 4*, Rudolf Jaenisch 3*

1 The Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
2 Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Schools of Medicine and Dentistry, Birmingham, AL 35294, USA.
3 The Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.; MIT Department of Biology, Cambridge, MA 02142, USA.
4 MIT Department of Biology, Cambridge, MA 02142, USA.

* To whom correspondence should be addressed.
Tim M. Townes , E-mail: ttownes{at}uab.edu
Rudolf Jaenisch , E-mail: Jaenisch{at}wi.mit.edu

It has recently been demonstrated that mouse and human fibroblasts can be reprogrammed into an embryonic stem cell–like state by introducing combinations of four transcription factors. However, the therapeutic potential of such induced pluripotent stem (iPS) cells remained undefined. By using a humanized sickle cell anemia mouse model, we show that mice can be rescued after transplantation with hematopoietic progenitors obtained in vitro from autologous iPS cells. This was achieved after correction of the human sickle hemoglobin allele by gene-specific targeting. Our results provide proof of principle for using transcription factor–induced reprogramming combined with gene and cell therapy for disease treatment in mice. The problems associated with using retroviruses and oncogenes for reprogramming need to be resolved before iPS cells can be considered for human therapy.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Toward clinical therapies using hematopoietic cells derived from human pluripotent stem cells.
D. S. Kaufman (2009)
Blood 114, 3513-3523
   Abstract »    Full Text »    PDF »
Induced Pluripotent Stem Cells: It's Like Deja Vu All Over Again.
K. Schenke-Layland and W. R. MacLellan (2009)
Circulation 120, 1462-1464
   Full Text »    PDF »
Generation of Pig Induced Pluripotent Stem Cells with a Drug-Inducible System.
Z. Wu, J. Chen, J. Ren, L. Bao, J. Liao, C. Cui, L. Rao, H. Li, Y. Gu, H. Dai, et al. (2009)
J Mol Cell Biol 1, 46-54
   Abstract »    Full Text »    PDF »
Sox2 is dispensable for the reprogramming of melanocytes and melanoma cells into induced pluripotent stem cells.
J. Utikal, N. Maherali, W. Kulalert, and K. Hochedlinger (2009)
J. Cell Sci. 122, 3502-3510
   Abstract »    Full Text »    PDF »
A non-viral vector for potential DMD gene therapy study by targeting a minidystrophin-GFP fusion gene into the hrDNA locus.
J. Yang, X. Liu, J. Yu, L. Sheng, Y. Shi, Z. Li, Y. Hu, J. Xue, L. Wu, Y. Liang, et al. (2009)
Acta Biochim Biophys Sin
   Abstract »    Full Text »    PDF »
On the Road to iPS Cell Cardiovascular Applications.
T. J. Kamp and G. E. Lyons (2009)
Circ. Res. 105, 617-619
   Full Text »    PDF »
iPS Programmed Without c-MYC Yield Proficient Cardiogenesis for Functional Heart Chimerism.
A. Martinez-Fernandez, T. J. Nelson, S. Yamada, S. Reyes, A. E. Alekseev, C. Perez-Terzic, Y. Ikeda, and A. Terzic (2009)
Circ. Res. 105, 648-656
   Abstract »    Full Text »    PDF »
In vitro differentiation of retinal cells from human pluripotent stem cells by small-molecule induction.
F. Osakada, Z.-B. Jin, Y. Hirami, H. Ikeda, T. Danjyo, K. Watanabe, Y. Sasai, and M. Takahashi (2009)
J. Cell Sci. 122, 3169-3179
   Abstract »    Full Text »    PDF »
Emerging potential of transposons for gene therapy and generation of induced pluripotent stem cells.
T. VandenDriessche, Z. Ivics, Z. Izsvak, and M. K. L. Chuah (2009)
Blood 114, 1461-1468
   Abstract »    Full Text »    PDF »
Repair of Acute Myocardial Infarction by Human Stemness Factors Induced Pluripotent Stem Cells.
T. J. Nelson, A. Martinez-Fernandez, S. Yamada, C. Perez-Terzic, Y. Ikeda, and A. Terzic (2009)
Circulation 120, 408-416
   Abstract »    Full Text »    PDF »
Progress and future challenges in stem cell-derived liver technologies.
D. M. Dalgetty, C. N. Medine, J. P. Iredale, and D. C. Hay (2009)
Am J Physiol Gastrointest Liver Physiol 297, G241-G248
   Abstract »    Full Text »    PDF »
Calpeptin Increases the Activity of Upstream Stimulatory Factor and Induces High Level Globin Gene Expression in Erythroid Cells.
