CAREER: Mechanochemical signaling during somatic cell reprogramming

University Of Illinois At Urbana-Champaign, Urbana IL

Investigators

Abstract

1454616 Kilian, Kristopher Somatic cells were recently shown to revert to a primitive 'embryonic-like' pluripotent state upon forced expression of only four genes (2012 Nobel Prize in Physiology or Medicine). This technique could revolutionize medicine by enabling a patient's own cells to be reverted back and modified to correct mutations and regenerate injured tissues; however, the process in which cells reprogram is not well defined or understood, is very inefficient and takes considerable time. In this CAREER proposal, designer cell culture materials will be used to study how cells revert to pluripotency in order to develop a system that can quickly and efficiently reprogram a patients cells. The combination of approaches employed is expected to dramatically reduce reprogramming time, increase efficiency, and reduce the need for exogenous factors (e.g. lentivirus), which will prove transformative to commercial and clinical ventures that need to reproducibly generate induced pluripotent stem cells (iPSCs) for regenerative therapies. The emerging view of how materials influence cellular reprogramming that is supported by this research will be integrated into education and outreach activities by establishing a Stem Cell Engineering Training Institute (SCETI). In this institute, laboratory videos with senior undergraduates, and high school educators will be developed for use in an annual summer camp for high school girls - Girls Adventures in Mathematics Engineering and Science (GAMES) - and to augment the curriculum of a senior undergraduate course: Design and Use of Biomaterials. Most somatic cell reprogramming methods are performed on rigid plastic which leads to heterogeneity in cellular organization and proliferation. These conditions foster a slow stochastic process with rare reprogramming events initiated by a mesenchymal-to-epithelial transition (MET). The process of MET in vivo is regulated by microenvironments with defined biochemical and biophysical properties. Motivated by natural MET processes that occur during development, and the architecture of the early embryo where pluripotency is first established, the proposed work aims to control matrix composition, substrate mechanics and tissue geometry on the cell culture substrate,to more closely recapitulate in vivo architectures and to promote MET and accelerate somatic cell reprogramming. The success of this work will provide mechanistic insight into the de-differentiation process and yield a suite of commercially viable cell culture materials and reagents for somatic cell reprogramming. In addition to reprogramming to iPSCs, other explorations of reprogramming will benefit from the tools and methods developed in this work such as directed differentiation, trans-differentiation and intermediate de-differentiation events. This CAREER Award by the Biotechnology and Biochemical Engineering Program in the Chemical, Bioengineering, Environmental, and Transport Systems Division is co-funded by the Biomaterials Program of the Division of Materials Research.