The use of nanovibration to discover specific and potent bioactive metabolites that stimulate osteogenic differentiation in mesenchymal stem cells

Tom Hodgkinson, P. Monica Tsimbouri, Virginia Llopis-Hernandez, Paul Campsie, David Scurr, Peter G. Childs, David Phillips, Sam Donnelly, Julia A. Wells, Fergal J. O’Brien, Manuel Salmeron-Sanchez, Karl Burgess, Morgan Alexander, Massimo Vassalli, Richard O.C. Oreffo, Stuart Reid, David J. France, Matthew J. Dalby

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Abstract

Bioactive metabolites have wide-ranging biological activities and are a potential source of future research and therapeutic tools. Here, we use nanovibrational stimulation to induce osteogenic differentiation of mesenchymal stem cells, in the absence of off-target, nonosteogenic differentiation. We show that this differentiation method, which does not rely on the addition of exogenous growth factors to culture media, provides an artifact-free approach to identifying bioactive metabolites that specifically and potently induce osteogenesis. We first identify a highly specific metabolite, cholesterol sulfate, an endogenous steroid. Next, a screen of other small molecules with a similar steroid scaffold identified fludrocortisone acetate with both specific and highly potent osteogenic-inducing activity. Further, we implicate cytoskeletal contractility as a measure of osteogenic potency and cell stiffness as a measure of specificity. These findings demonstrate that physical principles can be used to identify bioactive metabolites and then enable optimization of metabolite potency can be optimized by examining structure-function relationships.

Original languageEnglish
Article numbereabb7921
Number of pages16
JournalScience Advances
Volume7
Issue number9
DOIs
Publication statusPublished - 26 Feb 2021

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