Archived record · Edyssy 2014

Angiomyogenesis With Myoblast Derived Ips Cells

Agency

NIHNational Institutes of Health

Principal investigator

Muhammad Ashraf

Institution

University of Cincinnati

Amount listed

$683,749

Period

June 1, 2012 to May 31, 2013

Abstract

DESCRIPTION (provided by applicant): 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. Public Health Relevance Statement: 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. 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. Acute myocardial infarction;Aftercare;Amaze;Animal Model;Animals;attenuation;Autologous;base;Behavior;Biology;Cardiac;Cardiac Myocytes;cardiogenesis;Cell Differentiation process;Cell Line;Cell Lineage;Cell Survival;Cell Therapy;cell type;Cells;Characteristics;Clinical;clinical application;Clinical Trials;clinically relevant;Collaborations;Data;Dermal;design;embryonic stem cell;Epigenetic Process;Ethical Issues;experience;Experimental Animal Model;Family suidae;Fibroblasts;functional outcomes;Generations;Genomics;Goals;Heart;heart function;Human;Human Development;human embryonic stem cell line;immunogenicity;Immunologics;improved;In Vitro;in vivo;induced pluripotent stem cell;Infarction;innovation;interdisciplinary approach;Investigation;Laboratories;Methods;MicroRNAs;Modeling;Modification;Molecular Biology;Morals;Mus;Muscle;Myoblasts;Myocardial;Myocardial Infarction;Nature;Non-Viral Vector;novel;Patients;Physiology;pluripotency;Pluripotent Stem Cells;Population;pre-clinical;pressure;programs;repaired;Research;Research Personnel;Safety;Secure;Skeletal muscle structure;Skeletal Myoblasts;small molecule;Somatic Cell;Source;stem;stem cell technology;Stem cells;Techniques;Technology;Testing;Therapeutic;Time;transcription factor;Transplantation;tumorigenesis;Ultrasonography;vector;Viral Vector;Work

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The record names Muhammad Ashraf at University of Cincinnati as principal investigator. When a professor holds an award like this, part of the budget usually goes to people: graduate research assistants, a postdoc or a technician. Shorter awards are often one year of a renewing project, so check whether it was continued. Look up the investigator’s current awards before you write; a 2014 record is a lead, not a promise. Before you do, read up on how a department turns grant money into admission offers.

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