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.
Highlights
Mesenchymal stem cells (MSCs), often categorized as adult stem cells are multipotent stem cells that could differentiate into at least three cell types namely, adipocytes, chondrocytes and osteocytes [16]
To generate sufficient quantities of exosomes for comparative analyses against those produced by hESC-derived MSCs (HuES9.E1) [80] and the MYC-234 immortalized HuES9.E1 or E1MYC [81], primary cord MSCs, p3 were infected with lentivirus carrying the MYC oncogene
Telomerase activity in CMSC3A1 cells was higher than that in HuES9.E1 but lower than that in E1MYC16.3 which was established by MYC transformation of HuES9.E1 (Figure 1D)
Summary
Mesenchymal stem cells (MSCs), often categorized as adult stem cells are multipotent stem cells that could differentiate into at least three cell types namely, adipocytes, chondrocytes and osteocytes [16] They are reported to be able to differentiate into endothelial, cardiomyocytes and neurons [7,8,9,10,11,12,13] with negligible risk of teratoma formation. This wide-ranging differentiation potential were used to rationalize MSC transplantation to treat musculoskeletal injuries, improve cardiac function in cardiovascular disease and ameliorate the severity of graft-versus-host-disease [14]. Many studies reported that MSCs derived from these latter tissues are more robust in their proliferative capacity, biological activity and therapeutic potency [20,51,52,53,54,55]
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