Role of murine induced pluripotent stem cells on the correction of cardiac and sk

Summary

Principal Investigator: Diego Fraidenraich
Abstract: Stem cells are regarded with great promise in the next decades for treatment of congenital disease. Well known for their capacity to differentiate into a broad spectrum of cell types (pluripotency), embryonic stem (ES) cells also secrete corrective factors that prevent lethal congenital heart defects from occurring. Using a mouse model of the "thin myocardial syndrome" (Id knockout mice), we have shown that secreted factors from ES cells normalize gene expression profiles in neighbor cells. The ES cells can rescue congenital heart defects not only when injected into Id KO blastocysts but also into mouse females that will bear Id KO embryos. The ES cells can also rescue muscular dystrophy when injected into mdx (a mouse model of Duchenne muscular dystrophy, DMD) blastocysts. Rather than factor secretion, the main mechanism of the rescue in this case is spreading of ES-derived dystrophin (the protein absent in DMD) throughout most of the musculature to stabilize the muscle. The potential use of ES cells to treat human disease is clouded by ethical concerns surrounding the destruction of human oocytes or fertilized embryos. The scientific community is looking for alternatives that would not use embryos as starting material. Recent experiments demonstrated that murine somatic cells de-differentiate to an embryonic stem cell-like status by the incorporation of transcription factors. These cells were named induced pluripotent stem cells (iPS cells). The iPS cells are similar to the ES cells. Remarkably, the generation of iPS cells does not require destruction of embryos, therefore there are no ethical concerns. In addition, a recent proof-of-principle experiment showed that iPS cells can correct disease (sickle cell anemia) in mice. In this application we would like to characterize the murine iPS cells in their role to rescue cardiac and skeletal muscle disease, exemplified by the Id knockout mice and the mdx mice. To this end, we will inject murine iPS cells into murine blastocysts (Id KO and mdx), intraperitoneally into female mice that will harbor mutant embryos (Id KO), and also intraperitoneally into mice predisposed to develop dilated cardiomyopathy (Id conditional KO). We hypothesize that iPS cells will rescue the cardiac phenotype of the Id KO embryos as well as muscular dystrophy in mdx mice. Survival of the Id KO embryos will be evaluated. Corrections will be evaluated at the histological (immunohistochemistry, H&E, immunofluorescence) and functional (echocardiography, treadmill) level. Secretion of potential rescue molecules in the thin myocardial syndrome (Id) rescue and spreading of dystrophin in the muscular dystrophy (mdx) rescue will be determined. These experiments will help elucidate the mechanisms that the iPS cells may utilize to effect corrections in muscle and will broaden the therapeutic applicability of the iPS cells. PUBLIC HEALTH RELEVANCE: ES cells have the unique capacity to differentiate into all cell types and to emit healing factors. This feature places them at the center of the regenerative medicine arena. Technical and ethical issues compromise the enthusiasm for the use of ES cells in a clinical setting. Therefore it becomes imperative to find alternatives that will render cells equally potent. Recently the induced pluripotent stem (iPS) cells emerged as the greatest alternative. The iPS cells phenocopy the ES cells in the most rigorous assays that are used to characterize the ES cells, including the capacity to form mouse chimeras. As the generation of iPS cells does not involve the use of embryos, the ethical concerns are eliminated. To assess the therapeutic potential of the iPS cells, it will be extremely important to test the role that the iPS cells play in correcting a variety of genetic diseases. In these application we propose to challenge the murine iPS cells in two muscular diseases (heart and skeletal muscle) that we showed can be corrected by ES cell treatment. The mechanism of the correction of both diseases by the ES cells is different - in one case secretion of factors and in another spreading of a structural protein. We plan to inject iPS cells into early embryos that are predisposed to develop these diseases. We also plan to inject the iPS cells into female mice before conception. Finally, we plan to inject the iPS cells into mice predisposed to develop dilated cardiomyopathy. In all cases we hope the iPS cells will prevent pathology from occurring. These experiments will help elucidate the molecular mechanisms that the iPS cells may utilize to effect corrections in cardiac and skeletal muscle and will broaden the therapeutic applicability of the iPS cells.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi IGF-II promotes stemness of neural restricted precursors
    Amber N Ziegler
    Department of Neurology and Neuroscience, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA
    Stem Cells 30:1265-76. 2012
  2. pmc Rescue of developmental defects by blastocyst stem cell injection: towards elucidation of neomorphic corrective pathways
    Qingshi Zhao
    Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07107, USA
    J Cardiovasc Transl Res 3:66. 2010
  3. pmc Developmental ablation of Id1 and Id3 genes in the vasculature leads to postnatal cardiac phenotypes
    Qingshi Zhao
    Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, UMDNJ, Newark, NJ 07107 1709, USA
    Dev Biol 349:53-64. 2011
  4. pmc Differential requirement for utrophin in the induced pluripotent stem cell correction of muscle versus fat in muscular dystrophy mice
    Amanda J Beck
    Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, United States of America
    PLoS ONE 6:e20065. 2011
  5. pmc Dystrophin-compromised sarcoglycan-δ-knockout diaphragm requires full wild-type embryonic stem cell reconstitution for correction
    Joseph M Vitale
    Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07107, USA
    J Cell Sci 125:1807-13. 2012

