Mesenchymal stromal/stem cells (MSCs) exist in almost all tissues, possessing the potential to differentiate into specialized cell types and exert immunomodulatory functions. Thus, they have attracted much attention as a promising therapeutic candidate. Recent studies have demonstrated that paracrine signaling is mainly responsible for the involvement of MSCs in the modulation of immune responses and the progression of diseases. Through release of secretome consisting of a diverse range of cytokines, chemokines, and extracellular vesicles (EVs), MSCs convey regulatory messages to recipient immune cells in the microenvironment. In this review, we focus on the recent advances in how MSCs contribute to immunomodulation through the secretion of paracrine factors. The further improved understanding of the molecular mechanism underlying the interactions between MSCs and immune cells highlights the paracrine biology of MSCs in the modulation of the immune microenvironment and promotes the clinical application of MSCs in regenerative medicine and immune diseases.

Programmed cell death ligand-1 (PD-L1) overexpressed on cancer cells has emerged as a key inhibitor that maintains the immunosuppressive microenvironment through its interaction with the PD-1 receptor in cancer. Here, we demonstrated that miR-424-5p delivery via extracellular vesicles (EVs) derived from adipose tissue-mesenchymal stromal cells (AT-MSCs) partly promotes proinflammation and enhances antitumor cytotoxicity in vitro and in vivo. Triple negative breast cancer (TNBC) exhibits increased expression of PD-L1, and PD-L1 is positively correlated with the overall survival of patients with TNBC. PD-L1 shows relatively higher expression in MDA-MB-231 (MM231) cells and can be downregulated by miR-424-5p. Furthermore, miR-424-5p transported by EVs can increase the secretion of proinflammatory cytokines, decrease the secretion of anti-inflammatory cytokines and promote the apoptosis of tumor cells. The intratumoral administration of miR-424-5p-EVs significantly slowed tumor growth. In conclusion, these results demonstrate that EVs may serve as a delivery system for novel immunotherapies for TNBC through the miR-424-5p/PD-L1 pathway.

Triple-negative breast cancer (TNBC) is a particularly aggressive and invasive breast cancer subtype and is associated with poor clinical outcomes. Treatment approaches for TNBC remain limited partly due to the lack of expression of well-known molecular targets. Small extracellular vesicles (sEVs) carrying a variety of bioactive contents play an important role in intercellular communications. The biomolecules including nucleic acids, proteins, and metabolites can be transferred locally or systematically to recipient cells and regulate their biological states and are involved in physiological and pathological processes. Recently, despite the extensive attraction to the physiological functions of sEVs, few studies focus on the roles of sEVs in TNBC. In this review, we will summarize the involvement of sEVs in the tumor microenvironment of TNBC. Moreover, we will discuss the potential roles of sEVs as diagnostic markers and treatment therapy in this heterogeneous breast cancer subtype. We finally summarize the clinical application of sEVs in TNBC.

Coronavirus disease 2019 (COVID-19) caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has reached a global epidemic across the world after first reported in Wuhan, China’s Hubei province in December 2019. The pandemic is also associated with acute respiratory distress syndrome (ARDS) characterized by excess inflammation, progressive arterial hypoxemia and dyspnea. Mesenchymal stem/ stromal cells (MSCs) have been investigated as treatment for ARDS due to immunomodulatory property. Exosomes derived from MSCs play an important role in paracrine signaling of MSCs, thereby contributed to immunomodulation of the immune microenvironment. Exosomes are emerged as potential alternative to MSC cell therapy with superiority of safety. In this review, we will introduce MSC-derived exosomes and briefly discuss current progress on MSCs and exosomes in ARDS, which may have clinical implications in pathogenesis and treatment of COVID-19.