Coronary artery disease (CAD) is the number one cause of death in developed countries (1,2). In the UK alone, there are 2 million people with CAD and 188,000 require treatment for a myocardial infarction (MI) each year. Because of the limited regenerative capacity of the human heart (3), an acute MI causes permanent damage that may ultimately result in heart failure (HF). The management of chronic HF has improved considerably in recent years but, at the same time, healthcare and social costs have rocketed. Therefore, there is an urgent need for new strategies potentially transforming palliative care into curative therapy.
Cardiovascular regenerative medicine is an exciting and rapidly expanding field of research that aims to improve the treatment of CAD through novel healing modalities, such as gene therapy, stem cell therapy, and tissue engineering. Clinical trials using skeletal myoblasts, bone marrow-derived cells and mesenchymal stem cells (MSCs) have shown feasibility and initial evidence of efficacy (4-6). However, the mechanisms underpinning the benefit of cell therapy remain matter of debate among scientists and clinicians. The direct participation of transplanted cells in vascular and cardiac repair has been toughly disputed (7,8). The prevalent view among the scientific community is that factors secreted by exogenous cells are pivotal in promotion of tissue healing and can also incite resident cells to change their secretome (9,10). Stem cells secrete potent combinations of trophic factors that help cardiac repair and regeneration at multiple points, such as supporting cardiomyocyte viability, differentiation of resident stem/progenitor cells, and angiogenesis, while modulating inflammatory and pro-fibrotic responses (9,11-13).
A recent study from Qiao et al. indicates that microRNA-21-5p dysregulation in exosomes derived from patients with HF compromises the regenerative potential of these secreted vesicles thereby resulting in delayed recovery in a murine model of MI (14). The authors also reported that other microRNAs contained in the exosomes can contribute in the observed adverse effects (14). This microRNA has been implicated in cardiac remodeling, including the induction of fibrosis (15), though this observation was not confirmed by others (16). MI is associated with recruitment of circulating monocytes. Importantly, microRNA-21-5p is the microRNA most represented in macrophages and its downregulation has been associated with induction of atherosclerosis, plaque instability, and vascular inflammatory reaction (17). Mechanistically, the lack of microRNA‐21 in macrophages upregulated the expression of the target mitogen‐activated protein kinase kinase 3, thereby leading to the activation of the p38‐CHOP and cJNK signaling pathways; the ultimate effect being the induction of macrophage apoptosis (17). Moreover, ablation of microRNA‐21 in macrophages reduces the clearance of apoptotic cells, which is key for the resolution of inflammation. This means that downregulation of the microRNA can lead to unresolved inflammation in the injured tissue (17). It would be interesting to understand if macrophages from patients with HF have a deficit in microRNA‐21 and this contributes to an imbalance between inflammation and angiogenesis. In addition, the microarray used by the authors did not include some microRNAs that are contained in the soluble fraction of the stromal cell secretome. For instance, stromal cells-secreted microRNA-132 acts as a paracrine inducer of cardiac repair (18). In vitro studies demonstrated that microRNA-132 activates vascular growth while inhibiting myofibroblast differentiation into collagen-producing fibroblasts, these effects being mediated by suppression of Ras-GTPase activating protein and methyl-CpG-binding protein 2 (18). In infarcted hearts of mice with coronary artery ligation, intra-myocardial delivery of human pericytes, which belong to the perivascular stromal cell population, reportedly improved indexes of cardiac contractility, reparative neovascularization, and interstitial fibrosis, but these benefits were negated to the same pericytes transfected with anti-microRNA-132 (18).
The study by Qiao et al. provides important cumulative evidence supporting the theory that stromal cells have a potential in regenerative medicine and that their secretome can be a source of curative agents. It remains to be elucidated whether the failure of this endogenous mechanism has any relevance in the pathogenesis and progression of HF. Moreover, the authors highlight that their findings may account for the modest benefit of patients’ autologous cell therapies reported in recent clinical trials. Certainly, this possibility should be taken in consideration. However, the experimental approach they have adopted consisted in the transfer of exosomes genetically modified to inhibit or overexpress the microRNA-21. Since the observed defect was discovered in HF patients, the obvious experimental recipient would have been mice with chronic HF rather than MI. Despite of the above incongruence, this excellent study contributes in the advancement of potential mechanisms of cardiac repair and may have an impact in the generation of new exosome-based therapies.
