Using endogenous mesenchymal stem cells for treating myocardial infarction and other cardiovascular conditions typically results in poor efficacy, in part owing to the heterogeneity of the harvested cells and of the patient responses. Here, by means of high-throughput screening of the combinatorial space of mechanical-strain level and of the presence of particular kinase inhibitors, we show that human mesenchymal stem cells can be mechanically and pharmacologically conditioned to enhance vascular regeneration in vivo. Mesenchymal stem cells conditioned to increase the activation of signalling pathways mediated by Smad2/3 (mothers against decapentaplegic homolog 2/3) and YAP (Yes-associated protein) expressed markers that are associated with pericytes and endothelial cells, displayed increased angiogenic activity in vitro, and enhanced the formation of vasculature in mice after subcutaneous implantation and after implantation in ischaemic hindlimbs. These effects were mediated by the crosstalk of endothelial-growth-factor receptors, transforming-growth-factor-beta receptor type 1 and vascular-endothelial-growth-factor receptor 2. Mechanical and pharmacological conditioning can significantly enhance the regenerative properties of mesenchymal stem cells.
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We acknowledge funding through the American Heart Association (grant no. 17IRG33410888), the DOD CDMRP (grant nos W81XWH-16-1-0580 and W81XWH-16-1-0582) and the National Institutes of Health (grant nos 1R21EB023551-01, 1R21EB024147-01A1 and 1R01HL141761-01) to A.B.B.
J.L. and A.B.B. have filed a patent (USPTO (US20200268801A1)) on the technology/techniques described in this paper.
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Lee, J., Henderson, K., Massidda, M.W. et al. Mechanobiological conditioning of mesenchymal stem cells for enhanced vascular regeneration. Nat Biomed Eng 5, 89–102 (2021). https://doi.org/10.1038/s41551-020-00674-w
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