We are interested in developing technologies to precisely program cell biology in order to generate cell sources that would be useful for disease modeling, drug screening, and regenerative medicine. For example, we are pursuing genetic reprogramming as an alternative means for generating various cell sources for science and medicine. This involves reprogramming the gene expression profile of an easily accessible cell type, such as skin cells, by activating the gene network corresponding to a cell type responsible for the regeneration of a specific tissue, such as muscle, bone, cartilage, blood vessels, heart tissue, etc. For example, we are using genetic reprogramming to convert fibroblasts into neuronal cells (Black et al., Cell Stem Cell 2016) and skeletal muscle cells (Kabadi et al., ACS Synthetic Biology 2014). These approaches can be used to better understand the mechanisms of disease and develop optimal patient-specific drug treatments. In the future, these technologies could potentially be used to engineer cells that can regenerate diseased or damaged tissues.
Figure 1. Mouse embryonic fibroblasts converted to neuronal cells by targeted epigenetic remodeling with CRISPR/Cas9-based transcription factors (Black et al., Cell Stem Cell 2016).
1. JB Black, AF Adler, HG Wang, AM D’Ippolito, HA Hutchinson, TE Reddy, GS Pitt, KW Leong, and CA Gersbach. Targeted Epigenetic Remodeling of Endogenous Loci by CRISPR/Cas9-Based Transcriptional Activators Directly Converts Fibroblasts to Neuronal Cells. Cell Stem Cell (2016).
2. TM Gibson and CA Gersbach. Single-molecule analysis of myocyte differentiation reveals bimodal lineage commitment. Integrative Biology 7, 663 - 671 (2015).
3. BO Diekman*, PI Thakore*, SK O'Connor, VP Willard, JM Brunger, N Christoforou, KW Leong, CA Gersbach*, F Guilak*. Knockdown of the cell cycle inhibitor p21 enhances cartilage formation by induced pluripotent stem cells. Tissue Engineering ;21(7-8):1261-74 (2014).
4. AM Kabadi, PI Thakore, CM Vockley, DG Ousterout, TM Gibson, F Guilak, TE Reddy, CA Gersbach. Enhanced MyoD-Induced Transdifferentiation to a Myogenic Lineage by Fusion to a Potent Transactivation Domain. ACS Synthetic Biology 3(10):702-3 (2014).
5. S Chakraborty, H Ji, AM Kabadi, CA Gersbach, N Christoforou, KW Leong. A CRISPR/Cas9-Based System for Reprogramming Cell Lineage Specification. Stem Cell Reports 3(6):940-7 (2014).
6. KA Glass, J Link, JM Brunger, FT Moutos, CA Gersbach,* F Guilak*. Tissue-engineered cartilage with inducible and tunable immunomodulatory properties. Biomaterials 35(22):5921-31 (2014).
7. JM Brunger, NPT Huynh, CM Guenther, P Perez-Pinera, FT Moutos, CA Gersbach,* F Guilak*. Scaffold-mediated lentiviral transduction for functional tissue engineering of cartilage. Proc. Natl. Acad. Sci. USA. 111(9):E798-806 (2014).
8. CA Gersbach, JM Le Doux, RE Gulderg, AJ Garcia. Inducible Regulation of Runx2-Stimulated Osteogenesis. Gene Therapy 13(11):873-82 (2006).
9. CA Gersbach, BA Byers, GK Pavlath, AJ Garcia. Runx2/Cbfa1 Stimulates Transdifferentiation of Primary Skeletal Myoblasts into a Mineralizing Osteoblastic Phenotype. Experimental Cell Research 300(2):406-417 (2004).