Recent advances in stem cell biology hold great potential in developing new approaches for the treatment ofmany devastating diseases, including musculoskeletal disorders (MSDs). Stem cell-based therapies forregenerating functional muscle cells and restoring muscular functions to damaged skeletal muscles can becritical for the development of therapeutic advances in musculoskeletal disease and disorder. Such approaches,however, require the generation of engraftable cell sources of functional myogenic cells and better control ofstem cell myogenic differentiation in an effective, selective, and safe manner. To this end, the main goal of this proposal is to develop a bio-inspired platform that can replicate the structureand function on endogenous proteins called transfection factors (TFs; MyoD and Myogenin), which are specificfor muscle-specific genes and responsible for orchestrating overall stem differentiation into muscle cells. Ourbio-inspired platform called NanoScript, is a nanoparticle-based transcription factor that behaves and functionjust like natural TF proteins. This NanoScript platform is designed to be gene-specific and can effectively activatetargeted gene expressions (e.g. MyoD, Myogenin and the related endogenous genes) in a non-toxic and non-viral manner. Out central hypothesis, based upon recent achievement and preliminary data, is that our proposedNanoScript platform can effectively generate functional muscle cells from human patient-derived adipose-derived mesenchymal stem cells (AMDSCs), which are an abundant source of stem cells, with patient-specificstem cells treatment possibilities. We propose to test our central hypothesis and achieve our objectives by addressing the following specificaims: Aim1: Design and synthesize muscle cell-specific TFs (MRF) and epigenetic modulators for theconstruction of enhanced muscle cell-specific NanoScripts [NanoScripts-MRF]. Aim2: Utilize NanoScript toactivate muscle-specific genes in ADMSCs for generating muscle cells. The proposed research is innovative, as this concept of developing a TF emulator by integrating twomultidisciplinary approaches (chemical biology and nanomedicine) onto a single nano-platform for non-viral generegulation in stem cells has not been developed. The proposed research is significant, since we will develop aninnovative technology platform and our NanoScript is an easily tunable and robust platform, it can be furtherdeveloped to combine with epigenetic modulators or other synergists for effective and selective induction offunctional muscle cells. Collectively, upon successful completion of the proposed study, our expectations arethat NanoScript-MRF will activate transcription of the muscular-specific genes containing their cognate TFconsensus DNA binding domain, which will lead to an enhanced stem differentiation into muscle cells. BecauseNanoScript is non-toxic and non-viral, the generated muscle cells will be considered for translation into in vivoanimal studies in future studies.
|Effective start/end date||9/26/17 → 8/31/19|
- National Institutes of Health (NIH)