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. 2020 Mar 31;24(11):3923–3937. doi: 10.1007/s00784-020-03259-8

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© The Author(s) 2020

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 8 — Model for the effects of the two investigated HA formulations on the behavior and functionality of mesenchymal stromal ST2 and pre-osteoblastic MC3T3-E1 cells. Treatment of each of the two cell lines, used as a progenitor source of osteoblasts, with HA (a structural formula is presented) results in induced cellular proliferation and bone matrix production, as suggested by the upregulated expression of Col1a1, Col1a2, and Spp1 genes encoding bone matrix proteins. These effects are accompanied and likely influenced by induced TGF-β and FGF signaling in the HA-treated cells. Signaling through both BMP-induced Smad and Wnt pathways is strongly downregulated upon HA treatment, which results in inhibited progression of the osteogenic differentiation as evidenced by decreased expression of intermediate and late osteogenic differentiation marker genes such as Runx2, Bglap2, Ibsp, and Alpl. Finally, HA maintains the stemness of osteoprogenitors by inducing the expression of the transcription factor Sox2 and its direct targets Yap1 and Bmi1. Inhibited Wnt signaling and induced TGF-β/FGF signaling may contribute to the self-renewal capability of HA-treated osteoprogenitors. Taken together, our results suggest a prominent role of HA in inducing the growth, and maintaining the stemness and differentiation potential of mesenchymal stromal and pre-osteoblastic cells. Solid lines in the model represent direct evidence and common knowledge; dashed lines display links that are solidly supported by literature reports. For more details on the displayed links between the HA-induced functionalities, please refer to the text