Cardiovascular disease is the leading cause of death in the world. This field has been the focus of several novel stem/progenitor cell-based therapies. These therapies have shown promising results in human clinical trials. Studies have demonstrated that cardiac progenitor cells (CPC; c-kit+/Lin−) and cardiomyocyte-derived cells (CDCs) from human neonatal cardiac tissue can reduce heart scar size, improve heart function, and alleviate poor myocardial remodeling more effectively than adult-derived cells. Although a phase 1 clinical trial was conducted using purified adult or developmental CPCs or CDCs with transplantation as a regenerative therapy, one of the main limiting factors in enhancing clinical outcomes was the inability to non-invasively monitor transplanted cells and their therapeutic effects during myocardial remodeling.
In addition, resident cardiac/progenitor cells have a low occupancy rate. Components of the stem cell secretory group, including exosomes, promote myocardial recovery through a donor age-dependent pathway. The increased index of exosomes studied in relation to cardiac repair highlights the therapeutic potential of these miRNA-containing small vesicles (30 to 150 nm), which are derived from the fusion of multivesicular and plasma membranes. Exosomes carry the proteins needed to repair damaged hearts, as well as miRNAs, which can promote long-term repair by altering the transcriptome of target cells/tissue.
Although pre-clinical studies demonstrate that intramyocardial transplantation of CPC or CDC rescues infarcted myocardium and improves cardiac function, the underlying mechanisms driving these beneficial effects are unclear. Previously, scientists conducted an in-depth analysis of the CPC secretion group (secretome), demonstrating that a single intramyocardial injection of exosomes from neonatal CPC can promote myocardial recovery (Figure 1.) These results indicate that at least part of the therapeutic efficacy of CPC or CDC may be due to their exosomes. Previous studies have reported that circulating tissue-specific exosomes from transplanted solid organs are observed in the plasma of the recipient. Exosomes contain specific proteome and RNA characteristics that reflect the state of the cells from which they are derived.
Stem cell transplantation has been hampered by the lack of simple and efficient methods for non-invasive monitoring of transplanted cells in target organs. Recently, researchers from the University of Maryland and the University of Pennsylvania published an article in Science Translational Medicine in which they describe a method for isolating exosomes from blood to monitor human CDCs and CPCs transplanted into rat hearts post-infarction. They demonstrate that tissue-specific exosomal characterization in circulation enables non-invasive monitoring of transplanted solid organs in a time-sensitive, condition-specific manner. This study established that quantification and characterization of transplanted cell-derived exosomes in recipient plasma will enable reliable, non-invasive monitoring of the conditional activity of transplanted cells. To test this hypothesis, the researchers used a human-rat heterogeneous myocardial infarction model to compare two progenitor cell types: CDCs and c-kit+ CPCs. Both are from the right atrial appendage of an adult undergoing cardiopulmonary bypass. The experimental results show that CPC is superior to CDC in cell-based and in vivo regeneration assays.
To monitor the activity of transplanted CDCs or CPCs non-invasively in vivo, the researchers purified progenitor-specific exosomes from total plasma exosomes of the recipient. At 7 days post-transplantation, the concentration of plasma CPC-specific exosomes increased approximately two-fold compared to CDC-specific exosomes. Bioinformatic pathway analysis indicated miRNA cargoes of circulating exosomes are different than those secreted by cells in vitro. This strongly suggests that these stem/progenitor cells are highly dependent on their microenvironment. Controlling these stem/progenitor cells in suitable microenvironments and producing functional exosomes as a potent therapeutic drugs will be critical for the future of regenerative medicine.
In summary, this study demonstrates that progenitor-specific exosomes are present in the receptor cycle and can be monitored non-invasively. A head-to-head comparison was performed in a heterogeneous rodent MI model to study the cardiac repair potential of CDC and CPC from two fully studied progenitor cells from the same human heart biopsy. The monitoring potential of stem/progenitor-specific exosomes was verified and demonstrated that exosome miRNAs reflect functional myocardial repair of transplanted stem cells. These findings demonstrate the potential of circulating progenitor-specific exosomes as a liquid biopsy, which provides a non-invasive monitoring protocol for the state of transplanted cells. This paper also sheds light on the potential clinical application of cell-specific exosomes for monitoring allogeneic cell therapies. To read more, please click here.