Topographical extracellular matrix cues on anticancer drug-induced cytotoxicity in stem cells.

Abstract

In recent years, cell chip-based platforms have begun to show promise as a means of corroborating the findings of in vivo animal tests for cytotoxicity, and perhaps in the future partially replacing the need for such animal models. In contrast to the conventional culture methods, micro- and nanofabrication techniques can be utilized to provide a set of mechanostimulatory signals to the cells that mimic the context of extracellular matrix (ECM) of the tissue in which a particular cell line resides. Here, we report periodic lateral topographic striations, with a pitch ranging approximately from 200 to 800 nm with an intention to mimic a common geometry of fibrils in the ECM such as collagen or elastin, as a platform for investigating anticancer drug-induced cytotoxicity in stem cells. The ECM cues could facilitate perimeter, elongation, and gap junction formation of mesenchymal stem cells (MSCs), which eventually influenced the fate of cells in terms of death and survival against the common chemotherapeutic agent cisplatin. Interestingly, the appropriate inhibition of gap junctions of MSCs on the ECM mimicking substrates could prevent the cisplatin-induced cytotoxicity through the inhibition of the cisplatin-induced 'death signal communication' as compared to that on the flat substrates. Our results imply that nanoscale topography is an important consideration for chip-based cytotoxicity assays, which uniquely enable the consideration and rational design of ECM-like topographic features, and furthermore, that the natural topography of the ECM in the context of stem cell niches may serve as an important indicator for chemotherapeutic agent sensitivity.