Mesenchymal stem cells (MSCs) are becoming competitive candidates for an increasing number of different therapeutic applications. This is due to their potent immunosuppressive and anti-inflammatory activities that have been extensively explored for the treatment of several medical conditions, ranging from autoimmune diseases to addressing the immunological complications of clinical transplantation. However, the mechanisms underlying MSC therapeutic activity remain largely unknown and there are many challenges to be addressed. Such challenges include the issue that the vast majority of infused MSCs reside transiently in the lungs and become undetectable within a few hours. Therefore, understanding the fate of infused MSCs could help predict clinical responses.

Programmed cell death (apoptosis, pyroptosis, necroptosis, ferroptosis, autophagy, etc.) plays a central role in organ development and homeostasis. Impaired regulation of these processes is often associated with the onset of several human diseases. In recent years, the scientific community has investigated programmed cell death, in particular, research has focused on the connections between apoptosis, MSCs, and tissue regeneration. Cytokines, chemokines, and organelles involved in the activation and inhibition of the apoptotic pathways of MSCs have been carefully described, however, the explicit signaling pathway involved is yet to be fully elucidated. More importantly, MSC programmed cell death has been reported to play a pivotal role in the immunomodulatory function of MSCs, which supersedes the previous understanding that the therapeutic effect of MSCs is attributed to the biologically active molecules. The phenomenon of MSCs undergoing programmed cell death after intravenous administration has been observed, even in the absence of host cytotoxic or alloreactive cells. Deletion of the apoptotic effectors BAK and BAX prevents MSC death and attenuates their immunomodulatory effects in disease models used to determine MSC potency. In this scenario, it has been suggested that multiple cells and molecules, such as cytotoxic T lymphocyte, macrophagocyte, apoptotic body, and indoleamine 2, 3-dioxygenase (IDO), could be involved in the process of MSC apoptosis. Understanding the molecular mechanisms of programmed cell death of MSC, especially the influence of apoptosis, will improve the safety and effectiveness of MSC treatment and help to achieve more successful therapeutic effects.

The aim of this Special Issue is to collect original research and review articles that will improve the understanding of the role of programmed cell death in MSC application in cell therapy. In addition, we welcome research investigating the role of MSC programmed cell death in the application of tissue repair strategies based on the immunomodulatory properties of MSCs.

Potential topics include but are not limited to the following:

• Programmed cell death during MSC transplantation
• Effects of MSC apoptosis on cell therapy
• Therapeutic strategies of MSCs in various medical conditions
• Underlying mechanisms of MSCs in various applications
• Programmed cell death of MSC in cell therapy
• Signaling pathways of programmed cell death of MSC in cell therapy
• The role of programmed cell death of MSC in cell therapy
• Outcomes of MSC in cell therapy
• Associated factors initiating programmed cell death of MSC
• The role of immune cells in the course of programmed cell death of MSC
• The interaction between MSCs and microenvironment in the course of programmed cell death