Ex vivo expansion and differentiation of human pancreatic β-cell are enabling steps of paramount importance for accelerating the development of therapies for diabetes. The success of regenerative strategies depends on their ability to reproduce the chemical and biophysical properties of the microenvironment in which β-cells develop, proliferate and function. In this paper we focus on the biophysical properties of the extracellular environment and exploit the cluster-assembled zirconia substrates with tailored roughness to mimic the nanotopography of the extracellular matrix. We demonstrate that β-cells can perceive nanoscale features of the substrate and can convert these stimuli into mechanotransductive processes which promote long-term in vitro human islet culture, thus preserving β-cell differentiation and function. Proteomic and quantitative immunofluorescence analyses demonstrate that the process is driven by nanoscale topography, via remodelling of the actin cytoskeleton and nuclear architecture. These modifications activate a transcriptional program which stimulates an adaptive metabolic glucose response. Engineered cluster-assembled substrates coupled with proteomic approaches may provide a useful strategy for identifying novel molecular targets for treating diabetes mellitus and for enhancing tissue engineering in order to improve the efficacy of islet cell transplantation therapies.
|Original language||English (US)|
|State||Published - Dec 1 2018|
Bibliographical noteFunding Information:
We would like to thank Giulia Crosta for his assistance in data collection, Carsten Schulte for drawing Figure 7 and for valuable discussions, Eleanor Lea for manuscript editing. This work was supported by Università degli Studi di Milano (Piano di Sostegno per la Ricerca, Università degli Studi di Milano, 2015–2017 Linea2 - Azione A) (to C.P.). E.S.D.C. was the recipient of Postdoctoral fellowships from the Università degli Studi di Milano. This work was also supported by the “National Funding for Basic Research” (FIRB) as part of a project entitled “Oxides at the Nanoscale: Functionalities and Applications” (FIRB RBAP11AYN) and by the European Union project “FutureNanoNeeds” grant “Framework to respond to regulatory needs of future nanomaterials and markets” (FP7-NMP-2013-LARGE-7).
© 2018 The Author(s).
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