Scientific Experts

  • Diego Fraidenraich
  • Qingshi Zhao
  • Joseph M Vitale
  • Joel S Schneider
  • Amanda J Beck
  • Corey Chang
  • Amber N Ziegler
  • Jennifer Michaels
  • Mantu Bhaumik
  • Richard Gordan
  • Mei Qin
  • William A Tyler
  • John E Pintar
  • Teresa L Wood
  • Steven W Levison
  • Hyung Song Nam
  • Aneela Altaf
  • Bin Tian
  • Ji Yeon Park
  • Shumin Gao
  • Samuel J Leibovich
  • Genie Elson
  • Robert Grange
  • Amanda Beck
  • Andre Terzic

Detail Information

Publications5

  1. ncbi IGF-II promotes stemness of neural restricted precursors
    Amber N Ziegler
    Department of Neurology and Neuroscience, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA
    Stem Cells 30:1265-76. 2012
    ..Our data support the conclusion that IGF-II promotes the self-renewal of neural stem/progenitors via the IR. By contrast, IGF-1R functions as a mitogenic receptor to increase precursor abundance...
  2. pmc Rescue of developmental defects by blastocyst stem cell injection: towards elucidation of neomorphic corrective pathways
    Qingshi Zhao
    Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07107, USA
    J Cardiovasc Transl Res 3:66. 2010
    ..Thus, blastocyst injection of ESCs not only allows the study of disease prevention, but also unveils novel pathways whose activation may aid in the correction of congenital or acquired disease...
  3. pmc Developmental ablation of Id1 and Id3 genes in the vasculature leads to postnatal cardiac phenotypes
    Qingshi Zhao
    Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, UMDNJ, Newark, NJ 07107 1709, USA
    Dev Biol 349:53-64. 2011
    ..These findings provide important insights into the role/s of the endocardial network of the endothelial lineage in the development of cardiac disease, and highlight IGFbp3 as a potential link between Id and its vascular effectors...
  4. pmc Differential requirement for utrophin in the induced pluripotent stem cell correction of muscle versus fat in muscular dystrophy mice
    Amanda J Beck
    Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, United States of America
    PLoS ONE 6:e20065. 2011
    ..Furthermore, the results highlight a potential (utrophin-independent) non-cell autonomous role for iPSC-dystrophin in the corrections of non-muscle tissue like fat, which is intimately related to the muscle...
  5. pmc Dystrophin-compromised sarcoglycan-δ-knockout diaphragm requires full wild-type embryonic stem cell reconstitution for correction
    Joseph M Vitale
    Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07107, USA
    J Cell Sci 125:1807-13. 2012
    ..The results suggest that the SGδ-KO mouse model of LGMD is not amenable to ESC treatment...