I-J. Lin, Z. Zhou, V. J. Crusselle-Davis, B. Moghimi, K. Gandhi, A. Anantharaman, D. Pantic, S. Huang, G. Jayandharan, L. Zhong, et al. (2009)
J. Biol. Chem. 284, 20130-20135
   Abstract »    Full Text »    PDF »
Surface antigen phenotypes of hematopoietic stem cells from embryos and murine embryonic stem cells.
S. L. McKinney-Freeman, O. Naveiras, F. Yates, S. Loewer, M. Philitas, M. Curran, P. J. Park, and G. Q. Daley (2009)
Blood 114, 268-278
   Abstract »    Full Text »    PDF »
Induced pluripotent stem cells offer new approach to therapy in thalassemia and sickle cell anemia and option in prenatal diagnosis in genetic diseases.
L. Ye, J. C. Chang, C. Lin, X. Sun, J. Yu, and Y. W. Kan (2009)
PNAS 106, 9826-9830
   Abstract »    Full Text »    PDF »
Cellular reprogramming and pluripotency induction.
M. W. Lensch (2009)
Br. Med. Bull. 90, 19-35
   Abstract »    Full Text »    PDF »
Transcriptome transfer produces a predictable cellular phenotype.
J.-Y. Sul, C.-w. K. Wu, F. Zeng, J. Jochems, M. T. Lee, T. K. Kim, T. Peritz, P. Buckley, D. J. Cappelleri, M. Maronski, et al. (2009)
PNAS 106, 7624-7629
   Abstract »    Full Text »    PDF »
Differentiation therapy of leukemia: 3 decades of development.
D. Nowak, D. Stewart, and H. P. Koeffler (2009)
Blood 113, 3655-3665
   Abstract »    Full Text »    PDF »
Reprogramming to a muscle fate by fusion recapitulates differentiation.
J. H. Pomerantz, S. Mukherjee, A. T. Palermo, and H. M. Blau (2009)
J. Cell Sci. 122, 1045-1053
   Abstract »    Full Text »    PDF »
Identification of Differentially Expressed Genes Between Cloned and Zygote-Developing Zebrafish (Danio rerio) Embryos at the Dome Stage Using Suppression Subtractive Hybridization.
D. Luo, W. Hu, S. Chen, Y. Xiao, Y. Sun, and Z. Zhu (2009)
Biol Reprod 80, 674-684
   Abstract »    Full Text »    PDF »
The endothelial antigen ESAM marks primitive hematopoietic progenitors throughout life in mice.
T. Yokota, K. Oritani, S. Butz, K. Kokame, P. W. Kincade, T. Miyata, D. Vestweber, and Y. Kanakura (2009)
Blood 113, 2914-2923
   Abstract »    Full Text »    PDF »
Assessment of the developmental competence of human somatic cell nuclear transfer embryos by oocyte morphology classification.
Y. Yu, Q. Mai, X. Chen, L. Wang, L. Gao, C. Zhou, and Q. Zhou (2009)
Hum. Reprod. 24, 649-657
   Abstract »    Full Text »    PDF »
Epigenetic reprogramming and induced pluripotency.
K. Hochedlinger and K. Plath (2009)
Development 136, 509-523
   Abstract »    Full Text »    PDF »
From the Cover: Phenotypic correction of murine hemophilia A using an iPS cell-based therapy.
D. Xu, Z. Alipio, L. M. Fink, D. M. Adcock, J. Yang, D. C. Ward, and Y. Ma (2009)
PNAS 106, 808-813
   Abstract »    Full Text »    PDF »
Reprogramming of murine and human somatic cells using a single polycistronic vector.
B. W. Carey, S. Markoulaki, J. Hanna, K. Saha, Q. Gao, M. Mitalipova, and R. Jaenisch (2009)
PNAS 106, 157-162
   Abstract »    Full Text »    PDF »
The significance of induced pluripotent stem cells for basic research and clinical therapy.
J R Meyer (2008)
J. Med. Ethics 34, 849-851
   Abstract »    Full Text »    PDF »
Mouse Meningiocytes Express Sox2 and Yield High Efficiency of Chimeras after Nuclear Reprogramming with Exogenous Factors.
D. Qin, Y. Gan, K. Shao, H. Wang, W. Li, T. Wang, W. He, J. Xu, Y. Zhang, Z. Kou, et al. (2008)
J. Biol. Chem. 283, 33730-33735
   Abstract »    Full Text »    PDF »
Hemoglobin research and the origins of molecular medicine.
