Chronic lymphocytic leukemia (CLL) is caused by the accumulation of malignant B cells due to a defect in apoptosis and the presence of small population of proliferating cells principally in the lymph nodes. The abnormal survival of CLL B cells is explained by a plethora of supportive stimuli produced by the surrounding cells of the microenvironment, including follicular dendritic cells (FDCs), and mesenchymal stromal cells (MSCs). This crosstalk between malignant cells and normal cells can take place directly by cell-to-cell contact (assisted by adhesion molecules such as VLA-4 or CD100), indirectly by soluble factors (chemokines such as CXCL12, CXCL13, or CCL2) interacting with their receptors or by the exchange of material (protein, microRNAs or long non-coding RNAs) via extracellular vesicles. These different communication methods lead to different activation pathways (including BCR and NFκB pathways), gene expression modifications (chemokines, antiapoptotic protein increase, prognostic biomarkers), chemotaxis, homing in lymphoid tissues and survival of leukemic cells. In addition, these interactions are bidirectional, and CLL cells can manipulate the normal surrounding stromal cells in different ways to establish a supportive microenvironment. Here, we review this complex crosstalk between CLL cells and stromal cells, focusing on the different types of interactions, activated pathways, treatment strategies to disrupt this bidirectional communication, and the prognostic impact of these induced modifications.

Intercellular communication, through direct and indirect cell contact, is mandatory in multicellular organisms. These last years, the microenvironment, and in particular, transfer by extracellular vesicles (EVs), has emerged as a new communication mechanism. Different biological fluids and cell types are common sources of EVs. EVs play different roles, acting as signalosomes, biomarkers, and therapeutic agents. As therapeutic agents, MSC-derived EVs display numerous advantages: they are biocompatible, non-immunogenic, and stable in circulation, and they are able to cross biological barriers. Furthermore, EVs have a great potential for drug delivery. Different EV isolation protocols and loading methods have been tested and compared. Published and ongoing clinical trials, and numerous preclinical studies indicate that EVs are safe and well tolerated. Moreover, the latest studies suggest their applications as nanocarriers. The current review will describe the potential for MSC-derived EVs as drug delivery systems (DDS) in disease treatment, and their advantages. Thereafter, we will outline the different EV isolation methods and loading techniques, and analyze relevant preclinical studies. Finally, we will describe ongoing and published clinical studies. These elements will outline the benefits of MSC-derived EV DDS over several aspects.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Treatment of PDAC remains a major challenge. This study aims to evaluate, in vitro, the use of human umbilical cord mesenchymal stromal cell (UC-MSC)-derived EVs to specifically target pancreatic cancer cells. EVs were isolated from the FBS-free supernatants of the cultured UC-MSCs by ultracentrifugation and characterized by several methods. EVs were loaded with scramble or KRASG12D-targeting siRNA by electroporation. The effects of control and loaded EVs on different cell types were evaluated by assessing cell proliferation, viability, apoptosis and migration. Later, the ability of EVs to function as a drug delivery system for doxorubicin (DOXO), a chemotherapeutic drug, was also evaluated. Loaded EVs exhibited different kinetic rates of uptake by three cell lines, namely, BxPC-3 cells (pancreatic cancer cell line expressing KRASwt), LS180 cells (colorectal cell line expressing KRASG12D) and PANC-1 cells (pancreatic cell line expressing KRASG12D). A significant decrease in the relative expression of the KRASG12D gene after incubation with KRAS siRNA EVs was observed by real-time PCR. KRASG12D siRNA EVs significantly reduced the proliferation, viability and migration of the KRASG12D cell lines compared to scramble siRNA EVs. An endogenous EV production method was applied to obtain DOXO-loaded EVs. Briefly, UC-MSCs were treated with DOXO. After 24 h, UC-MSCs released DOXO-loaded EVs. DOXO-loaded EVs were rapidly taken up by PANC-1 cells and induced apoptotic cell death more efficiently than free DOXO. In conclusion, the use of UC-MSC-derived EVs as a drug delivery system for siRNAs or drugs could be a promising approach for the targeted treatment of PDAC.