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

Hodgkinson, Thomas and Monica Tsimbouri, P. and Llopis-Hernandez, Virginia and Campsie, Paul and Scurr, David and Childs, Peter G. and Phillips, David and Donnelly, Sam and Wells, Julia and Salmerón-Sánchez, Manuel and Burgess, Karl E V and Alexander, Morgan and Vassalli, Massimo and Oreffo, Richard and Reid, Stuart and France, David J. and Dalby, Matthew J. (2021) The use of nanovibration to discover specific and potent bioactive metabolites that stimulate osteogenic differentiation in mesenchymal stem cells. Science Advances, 7 (9). eabb7921. ISSN 2375-2548 (https://doi.org/10.1126/sciadv.abb7921)

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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.

ORCID iDs

Hodgkinson, Thomas, Monica Tsimbouri, P., Llopis-Hernandez, Virginia, Campsie, Paul ORCID logoORCID: https://orcid.org/0000-0003-4570-7133, Scurr, David, Childs, Peter G. ORCID logoORCID: https://orcid.org/0000-0001-7603-9911, Phillips, David, Donnelly, Sam, Wells, Julia, Salmerón-Sánchez, Manuel, Burgess, Karl E V, Alexander, Morgan, Vassalli, Massimo, Oreffo, Richard, Reid, Stuart, France, David J. and Dalby, Matthew J.;
CORE (COnnecting REpositories)