A. N. Schechter (2008)
Blood 112, 3927-3938
   Abstract »    Full Text »    PDF »
Induced Pluripotent Stem Cells Generated Without Viral Integration.
M. Stadtfeld, M. Nagaya, J. Utikal, G. Weir, and K. Hochedlinger (2008)
Science 322, 945-949
   Abstract »    Full Text »    PDF »
Induced Pluripotency of Mouse and Human Somatic Cells.
N. Maherali and K. Hochedlinger (2008)
Cold Spring Harb Symp Quant Biol
   Abstract »    PDF »
Reprogramming of Somatic Cell Identity.
J. Hanna, B.W. Carey, and R. Jaenisch (2008)
Cold Spring Harb Symp Quant Biol
   Abstract »    PDF »
Understanding pluripotency--how embryonic stem cells keep their options open.
B.V. Johnson, N. Shindo, P.D. Rathjen, J. Rathjen, and R.A. Keough (2008)
Mol. Hum. Reprod. 14, 513-520
   Abstract »    Full Text »    PDF »
Metalloproteinase regulation improves in vitro generation of efficacious platelets from mouse embryonic stem cells.
H. Nishikii, K. Eto, N. Tamura, K. Hattori, B. Heissig, T. Kanaji, A. Sawaguchi, S. Goto, J. Ware, and H. Nakauchi (2008)
J. Exp. Med. 205, 1917-1927
   Abstract »    Full Text »    PDF »
Get With the (Re)Program: Cardiovascular Potential of Skin-Derived Induced Pluripotent Stem Cells.
N. L. Tulloch, L. Pabon, and C. E. Murry (2008)
Circulation 118, 472-475
   Full Text »    PDF »
Generation of Functional Murine Cardiac Myocytes From Induced Pluripotent Stem Cells.
C. Mauritz, K. Schwanke, M. Reppel, S. Neef, K. Katsirntaki, L. S. Maier, F. Nguemo, S. Menke, M. Haustein, J. Hescheler, et al. (2008)
Circulation 118, 507-517
   Abstract »    Full Text »    PDF »
Genetic Enhancement of Stem Cell Engraftment, Survival, and Efficacy.
M. S. Penn and A. A. Mangi (2008)
Circ. Res. 102, 1471-1482
   Abstract »    Full Text »    PDF »
Development of single mouse blastomeres into blastocysts, outgrowths and the establishment of embryonic stem cells.
C. Lorthongpanich, S.-H. Yang, K. Piotrowska-Nitsche, R. Parnpai, and A. W S Chan (2008)
Reproduction 135, 805-813
   Abstract »    Full Text »    PDF »
Stem Cells and Transplant Arteriosclerosis.
Q. Xu (2008)
Circ. Res. 102, 1011-1024
   Abstract »    Full Text »    PDF »
The Management of Heart Failure: The Past, the Present, and the Future.
E. Braunwald (2008)
Circ Heart Fail 1, 58-62
   Full Text »    PDF »
Generation of isogenic pluripotent stem cells.
J. A. Byrne (2008)
Hum. Mol. Genet. 17, R37-R41
   Abstract »    Full Text »    PDF »
Seminal discoveries in regenerative medicine: contributions of the male germ line to understanding pluripotency.
N. Geijsen and D. L. Jones (2008)
Hum. Mol. Genet. 17, R16-R22
   Abstract »    Full Text »    PDF »
Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease.
M. Wernig, J.-P. Zhao, J. Pruszak, E. Hedlund, D. Fu, F. Soldner, V. Broccoli, M. Constantine-Paton, O. Isacson, and R. Jaenisch (2008)
PNAS 105, 5856-5861
   Abstract »    Full Text »    PDF »
Towards the genetic treatment of {beta}-thalassemia: new disease models, new vectors, new cells.
P. Moi and M. Sadelain (2008)
Haematologica 93, 325-330
   Full Text »    PDF »
A New Dawn for Stem-Cell Therapy.
D. R. Higgs (2008)
N. Engl. J. Med. 358, 964-966
   Full Text »    PDF »
The See-saw of Differentiation: Tipping the Chromatin Balance.
K. Muegge, S. Xi, and T. Geiman (2008)
Mol. Interv. 8, 15-18
   Abstract »    Full Text »    PDF »
Gene Replacement Therapy for Sickle Cell Disease and Other Blood Disorders.
T. M. Townes (2008)
Hematology 2008, 193-196
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)