**5. Conclusions**

The world of biomaterials, specifically polymers, lingers to impact the biomedicine field. Various materials are currently under investigation to produce ECM with varying stiffness for tissue engineering. Matrix stiffness regulates the MSCs' differentiation into mature specific cells by activating transcription factors that upregulate the genes responsible for the initiation and progression of particular cell linage differentiation. Rigid matrices lead to increased MSCs spreading and improved actomyosin contractility, promoting osteogenic differentiation. This enhanced potential is accompanied by increased Runx2, β-catenin, and Smad, implying the significant impact of mechanosensing of the matrix stiffness and its role in determining cell fate. The comprehensive signaling mechanisms by which micro-environmental stiffness controls the lineage specification of MSCs are still unknown. Additional research is needed to understand the variety of potential signaling forces involved in MSCs' osteogenic differentiation that can lead to the development of new therapeutic modalities addressing bone disorders. Moreover, we believe that further research on the implicated mechanical and physical factors, such as topographic changes and external mechanical forces affecting cell properties, including cell shape and colony size, can offer a broader understanding of cell-fate determination.

**Author Contributions:** All authors contributed equally. All authors have read and agreed to the published version of the manuscript.

**Funding:** This publication was funded by the Christian Albrechts University of Kiel, Germany.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.
