Emerging Role of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Pathogenesis of Haematological Malignancies

Abstract

Homoeostasis of bone marrow microenvironment depends on a precise balance between cell proliferation and death, which is supported by the cellular-extracellular matrix crosstalk. Multipotent mesenchymal stromal cells (MSC) are the key elements to provide the specialized bone marrow microenvironment by supporting, maintaining, and regulating the functions and fate of haematopoietic stem cells. Despite the great potential of MSC for cell therapy in several diseases due to their regenerative, immunomodulatory, and anti-inflammatory properties, they can also contribute to modulate tumor microenvironment. The extracellular vesicles that comprise exosomes and microvesicles are important mediators of intercellular communication due to their ability to change phenotype and physiology of different cell types. These vesicles may interact not only with neighbouring cells but also with cells from distant tissues to either maintain tissue homoeostasis or participate in disease pathogenesis. This review focuses on the current knowledge about the physiological role of MSC-extracellular vesicles, as well as their deregulation in haematological malignancies and their potential applications as biomarkers for diagnosis, progression, and treatment monitoring of such diseases.

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

“…The MM-conditioned MSCs have been shown to suppress T-cell activation and proliferation, impair DC maturation and induce Tregs via the secretion of several factors, including IL-6, TGF-β, IL-10, PGE2, and upregulated expression of several surface molecules such as VCAM-1, intracellular adhesion molecule-1 (ICAM-1) and CD40 [27][28][29][30][31][32]. Additionally, MSCs can exert their immunomodulatory activities by the secretion of extracellular vesicles [33,34]. Osteoclasts and other myeloid cells contribute to an immunosuppressive environment especially by the production of A proliferation inducing ligand (APRIL), which is the ligand for BCMA that is expressed on MM-cells and for TACI that is expressed on MM-cells and Tregs.…”

Extracellular Vesicles in the Tumour Microenvironment: Eclectic Supervisors

“…It has been reported that a more efficient tumour growth and metastasis formation occurs when myeloma cells are administered together with MSC-EV [50]. Furthermore, MSC-EV regulate self-renewal, inhibit differentiation of haematopoietic stem cells (HSC) and exert immunomodulatory action by activating neutrophils and inhibiting the DC, NK, B, and T-cell proliferation of [51]. This implies that the immune regulatory processes in the TME are strictly controlled by MSC-EV [52].…”

Latest Advances in Targeting the Tumor Microenvironment for Tumor Suppression

“…Mesenchymal progenitor cells were firstly isolated three decades ago from bone marrow (BM-MSC). Since this first characterization, it was shown that MSCs can be isolated from most tissues including fat tissue (adipocyte-derived mesenchymal stem cells), skin, heart, kidney, etc., or from perivascular space (pericyte-derived MSCs) [161,162]. They are capable of differentiating into fibroblasts, adipocytes, osteoblasts, chondroblasts, vascular and perivascular structures, etc.…”

“…They do not express CD45, CD34, CD14, CD19, and human leucocyte antigen DR (HLA-DR) [161]. MSCs possess hallmark characteristics of stem cells or at least progenitor cells with regard to their self-renewal and differentiation properties [162]. MSCs could be used as therapeutic agents for regenerative medicine as they could contribute to tissue healing, mainly through the secretion of paracrine factors such as cellular adhesion molecules (including VCAM-1 and ICAM-1), growth factors (including TFG-β, EGF, HGF), cytokines (such as IL-1α, IL-1β, IL-6, and IL-8), angiogenic factors (such as VEGF and PDGF), and immunomodulatory molecules (PGE2).…”

“…These infiltrated MSCs were described as having a role to play in ovarian cancer progression by releasing IL-6, CXCR1/2 ligands (CXCL1, CXCL2, and IL-8), and related cytokine leukemia inhibitory factor (LIF) [167,169]. MSCs are also able to promote tumor growth and metastasize through direct cell-to-cell contact or through their secreted exosomes, which are able to carry different molecules such as IL-6, TFG-β1, CCL2, and fibronectin, or miR-375, miR340 and miR-155 [162]. These exosomes also participate in tumor homing in vivo, indicating that MSCs play a role in metastasis [170].…”