Provenance and Peer Review: This article was commissioned and reviewed by the Section Editor Yuan Xie (Shanghai Tongji Hospital, Shanghai, China).
Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/ncri.2019.10.01). The author has no conflicts of interest to declare.
Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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- Templin C, Lüscher TF, Landmesser U. Cell-based cardiovascular repair and regeneration in acute myocardial infarction and chronic ischemic cardiomyopathy-current status and future developments. Int J Dev Biol 2011;55:407-17. [Crossref] [PubMed]
- Bhatnagar P, Wickramasinghe K, Williams J, et al. The epidemiology of cardiovascular disease in the UK 2014. Heart 2015;101:1182-9. [Crossref] [PubMed]
- Laflamme MA, Murry CE. Heart regeneration. Nature 2011;473:326-35. [Crossref] [PubMed]
- Menasché P, Alfieri O, Janssens S, et al. The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation 2008;117:1189-200. [Crossref] [PubMed]
- de Jong R, Houtgraaf JH, Samiei S, et al. Intracoronary stem cell infusion after acute myocardial infarction: a meta-analysis and update on clinical trials. Circ Cardiovasc Interv 2014;7:156-67. [Crossref] [PubMed]
- Hare JM, Traverse JH, Henry TD, et al. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol 2009;54:2277-86. [Crossref] [PubMed]
- Balsam LB, Wagers AJ, Christensen JL, et al. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 2004;428:668-73. [Crossref] [PubMed]
- Murry CE, Soonpaa MH, Reinecke H, et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 2004;428:664-8. [Crossref] [PubMed]
- Gnecchi M, He H, Liang OD, et al. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med 2005;11:367-8. [Crossref] [PubMed]
- Tang XL, Li Q, Rokosh G, et al. Long-Term Outcome of Administration of c-kit(POS) Cardiac Progenitor Cells After Acute Myocardial Infarction: Transplanted Cells Do not Become Cardiomyocytes, but Structural and Functional Improvement and Proliferation of Endogenous Cells Persist for at Least One Year. Circ Res 2016;118:1091-105. [Crossref] [PubMed]
- Baraniak PR, McDevitt TC. Stem cell paracrine actions and tissue regeneration. Regen Med 2010;5:121-43. [Crossref] [PubMed]
- Rao KS, Aronshtam A, McElory-Yaggy KL, et al. Human epicardial cell-conditioned medium contains HGF/IgG complexes that phosphorylate RYK and protect against vascular injury. Cardiovasc Res 2015;107:277-86. [Crossref] [PubMed]
- Zhou B, Honor LB, He H, et al. Adult mouse epicardium modulates myocardial injury by secreting paracrine factors. J Clin Invest 2011;121:1894-904. [Crossref] [PubMed]
- Qiao L, Hu S, Liu S, et al. microRNA-21-5p dysregulation in exosomes derived from heart failure patients impairs regenerative potential. J Clin Invest 2019;129:2237-50. [Crossref] [PubMed]
- Thum T, Gross C, Fiedler J, et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 2008;456:980-4. [Crossref] [PubMed]
- Patrick DM, Montgomery RL, Qi X, et al. Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice. J Clin Invest 2010;120:3912-6. [Crossref] [PubMed]
- Canfrán-Duque A, Rotllan N, Zhang X, et al. Macrophage deficiency of miR-21 promotes apoptosis, plaque necrosis, and vascular inflammation during atherogenesis. EMBO Mol Med 2017;9:1244-62. [Crossref] [PubMed]
- Katare R, Riu F, Mitchell K, et al. Transplantation of human pericyte progenitor cells improves the repair of infarcted heart through activation of an angiogenic program involving micro-RNA-132. Circ Res 2011;109:894-906. [Crossref] [PubMed]
Cite this article as: Madeddu P. The exosomes carry new hope for cardiac regeneration. Non-coding RNA Investig 2019;3:27.