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

Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Science (Impact Factor: 33.61). 12/2007; 318(5858):1920-3. DOI: 10.1126/science.1152092
Source: PubMed


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.

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Available from: Chiao-Wang Sun
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    • "Great achievements have so far been made in the application of iPSC transplantation. For example , the successful corrections of sickle cell anemia, Fanconi anemia, and tyrosinemia111213via the transplantation of iPSC-derived differentiated cell types into diseased mouse models. The shortcoming of this research is to use the same strain of C57BL/6 (B6) mice as recipients to test the immune rejection of the iPSCs, derived from mice which are within the same strain but are not the same individual mice, between the donors of iPSCs and the recipients[1]. "
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    ABSTRACT: To investigate the immune-rejection and tumor-formation potentials of induced pluripotent stem cells and other stem cells, we devised a model—designated the “Mouse Clone Model”—which combined the theory of somatic animal cloning, tetraploid complementation, and induced pluripotent stem cells to demonstrate the applicability of stem cells for transplantation therapy.
    Full-text · Article · Jan 2015 · Stem Cell Research & Therapy
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    • "For example, Parkinson's disease model rats were effectively treated by cell replacement therapy with terminally-differentiated neurons derived from reprogrammed fibroblasts, with little immune rejection [69]. Moreover, iPSCs corrected through gene editing displayed the therapeutic potential to cure genetic disorders in a mouse model of sickle cell anemia, together with reduced immunogenicity [70]. "
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    ABSTRACT: Induced pluripotent stem cells (iPSCs) were first described in 2006 and have since emerged as a promising cell source for clinical applications. The rapid progression in iPSC technology is still ongoing and directed toward increasing the efficacy of iPSC production and reducing the immunogenic and tumorigenic potential of these cells. Enormous efforts have been made to apply iPSC-based technology in the clinic, for drug screening approaches and cell replacement therapy. Moreover, disease modeling using patient-specific iPSCs continues to expand our knowledge regarding the pathophysiology and prospective treatment of rare disorders. Furthermore, autologous stem cell therapy with patient-specific iPSCs shows great propensity for the minimization of immune reactions and the provision of a limitless supply of cells for transplantation. In this review, we discuss the recent updates in iPSC technology and the use of iPSCs in disease modeling and regenerative medicine.
    Full-text · Article · Sep 2014 · The Korean Journal of Internal Medicine
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    • "Induced pluripotent stem cells were first established in 2006 by Takahashi and Yamanaka [1] who used retrovirus to transduce 24 pluripotency associated genes into mouse fibroblasts, identifying four genes, Oct-4, SOX-2, C-myc and Klf-4, required to mediate reprogramming. The cells are similar to embryonic pluripotent stem cells (ESCs) in their morphology, pluripotency marker expression, self-renewal property and ability to differentiate into the three primary germ layers both in vivo and in vitro [2], [3], [4], [5], [6], [7]. However, they do not have the ethical barriers of ESCs [4]. "
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    ABSTRACT: Induced pluripotent stem cells (iPSC) are an attractive progenitor source for the generation of in vitro blood products. However, before iPSC-derived erythroid cells can be considered for therapeutic use their similarity to adult erythroid cells must be confirmed. We have analysed the proteome of erythroid cells differentiated from the iPSC fibroblast derived line (C19) and showed they express hallmark RBC proteins, including all those of the ankyrin and 4.1R complex. We next compared the proteome of erythroid cells differentiated from three iPSC lines (C19, OCE1, OPM2) with that of adult and cord blood progenitors. Of the 1989 proteins quantified <3% differed in level by 2-fold or more between the different iPSC-derived erythroid cells. When compared to adult cells, 11% of proteins differed in level by 2-fold or more, falling to 1.9% if a 5-fold threshold was imposed to accommodate slight inter-cell line erythropoietic developmental variation. Notably, the level of >30 hallmark erythroid proteins was consistent between the iPSC lines and adult cells. In addition, a sub-population (10-15%) of iPSC erythroid cells in each of the iPSC lines completed enucleation. Aberrant expression of some cytoskeleton proteins may contribute to the failure of the majority of the cells to enucleate since we detected some alterations in cytoskeletal protein abundance. In conclusion, the proteome of erythroid cells differentiated from iPSC lines is very similar to that of normal adult erythroid cells, but further work to improve the induction of erythroid cells in existing iPSC lines or to generate novel erythroid cell lines is required before iPSC-derived red cells can be considered suitable for transfusion therapy.
    Full-text · Article · Jul 2014 · PLoS ONE
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