Numerous stimuli control and manipulate the cellular microenvironment to direct stem cell behavior in terms of proliferation, differentiation, function, and cellular cross-talk. These include cell-cell interactions, the stem cell secretome profile (e.g., proteins, metabolites, and extracellular vesicles), immunomodulation, the biochemical composition of the extracellular matrix (ECM), and mechanical features of ECM (e.g., elasticity, topography).

It is well known that adult stem cells reside within instructive and tissue-specific niches that physically localize them and maintain their stem-cell fate, and that these cells and the ECM strongly interact throughout development, as well as during disease and repair. Over the last few decades, significant effort has been placed on untangling the dynamic interaction between these two players in order to explain biological process and the development of diseases. Understanding this cross-talk is a fundamental prerequisite for engineering functional microenvironments able to instruct stem cells with specific inputs.

Recent efforts in the design of biomimetic biomaterials, in the development of more complex and engineered in vitro cell culture, and in organoid technologies, together with new understanding of stem cell type heterogeneity and behavior within the niche, have provided a new impetus to study in vitro biological processes. Consequently, we are able to build more complex and controlled environments for directing stem cell fate which are more similar to both physiological and pathological conditions. These advanced and more predictive in vitro models offer the chance to better elucidate several biological events and to discover disruptive preclinical strategies.

This special issue therefore invites contributions of both original research and review articles reporting recent efforts in the study and development of cell-instructive microenvironments to direct stem cell fate.

Potential topics include but are not limited to the following:

• The use of biomaterials for directing stem cell fate
• Development of 3D stem cell disease models
• The development of organoid technology within the right environment in order to direct stem cell fate
• Stem cell niche microenvironments (ECM, heterogeneous cell populations, secretome characterization, etc.)