CD146+ Endometrial-Derived Mesenchymal Stem/Stromal Cell Subpopulation Possesses Exosomal Secretomes with Strong Immunomodulatory miRNA Attributes

Abstract

The perivascular localization of endometrial mesenchymal stem/stromal cells (eMSC) allows them to sense local and distant tissue damage, promoting tissue repair and healing. Our hypothesis is that eMSC therapeutic effects are largely exerted via their exosomal secretome (eMSC EXOs) by targeting the immune system and angiogenic modulation. For this purpose, EXOs isolated from Crude and CD146+ eMSC populations were compared for their miRNA therapeutic signatures and immunomodulatory functionality under inflammatory conditions. eMSC EXOs profiling revealed 121 in Crude and 88 in CD146+ miRNAs, with 82 commonly present in both populations. Reactome and KEGG analysis of miRNAs highly present in eMSC EXOs indicated their involvement among others in immune system regulation. From the commonly present miRNAs, four miRNAs (hsa-miR-320e, hsa-miR-182-3p, hsa-miR-378g, hsa-let-7e-5p) were more enriched in CD146+ eMSC EXOs. These miRNAs are involved in macrophage polarization, T cell activation, and regulation of inflammatory cytokine transcription (i.e., TNF-α, IL-1β, and IL-6). Functionally, stimulated macrophages exposed to eMSC EXOs demonstrated a switch towards an alternate M2 status and reduced phagocytic capacity compared to stimulated alone. However, eMSC EXOs did not suppress stimulated human peripheral blood mononuclear cell proliferation, but significantly reduced secretion of 13 pro-inflammatory molecules compared to stimulated alone. In parallel, two anti-inflammatory proteins, IL-10 and IL-13, showed higher secretion, especially upon CD146+ eMSC EXO exposure. Our study suggests that eMSC, and even more, the CD146+ subpopulation, possess exosomal secretomes with strong immunomodulatory miRNA attributes. The resulting evidence could serve as a foundation for eMSC EXO-based therapeutics for the resolution of detrimental aspects of tissue inflammation.

CD10-Bound Human Mesenchymal Stem/Stromal Cell-Derived Small Extracellular Vesicles Possess Immunomodulatory Cargo and Maintain Cartilage Homeostasis under Inflammatory Conditions

“…We and others have isolated and characterized sEVs from various MSC sources (i.e., bone marrow, umbilical cord, adipose tissues, endometrium). Our results support a therapeutic potential through robust anti-inflammatory, anti-fibrotic, and angiogenesisremodeling capacities [19][20][21]. Our hypothesis is that CD10 expression levels in IFP-MSC are directly related to the immunomodulatory and chondroprotective effects of their derived sEVs.…”

Modification of Mesenchymal Stem/Stromal Cell-Derived Small Extracellular Vesicles by Calcitonin Gene Related Peptide (CGRP) Antagonist: Potential Implications for Inflammation and Pain Reversal

“…Similar to our previous studies [ 30 , 34 , 41 ], aCGRP IFP-MSC sEVs show high purity with <200 nm sizes and high expression levels of CD9 marker upon ultracentrifugation. Importantly, we have shown the successful transfer of AAV CGRP 8–37 within yielded sEVs.…”

Specific lipid magnetic sphere sorted CD146-positive bone marrow mesenchymal stem cells can better promote articular cartilage damage repair

“…Downregulation of CD146 accelerates cells senescence in human umbilical cord blood-derived MSCs [ 44 ]. Endometrial mesenchymal stem/stromal cells, and even more, the CD146 + subpopulation, possess exosomal secretomes with strong immunomodulatory miRNA attributes [ 45 ]. CD146 + perivascular cells, a component of MSCs, play a key role in the wound healing process [ 46 ].…”