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Microvesicles from Pluripotent Stem Cells Enhance Cardiac Regenerative Potential

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Review of “Human Induced Pluripotent Stem Cell-Derived Microvesicles Transmit RNAs and Proteins to Recipient Mature Heart Cells Modulating Cell Fate and Behavior” from Stem Cells by Stuart P. Atkinson.

Microvesicles (MVs) have the ability to transfer bioactive molecules from one cell to another and represent an important mechanism in cell-to-cell communication. Previous studies identified a link between MV release from endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs) and tissue regeneration [1], while MVs derived from embryonic stem cells (ESCs) can revert hematopoietic progenitor cells back to a more primitive state [2]. 

This led researchers from the group of Ewa K. Zuba-Surma (Jagiellonian University, Krakow, Poland) to assess whether human induced pluripotent stem cells derived MVs (iPSC-MVs) had a pro-regenerative capacity and, if present, whether they could harness this ability for therapeutic purposes. Their results, published in Stem Cells, show that clinically relevant iPSC-MVs enhanced the cardiac and endothelial differentiation potential of cardiac MSCs (cMSCs) (See Figure) [3].

The authors generated iPSCs from umbilical cord-mesenchymal stem cells (UC-MSCs) using techniques which ensured serum-free, feeder-free, and integration-free conditions, and, therefore, maximized the potential clinical applicability of MVs derived from the cells. Collection and ultracentrifugation of iPSC culture media permitted the collection of MVs containing mRNA transcripts related to pluripotency and cardiac and endothelial differentiation, high levels of micro(mi)RNAs whose target genes included those associated with Wnt, PI3K-Akt, MAPK signaling, cancer, and regulation of actin cytoskeleton, among others, and high levels of proteins involved in receptor binding, phosphorylation, and signal transduction.

Co-incubation experiments with fluorescently labeled MVs and hiPSCs demonstrated that transfer of cellular contents only required a short period of time and that this led to a selective increase in the levels of some mRNAs and miRNAs in cMSCs, while protein content assessment demonstrated differing patterns before and after MV incubation. The transfer of these components mediated an increase in cMSC metabolism, an increase in proliferation under normoxic and hypoxic conditions, and endowed cells with pro-survival properties. MV treatment also boosted the expression of some cardiac and endothelial transcripts during lineage-directed differentiation, suggesting that MV treatment could boost differentiation efficiency.

This study represents the first description of the regenerative potential for MVs derived from clinically-relevant patient-specific iPSCs, and may represent an important step forward in cardiac repair. The transfer of pluripotency-associated mRNAs/miRNAs/proteins in MVs appears to be sufficient to boost the activity of cMSCs, although the authors found that they could also efficiently transfer exogenous proteins. MVs may, therefore, be “hijacked” and could act as cargo transporters which could safely, quickly, and effectively transfer factors which could enhance their stemness or boost differentiation down a specific path.

Discussion Points

  • Do exosomes represent a promising cell-free stem cell therapy?
  • What exosomal contents mediate the pro-regenerative effects?
  • Will all cells respond in a similar manner to exosomal treatment?

References

  1. Camussi G, Deregibus MC, and Cantaluppi V Role of stem-cell-derived microvesicles in the paracrine action of stem cells. Biochem Soc Trans 2013;41:283-287.
  2. Ratajczak J, Miekus K, Kucia M, et al. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 2006;20:847-856.
  3. Bobis-Wozowicz S, Kmiotek K, Sekula M, et al. Human Induced Pluripotent Stem Cell-Derived Microvesicles Transmit RNAs and Proteins to Recipient Mature Heart Cells Modulating Cell Fate and Behavior. Stem Cells 2015;33:2748-2761.