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.

Download full-text


Available from: Chiao-Wang Sun,
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    The Korean Journal of Internal Medicine 09/2014; 29(5):547-557. DOI:10.3904/kjim.2014.29.5.547 · 1.43 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    PLoS ONE 07/2014; 9(7):e100874. DOI:10.1371/journal.pone.0100874 · 3.23 Impact Factor
  • Source
    • "Induced pluripotent stem (iPS) cells are generated from adult mature cells following transduction with the transcription factors Oct3/4, Sox2, Klf4, and c-Myc [1], [2]. They have the ability to differentiate into all cell types [3], [4], [5] and, therefore, have considerable potential for autologous stem cell therapies [6], [7]. Recently, it was shown that iPS cells do not elicit immune responses when they are transplanted into syngeneic mice [8], [9] or into autologous monkeys [10], [11]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent studies have revealed negligible immunogenicity of induced pluripotent stem (iPS) cells in syngeneic mice and in autologous monkeys. Therefore, human iPS cells would not elicit immune responses in the autologous setting. However, given that human leukocyte antigen (HLA)-matched allogeneic iPS cells would likely be used for medical applications, a more faithful model system is needed to reflect HLA-matched allogeneic settings. Here we examined whether iPS cells induce immune responses in the swine leukocyte antigen (SLA)-matched setting. iPS cells were generated from the SLA-defined C1 strain of Clawn miniature swine, which were confirmed to develop teratomas in mice, and transplanted into the testes (n = 4) and ovary (n = 1) of C1 pigs. No teratomas were found in pigs on 47 to 125 days after transplantation. A Mixed lymphocyte reaction revealed that T-cell responses to the transplanted MHC-matched (C1) iPS cells were significantly lower compared to allogeneic cells. The humoral immune responses were also attenuated in the C1-to-C1 setting. More importantly, even MHC-matched iPS cells were susceptible to innate immunity, NK cells and serum complement. iPS cells lacked the expression of SLA class I and sialic acids. The in vitro cytotoxic assay showed that C1 iPS cells were targeted by NK cells and serum complement of C1. In vivo, the C1 iPS cells developed larger teratomas in NK-deficient NOG (T-B-NK-) mice (n = 10) than in NK-competent NOD/SCID (T-B-NK+) mice (n = 8) (p<0.01). In addition, C1 iPS cell failed to form teratomas after incubation with the porcine complement-active serum. Taken together, MHC-matched iPS cells can attenuate cellular and humoral immune responses, but still susceptible to innate immunity in pigs.
    PLoS ONE 06/2014; 9(6):e98319. DOI:10.1371/journal.pone.0098319 · 3.23 Impact Factor
Show more