Table 1.
hBM-MSCs derived extracellular vesicles’ (EVs) effects on healthy hematopoiesis and hematological malignancies.
| Normal or Disease State | Source of MSC-EVs | EV Type | Biological Effect | Mechanism | Reference |
|---|---|---|---|---|---|
| Normal Hematopoiesis | BM-MSCs from healthy donors | all EVs | BM-MSCs-EVs reduced apoptosis, inhibited differentiation of target cells in vitro and increase engraftment of CD34+ umbilical cord blood cells in in vivo murine BM | Differential gene regulation comprising small RNA-target genes in CD34+ cells exposed to BM-MSC-EVs compared with naive CD34+ cells. Reduced caspase 3/7 activity, down-regulation of MPL and ZFP36 and up-regulation of chemotactic factors (IL1b, CSF2, CCL3, GATA2, and CXCR4) were the main molecular mechanisms | [49] |
| Normal Hematopoiesis | BM-MSCs and adipose-derived MSCs from C57BL/6 mice | all EVs | MSC-EVs prompt a loss of HSPC quiescence and expansion of myeloid biased lineage | Exosomes engaged TLR-4 followed by NF-κB upregulation that led to downstream activation of Hif-1 and CCL2 target genes and increased secretion of pro-inflammatory cytokines | [58] |
| MM | BM-MSC from patients with MM, Smoldering MM, MGUS, healthy donors, and a human stromal cell line HS-5 | Exosomes | HD-BM-MSCs-exosomes reduced MM cell proliferation while MM-BM-MSCs’ exosomes increased MM cell proliferation in vitro and increased cell adhesion capacity MM-BM-MSCs-exosomes promoted tumor growth and dissemination while HD-MSCs-exosomes inhibited tumor growth in an in vivo setting |
Differential miRNA and protein transfer | [59] |
| MM | BM-MSC from MM patients and healthy donors | Exosomes | Both MM-BM-MSCs- and normal-MSCs-exosomes induced drug resistance to Bortezumib in MM cells | Both MM and normal-BM-MSCs-exosomes activated chemotaxis (CXCR4, SDF-1-mediated, and MCP-1-mediated pathways), increased anti-apoptotic proteins (Bcl-2), and inhibited the activation of caspase-9 and caspase-3. Additionally, exosomes of both sources altered phosphorylation of p38, p53, and JNK as well as prevented the inhibition of AKT pathway. Exosomes managed to inhibit reduction of Bcl-2 caused by Bortezomib | [60] |
| MM | BM-MSC from MM patients and healthy donors | MVs | MM-MSCs-MV increased viability, proliferation, migration capacity, and translational activity of MM cells compared with HD-MSCs-MVs treated MM cells | MM-MSCs-MVs increased phosphorylation of MAPKs (pERK1/2 and pJNK) and activation of TI factors (peIF4E and peIF4GI) in MM cells compared with HD-MSCs- MVs | [61] |
| MM | BM-MSCs from healthy donors | Naïve exosomes Exosomes transfected with miR340 and miR365 mimics |
BM-MSCs’-exosomes from younger donors inhibited angiogenic response of MM-HR cells compared with BM-MSCs’-exosomes from older donors and control miR340-enriched exosomes inhibited angiogenesis and proliferation of MM-HR cells | miR340 enriched exosomes suppressed cMET translation | [62] |
| MM | 5TGM1 cells and C57BL6/KalwRij mouse model | Small EVs | EVs enhance the osteoclast activity and block the osteoblast differentiation in vitro and in vivo | The blockage of secreted exosomes with sphingomyelinase inhibitor GW4869 increase the cortical bone volume and sensitize the myeloma cells to bortezomid | [63] |
| MM | BM-MSCs from MM patients and healthy donors | Exosomes | MM-BM-MSCs-exosomes promote the secretion of IL-6 and suppress the osteoblastic differentiation and mineralization of BM-MCs | MM-BM-MSCs-exosomes increase the expression of APE1 and NF-kB and decrease the expression of Runx2, Osterix, and OCN | [64] |
| AML | BM-MSCs from AML patients and healthy donors | Exosomes | BM-MSCs-exosomes increased chemo-resistance to Cytarabine (for both exosome sources) and Quizartinib (only for AML-BMSCs-exosomes) of AML cells | [65] | |
| AML | AML cell lines and C57BL/Ka (B6), C57BL/Ka-Thy1.1-CD45.1, B6-Rag2−/−γc−/−, and NOD-SCID-γc−/− mouse models | Exosomes | AML-exosomes promote the leukemic cell survival and proliferation and suppress normal hematopoiesis | AML-exosomes induce the expression of DKK1, a suppressor of normal hematopoiesis and osteogenesis. AML-exosomes reduce the ability of BM cells to support normal hematopoiesis by downregulating CXCL12, KITL, and IGF1 (hematopoietic stem cell supporting factor) | [66] |
| MDS | BM-MSC from MDS patients and healthy donors | MVs | MDS-BM-MSCs-MVs increased viability and clonogenic capacity of CD34+ compared with untreated cells | Downregulation of MDM2 protein expression in CD34+ cells after exposure to MDS-MVs | [67] |
Abbreviations: AKT: Protein kinase B. AML: Acute Myeloid Leukemia. Bcl-2: B-cell lymphoma 2 gene. APE1: Apurinic/Apyrimidinic Endonuclease 1. hBM: human bone marrow. B6: C57BL/6 strain. B6-Rag2−/−: B6 recombination-activating gene–deficient. MSCs: mesenchymal stem cells. EVs: extracellular vesicles. BM-MSCs: bone marrow mesenchymal stromal cells. BM-MSC: bone marrow stroma cells. cMET: tyrosine-protein kinase Met. CCL2: C-C motif ligand 2 chemokine. CCL3: C-C motif ligand 3. CSF2: colony Stimulating Factor 2. CXCL12: C-X-C motif chemokine 12. CXCR4: Cys-X-Cys motif chemokine receptor type 4. C57BL/6: B6 mouse strain. CD34: marker of human HSPC. DKK1: Dickkopf-related protein 1. EVs: Extracellular vesicles. GATA2: GATA2 transcription factor. GW4869: neutral sphingomyelinase-2 specific inhibitor HD: healthy donor. Hif-1: Hypoxia-inducible factor 1. HR: hypoxia resistant. HSPC: hematopoietic stem and progenitor cells. IL1b: interleukin 1 beta. IGF1: Insulin-like Growth Factor 1. JNK: c-Jun N-terminal kinases. KITL: KIT ligand. MAPK: mitogen-activated protein kinase. MCP-1: Monocyte chemoattractant protein-1. MDM2: Mouse double minute 2 homolog. MDS: myelodysplastic syndromes. MGUS: monoclonal gammopathy of unknown significance. miR: microRNA. MM: Multiple Myeloma. MPL: myeloproliferative leukemia virus oncogene. MVs: Micro-vesicles. NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells. NOD-SCID: Nonobese Diabetic-Severe Combined Immunodeficiency. pErk1/2: phosphorylated extracellular-regulated kinase 1/2. peIF4E: phosphorylated eukaryotic translation initiation factor 4E. peIF4GI: phosphorylated eukaryotic translation initiation factor 4GI. pJNK: phosphorylated c-Jun N-terminal kinases. OCN: Osteocalcin. SDF-1: stromal cell-derived factor 1. TI factor: transcription initiation factor. TLR-4: Toll-like receptor 4. ZFP36: zinc finger protein 36. MVs: microvesicles.