Pretreatment of Cardiac Stem Cells With Exosomes Derived From Mesenchymal Stem Cells Enhances Myocardial Repair

Abstract

BackgroundExosomes derived from mesenchymal stem cells (MSCs) were proved to boost cell proliferation and angiogenic potency. We explored whether cardiac stem cells (CSCs) preconditioned with MSC exosomes could survive and function better in a myocardial infarction model.Methods and ResultsDiI‐labeled exosomes were internalized with CSCs. They stimulated proliferation, migration, and angiotube formation of CSCs in a dose‐dependent manner. In a rat myocardial infarction model, MSC exosome–preconditioned CSCs had significantly better survival, enhanced capillary density, reduced cardiac fibrosis, and restored long‐term cardiac function. MicroRNA profiling analysis revealed that a set of microRNAs were significantly changed in CSCs after MSC exosome treatment.ConclusionsPretreatment of CSCs with MSC exosomes provided a promising strategy to improve survival and angiogenic potency of CSCs.

Engineered Exosomes With Ischemic Myocardium‐Targeting Peptide for Targeted Therapy in Myocardial Infarction

“…Feng et al31 demonstrated that exosomes released from ischemic preconditioned MSCs contained an increased amount of miR‐22, which could exert a silence effect on methyl CpG binding protein 2 to ameliorate apoptosis in mice with AMI. Our group also proved that MSC‐derived exosomes could inhibit inflammation, augment vasculogenesis, and restore cardiac function in MI by activating and modifying the microRNA profiles of cardiac stem cells 32, 33. Despite these therapeutic effects of MSCs‐exosomes, targeting intended tissues or cells while avoiding nonintended delivery still remains challenging.…”

Stimulatory Effects of Mesenchymal Stem Cells on cKit + Cardiac Stem Cells Are Mediated by SDF1/CXCR4 and SCF/cKit Signaling Pathways

“…MSCs comprise a heterogeneous cell mixture of neural crest- and non-neural crest-derived cells 14, 15 that exert stimulatory effects on CSCs 7, 9, 10, 16, 17 . To address if MSCs stimulate cKit + cell migration, myocardial explants from the same PN3 cKit CreERT2 ;IRG tamoxifen-pulsed hearts were plated either with mitotically-arrested MSCs or on gelatin (control), and cell migration assessed using EGFP epifluorescence [Fig.…”

Exosomes as agents of change in the cardiovascular system

“…Intra-myocardial injection of exosome-primed fibroblasts in a rat MI model resulted in a significant angiogenic effect and reduction in scar mass, relative to injection with unprimed fibroblasts [94]. Similarly, pre-treatment of cardiac stem cells (CSCs) with MSC derived exosomes resulted in an altered miRNA expression profile, and transplantation of MSC exosome primed CSCs resulted in a better cardiac outcome [67]. In an acute MI rat model, 28 days after MI, the group treated with exosome-primed CSCs had significantly reduced ventricular fibrosis and a higher ejection fraction relative to control groups, as well as those treated with standard CSCs [67].…”

“…Similarly, pre-treatment of cardiac stem cells (CSCs) with MSC derived exosomes resulted in an altered miRNA expression profile, and transplantation of MSC exosome primed CSCs resulted in a better cardiac outcome [67]. In an acute MI rat model, 28 days after MI, the group treated with exosome-primed CSCs had significantly reduced ventricular fibrosis and a higher ejection fraction relative to control groups, as well as those treated with standard CSCs [67]. Fluorescence microscopy demonstrated that exosome primed CSCs had a larger number of engrafted cells that co-localized with capillaries; overall, the animals treated with exosome primed CSCs had a greater density of capillaries and arterioles relative to those treated with control CSCs [67].…”

“…In an acute MI rat model, 28 days after MI, the group treated with exosome-primed CSCs had significantly reduced ventricular fibrosis and a higher ejection fraction relative to control groups, as well as those treated with standard CSCs [67]. Fluorescence microscopy demonstrated that exosome primed CSCs had a larger number of engrafted cells that co-localized with capillaries; overall, the animals treated with exosome primed CSCs had a greater density of capillaries and arterioles relative to those treated with control CSCs [67]. As not all neovascularization was associated with engrafted CSCs, it is still likely that much of the therapeutic benefits of CSCs come from paracrine factors rather than CSC differentiation.…”