Abstract
Mesenchymal stem cells (MSCs) are used in many of the current stem cell-based clinical trials and their therapeutic efficacy has increasingly been attributed to secretion of paracrine factors. We have previously demonstrated that a therapeutic constituent of this secretion is exosome, a secreted bilipid membrane vesicle of ~50–100 nm with a complex cargo that is readily internalized by H9C2 cardiomyocytes. It reduces infarct size in a mouse model of myocardial ischemia/reperfusion (MI/R) injury. We postulate that this therapeutic efficacy is derived from the synergy of a select permutation of individual exosome components. To identify protein candidates in this permutation, the proteome was profiled and here we identified 20S proteasome as a protein candidate. Mass spectrometry analysis detected all seven α and seven β chains of the 20S proteasome, and also the three beta subunits of “immunoproteasome” with a very high confidence level. We demonstrated that a functional proteasome copurified with MSC exosomes with a density of 1.10–1.18 g/mL, and its presence correlated with a modest but significant reduction in oligomerized protein in a mouse model of myocardial infarction. Circulating proteasomes in human blood also copurified with exosomes. Therefore, 20S proteasome is a candidate exosome protein that could synergize with other constituents to ameliorate tissue damage.
Highlights
Mesenchymal stem cells (MSCs) are multipotent fibroblastlike cells that reside in many adult tissues such as bone marrow adipose tissue [1, 2], liver [3], muscle connective tissue [4], amniotic fluid [5], placenta [6, 7], umbilical cord blood [1], and dental pulp [8, 9]
We demonstrated that a functional proteasome copurified with MSC exosomes with a density of 1.10–1.18 g/mL, and its presence correlated with a modest but significant reduction in oligomerized protein in a mouse model of myocardial infarction
We subsequently demonstrated that this exosome population alone could reduce infarct size by ∼40% in a mouse model of myocardial ischemia/reperfusion injury and was the therapeutic agent in the secretion of mesenchymal stem cells [23]
Summary
Mesenchymal stem cells (MSCs) are multipotent fibroblastlike cells that reside in many adult tissues such as bone marrow adipose tissue [1, 2], liver [3], muscle connective tissue [4], amniotic fluid [5], placenta [6, 7], umbilical cord blood [1], and dental pulp [8, 9] Their differentiation potentials are primarily osteogenesis, chondrogenesis, and adipogenesis, MSCs have been reported to have the potential to differentiate into an amazing array of cell types that include nearly every major cell types in the adult body [10, 11]. It has been increasingly observed that the therapeutic efficacy of MSC therapy is not dependent on the engraftment of MSC at the site of injury or differentiation capability of the transplanted MSC [17,18,19,20], essentially eliminating the need for MSCs to be in the vicinity of their target tissue or to differentiate to exert a therapeutic effect. This paradigm shift in the therapeutic mechanism of MSC from one based on cell engraftment, differentiation and replacement to one based on secretion and paracrine signaling could potentially engender the development of biologic instead of cell-based therapeutics
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