Mesenchymal stem cells (MSCs) are becoming competitive candidates for increasing numbers of different therapeutic applications due to their huge expansion potential and unique immunomodulatory properties. The therapeutic effect of MSCs is mainly the result of their effective immunomodulatory function. MSCs are not immune cells but are a kind of precursor cell with a series of therapeutic molecules, with the ability to respond to the surrounding microenvironment.

The microenvironment in vivo is composed of cells, extracellular matrix, cytokines, and chemokines, as well as dynamic changes in nutritional availability. MSCs can regulate their own fate and behavior by sensing the surrounding microenvironment for indicators such as inflammation, infection, or tissue damage. Meanwhile, the release of cytokines, chemokines, and extracellular vesicles (EV) from MSCs may promote an immune response. MSCs have been shown to interact with the microenvironment during in vitro expansion and with the surrounding host microenvironment after transplantation using various delivery systems. These interactions can regulate the viability, migration, differentiation, and secretion of MSCs, and transplanted MSCs have shown plasticity in immune regulation as a method for dealing with these challenges. Therefore, MSC transplantation could be used as immunotherapy for patients with tissue or organ injury caused by chronic inflammation or autoimmune diseases. Understanding the molecular mechanisms of the MSC immune response, especially the influence of the microenvironment, will improve the safety and effectiveness of MSC treatment and help us achieve better therapeutic effects.

The aim of this Special Issue is to collect original research and review articles that will improve our understanding of the behavior of MSC transplants and their impact on the local tissue environment. In addition, we welcome research investigating the importance of the microenvironment in the application of tissue repair strategies based on the immunomodulatory properties of MSCs.

Potential topics include but are not limited to the following:

• Interactions between MSCs and the host extracellular microenvironment
• Interaction between MSCs and host cells in the stem cell niche
• Effects of microenvironment and inflammation on MSC behavior
• Effects of microenvironment and infection on MSC behavior
• Effects of microenvironment and tissue damage on MSC behavior
• The role of cytokines, chemokines, and EVs in MSC-based transplantation and therapeutics in autoimmune disease