Efficiency of Exosome Production Correlates Inversely with the Developmental Maturity of MSC Donor

Abstract

Mesenchymal stem cells (MSCs) derived from human embryonic stem cells (ESCs) and fetal tissues have been shown to secrete cardioprotective exosome, a protein-and RNA40 containing vesicle. Since the therapeutic efficacy of MSCs is inversely correlated with developmental stage of the donor, we determine if this correlation extended to the cardioprotective MSC exosomes by examining exosomes secreted by MSCs derived from non-embryonic/fetal tissues e.g. umbilical cord.Unlike ESC-and fetal-MSCs, cord-MSCs have a much smaller proliferative capacity. To circumvent this and produce sufficient MSC exosomes for testing, they were immortalized via MYC over-expression. Like ESC-MSCs, MYC immortalization of cord MSCs expanded their proliferative capacity to bypass senescence, reduced plastic adherence, enhanced growth rate, and eliminated in vitro adipogenic differentiation potential without compromising exosome production. Exosomes produced by immortalized cord-MSCs were cardioprotective, and were equally efficacious in reducing infarct size in a mouse model of myocardial ischemia/reperfusion injury. However, cord MSCs produced the least amount of exosomes followed by fetal-and then ESC-MSC in decreasing order of developmental maturity or youth of the donor tissues, suggesting that the inverse correlation between the therapeutic efficacy of MSC and developmental stage of the donor is underpinned by rate of exosome production.

Human multipotent mesenchymal stromal cells cytokine priming promotes RAB27B-regulated secretion of small extracellular vesicles with immunomodulatory cargo

“…Age was associated with lower RAB27B expression and sEV secretion by MSCs. This points to a new role of RAB27B and is consistent with previous data indicating that developmental maturity (embryonic stem cell [ESC]- vs UC-MSC) is inversely correlated with sEV yield [ 82 ]. We report that RAB27B mediates the release of anti-inflammatory sEVs by primed MSCs and that lower RAB27B expression is associated with age.…”

Mesenchymal Stromal Cell Secretome for the Treatment of Immune-Mediated Inflammatory Diseases: Latest Trends in Isolation, Content Optimization and Delivery Avenues

“…It is important to mention that variability introduced by the cell donor or origin makes the MSCs unpredictable and as a result, there is an increasing interest in their replacement by immortalized cell lines [93]. According to the latest research, immortalized MSC-derived secretome does not vary depending on tissue source or cell passage [74,94]. Furthermore, since an important quantity of cells are required for an optimal yield of secretome production, the use of immortalized MSCs with lower cost and better longevity results is appealing.…”

Exosomes/miRNAs as mediating cell-based therapy of stroke

“…Exosomes are released by most cell types under physiological conditions. The amount of exosomes released from MSCs is highly related to cellular proliferation rate, and the exosome production is inversely correlated to the developmental maturity of the MSCs (Chen et al, 2013b). The release of extracellular vesicles can be altered by cellular stress and damage (Hugel et al, 2005; Greenwalt, 2006).…”