The innovative approach of generating induced pluripotent stem (iPS) cells from fibroblasts opens amazing new doors for generating autologous, patient-specific pluripotent stem cell lines for individualized cell therapy. There is however much important research to be done on non-viral generation of iPS cells to optimize their generation, safety and efficacy before these are feasible for clinical application. Our research will use human skeletal muscle derived myoblasts rather than terminally differentiated fibroblasts for generation of iPS and their differentiation into cardiac progenitor cells. Our main hypothesis is that the specific combination of factors necessary for induction of the pluripotency is determined by the cell type and differentiation status of the somatic cells. We therefore propose that skeletal myoblasts (SMs) are superior candidates for induction to pluripotent state with fewer factors either alone or in combination with treatment with small molecules. The main hypothesis will be tested in the following distinct Aims.
Specific Aim -1 will be devoted to reprogram human SMs for pluripotency with fewer factors by employing non-viral strategy. The proposed studies will use human SMs as the candidate cells which unlike fibroblasts are multipotent and are easier to be reprogrammed as compared to the terminally differentiated fibroblasts. Secondly, the use of miRs for reprogramming of SMs without genomic integration would be highly innovative strategy.
Specific Aim -2 will focus on isolation of cardiac and vasculogenic lineages from SM derived iPS (SM-iPS) cells and study their in vitro differentiation behavior.
Specific Aim -3 will compare SM-iPS cells and their pre-programmed derivatives for their in vivo behavior, survival of the cell graft at various time-points and myocardial reparability in small animal model of acute myocardial infarction. Once their cardiogenic potential will be established, the best chosen cell types will be assessed in a large preclinical animal model in Specific Aim-4 to secure translational data for SM-iPS cells. The end points of the in vivo studies will be myoangiogenic differentiation of the engrafted cells, attenuation of infarct size and the functional benefits in terms of improved global heart function. These studies will involve multidisciplinary approach which will employ state of the art molecular biology, histochemical and immunohistochemical techniques and well integrative physiology involving well-established experimental animal model, pressure-volume loop and transthoracic ultrasonography for animal heart function. Our results are expected to enhance understanding of the potential of SM-iPS cells as a potential source of donor cells for myocardial repair without the problem of arrhythmogenicity and immunogenicity.
This proposal is designed to investigate angiomyogenic behavior of iPS cells derived from human skeletal myoblasts by using our novel non-viral/microRNA reprogramming approach. We anticipate improved angiomyogenesis in the infarcted heart after treatment with these reprogrammed stem cells without the problem of tumorigenesis and cell rejection. The use of large animal model for the assessment of in vivo effects of the transplanted iPS cells is expected to generate preclinical data with translational significance.
|Liang, Jialiang; Huang, Wei; Cai, Wenfeng et al. (2017) Inhibition of microRNA-495 Enhances Therapeutic Angiogenesis of Human Induced Pluripotent Stem Cells. Stem Cells 35:337-350|
|Wu, Shi-Zheng; Li, Ying-Lan; Huang, Wei et al. (2017) Paracrine effect of CXCR4-overexpressing mesenchymal stem cells on ischemic heart injury. Cell Biochem Funct 35:113-123|
|Cai, Wen-Feng; Huang, Wei; Wang, Lei et al. (2016) Induced Pluripotent Stem Cells derived Muscle Progenitors Effectively Mitigate Muscular Dystrophy through Restoring the Dystrophin Distribution. J Stem Cell Res Ther 6:|
|Kondo, Hideyuki; Kim, Ha Won; Wang, Lei et al. (2016) Blockade of senescence-associated microRNA-195 in aged skeletal muscle cells facilitates reprogramming to produce induced pluripotent stem cells. Aging Cell 15:56-66|
|Matsu-ura, Toru; Sasaki, Hiroshi; Okada, Motoi et al. (2016) Attenuation of teratoma formation by p27 overexpression in induced pluripotent stem cells. Stem Cell Res Ther 7:30|
|Cai, Wen-Feng; Liu, Guan-Sheng; Wang, Lei et al. (2016) Repair Injured Heart by Regulating Cardiac Regenerative Signals. Stem Cells Int 2016:6193419|
|Li, Longhu; Zhao, Dong; Jin, Zhe et al. (2015) Phosphodiesterase 5a Inhibition with Adenoviral Short Hairpin RNA Benefits Infarcted Heart Partially through Activation of Akt Signaling Pathway and Reduction of Inflammatory Cytokines. PLoS One 10:e0145766|
|Prasad, Vikram; Lorenz, John N; Lasko, Valerie M et al. (2015) SERCA2 Haploinsufficiency in a Mouse Model of Darier Disease Causes a Selective Predisposition to Heart Failure. Biomed Res Int 2015:251598|
|Chang, Dehua; Wen, Zhili; Wang, Yuhua et al. (2014) Ultrastructural features of ischemic tissue following application of a bio-membrane based progenitor cardiomyocyte patch for myocardial infarction repair. PLoS One 9:e107296|
|Wang, Yuhua; Huang, Wei; Liang, Jialiang et al. (2014) Suicide gene-mediated sequencing ablation revealed the potential therapeutic mechanism of induced pluripotent stem cell-derived cardiovascular cell patch post-myocardial infarction. Antioxid Redox Signal 21:2177-91|
Showing the most recent 10 out of 15 publications