Cardiac cell-derived exosomes: changing face of regenerative biology
Year: 2016
Type: editorial
Abstract: This editorial refers to ‘Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction’, by R. Gallet et al., on page 201. … The difference between past, present and future is only a stubbornly persistent illusion Repair of the damaged cardiac tissue has been considered the holy grail of cardiac medicine driving researchers for years. Myocardial damage in an adult heart leads to widespread cardiomyocyte loss without active replacement of the dead cardiac tissue, ultimately resulting in formation of scar at the site of injury. Current therapies are designed only to limit the extent of scar formation and are unable to offer restoration of lost cardiac tissue, leading to a progressive decline in cardiac function. As a consequence, cardiac diseases continue to rise and are a significant cause of morbidity and mortality around the world. The last 10 years have witnessed the dawn of stem cell therapy for cardiac repair with promising true cellular replacement and restoration of cardiac tissue damaged due to pathological injury. Multiple stem cell types derived from bone marrow, heart, adipose tissue, and cortical bone have been tested in small and large animal models of myocardial damage. Among these, stem cells derived from the heart hold particular interest and represent the most suitable cell type for cardiac repair.1 Different populations of cardiac stem cells have been reported to date and, importantly, all of them have been shown to differentiate into three cardiac cell types, i.e. myocytes, endothelial cells, and smooth muscle cells, contribute towards neovascularization, and significantly improve function after myocardial damage.1,2 Promising pre-clinical results have laid down the basis for multiple phase I and II trials conducted to test the safety and effectiveness of cardiac-derived stem cells for patients with cardiovascular diseases.3,4 The outcome largely shows that cardiac-derived stem cell therapy is safe for use in patients, yet the improvement in cardiac function is incremental and modest. Moreover, controversy exists regarding the exact mechanism behind the beneficial effect of stem cell therapy. Data from animal studies convincingly demonstrated transdifferentiation ability of cardiac stem cells1 in the heart, although investigators found very few adoptively transferred cells in the heart beyond the first few days of transplantation.5 Moreover, lack of available methodologies to trace transplanted stem cells effectively in patients with cardiovascular disorders certainly represents a limitation complicating evidence for transdifferentiation. As a result, development of strategies aimed at augmenting stem cell survival and their transdifferentiation ability have become the focus of current research. Alternatively, a large body of evidence implicates the ability of transplanted stem cells to secrete growth factors, cytokines, and chemokines at the site of injury as explaining their cardioprotective effects.6,7 Consequently, cardiac stem cells are not thought to stick around for a long time, but rather release paracrine factors that stimulate endogenous myocardial repair processes consisting of enhanced cardiomyocyte cell cycle activity, neovascularization, and increased stem cell participation in myocardial repair.8,9 Emerging data recently have linked exosomes as one of the main components of the paracrine signalling regulating the salutary effects of stem cells in a cell-free system independent of the burdens associated with whole-cell transplantation.10,11 A number of recent studies have effectively shown that exosomes derived from different stem cells including cardiac-derived stem cells are a viable therapy for augmentation of cardiac function recapitulating in large part the benefits of adoptive cell transfer. Nevertheless, there still remains a need for translation of small animal findings into a clinically relevant large animal model for myocardial damage. Exosome therapy recapitulates the benefits of cell therapy. CDC derived exosomes are generated by inward budding of endosomal membranes and accumulate in multivesicular bodies. They are released into extracellular space following the fusion of the endosomal compartment with the plasma membrane. Their cargo consists mainly of proteins and nucleic acids, with the greatest abundance and variety presented by miRNA and mRNA. Delivery of CDC exosomes to heart after injury recapitulates cardiac structural and functional effects, angiogenesis and immune modulation as seen by cell therapy. Comparative assessment of associated pros and cons of cell therapy vs. exosome therapy. Cell therapy offers direct cell injections; the surviving cells are capable of developing into cardiac tissue and stimulate endogenous myocardial repair processes (blue boxes) but carry a number of well-documented problems (red boxes). Exosome therapy relies on exosomes derived from the cells themselves and presents a cell-free system for myocardial repair without the burdens associated with cell transplantation (blue boxes). Nevertheless, there are some limitations (red boxes) associated with exosome therapy as highlighted. In conclusion, exosomes may significantly alter cardiac regenerative medicine, and this study provides the foundation for future research for development of a viable therapy based on exosomes for the repair of damaged cardiac tissue in heart failure patients. This work was supported in part by the National Institutes of Health grants HL091983, HL053354, and HL126186 (R.K.), and the American Heart Association Scientific development grant 15SDG22680018 (M.K.). Conflict of interest: none declared.
Source: European Heart Journal
Authors: Raj Kishore, Mohsin Khan
Institution: Temple University
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2524027519