Biomaterials for Cell Engineering and Regenerative Medicine
- Author(s): Downing, Timothy
- Advisor(s): Li, Song
- et al.
The promise of regenerative medicine relies on the ability to tightly control cell behavior. Given the broad influence of epigenetics in cell behavior and phenotype determination, it is critical to better understand how interactions with the physiological microenvironment and/or implanted materials affect cell's epigenetic state and, thus, identity. In this dissertation we demonstrate, for the first time, that biophysical cues (e.g., matrix topography and stiffness) can significantly improve the efficiency of cell reprogramming, the process of reverting somatic cells back to pluripotency, by inducing key epigenetic changes in adult fibroblasts. To help elucidate the role of biophysical factors in cell reprogramming we have utilized induced pluripotent stem cell (iPSC) technology in conjunction with various bioengineered substrates. These substrates include poly(dimethyl siloxane) (PDMS) microgrooves, aligned nanofibrous membranes, and polyacrylamide hydrogels. Our data largely suggest that cytoskeletal proteins play an important role in the process of cell reprogramming and that manipulation of the biophysical microenvironment can induce dramatic changes in histone acetylation and methylation patterns. These epigenetic changes significantly improve iPSC generation efficiency and replace the effects of potent small molecule epigenetic modifiers valproic acid (VPA) and tranylcypromine (TCP). Furthermore, we identify specific mediators of this epigenetic mechanomodulation, while distinguishing the role of cell shape in the observed histone modifications. This novel biophysical regulation of epigenetics has important implications in cell biology and in the optimization of materials for broad biological application. Finally, this dissertation work describes how drug-eluting microfibrous patches and nanofibrous scaffolds, in conjunction with iPSC-derived stem cells, can be utilized to combine the effects of biophysical guidance cues, therapeutic drug delivery, and cell engineering for the study and repair of spinal cord injury after both traumatic insult and neural tube defect.