Abstract
Background
Myocardial infarction (MI), a representative form of ischemic heart disease, remains a huge burden worldwide. This study aimed to explore whether extracellular vesicles (EVs) secreted from hyaluronic acid (HA)-primed induced mesenchymal stem cells (HA-iMSC-EVs) could enhance the cardiac repair after MI.
Results
HA-iMSC-EVs showed typical characteristics for EVs such as morphology, size, and marker proteins expression. Compared with iMSC-EVs, HA-iMSC-EVs showed enhanced tube formation and survival against oxidative stress in endothelial cells, while reduced reactive oxygen species (ROS) generation in cardiomyocytes. In THP-1 macrophages, both types of EVs markedly reduced the expression of pro-inflammatory signaling players, whereas HA-iMSC-EVs were more potent in augmenting anti-inflammatory markers. A significant decrease of inflammasome proteins was observed in HA-iMSC-EV-treated THP-1. Further, phospho-SMAD2 as well as fibrosis markers in TGF-β1-stimulated cardiomyocytes were reduced in HA-iMSC-EVs treatment. Proteomic data showed that HA-iMSC-EVs were enriched with multiple pathways including immunity, extracellular matrix organization, angiogenesis, and cell cycle. The localization of HA-iMSC-EVs in myocardium was confirmed after delivery by either intravenous or intramyocardial route, with the latter increased intensity. Echocardiography revealed that intramyocardial HA-iMSC-EVs injections improved cardiac function and reduced adverse cardiac remodeling and necrotic size in MI heart. Histologically, MI hearts receiving HA-iMSC-EVs had increased capillary density and viable myocardium, while showed reduced fibrosis.
Conclusions
Our results suggest that HA-iMSC-EVs improve cardiac function by augmenting vessel growth, while reducing ROS generation, inflammation, and fibrosis in MI heart.
Graphical Abstract
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Introduction
Ischemic heart disease (IHD) is a leading cause of death worldwide [1]. MI leads to myocardium loss, pathological remodeling, dysfunctional cardiac function, and heart failure [2]. MI is manifested by myocyte loss, which triggers a cascade of immune-inflammatory pathways and cellular processes such as complement activation, the generation of ROS, and the activation of inflammasomes. The recovery begins with the action of inflammatory cells, which replace the necrotic myocardium with granulation tissue. Also, fibroblasts generate a new collagen matrix, which eventually results in the formation of the post-infarction scar in the infarcted area [3,4,5].
Recent studies have demonstrated that mesenchymal stem cells (MSCs) can reduce inflammation, fibrotic, and injury to the parenchyma, thus contributing to tissue repair [6,7,8,9,10,11,12]. Earlier clinical studies have been shown that transplanted stem cells can promote tissue regeneration via engraftment in the myocardium, not via differentiation into cardiomyocytes [13, 14]. Despite the benefits, MSCs have not translated well into clinical practice because clinical trials have consistently failed to produce conclusive outcomes possibly due to the difficulties in preparing large scale of homogenous cells that can be applicable for therapeutical purposes [15]. In this regard, MSC-like cells derived from pluripotent stem cells (iMSCs) have tremendous advantages owing to their homogeneity and stable growth profile [16, 17]. These properties make it possible to generate a large quantity of clonally derived iMSCs in a scalable manner [18]. Several animal studies using iMSCs have shown significant benefits in tissue regeneration and repair [19,20,69] suggested that HA-iMSC-EVs share pharmacological functions with several drugs associated with cardiovascular diseases/development. HA is an unsulfated glycosaminoglycan with excellent viscoelasticity, high moisture retention capacity, biocompatibility, and hygroscopic properties [70]. Most cells in the body synthesize HA at some point in their cell cycle, implicating it in several fundamental biological processes. Wang et al. reported that HA oligosaccharides improve angiogenesis by upregulating VEGF secretion and myocardial function reconstruction after MI through the polarization of M2-type macrophages [71]. Le et al. also reported that HA-based microrods provide local biochemical and biomechanical signals to reprogram fibroblasts and attenuate cardiac fibrosis [72]. Recent study also reported that Hapln1-expressing epicardial cells were responsible for the processing and organization of HA within the ECM, which has recently been implicated in heart regeneration [73]. Furthermore, HA priming increased the trafficking, adhesion, and internalization of MSC EV into injured target cells, enhancing the therapeutic potency of the EV. HA may act as a bridge between MSC EV and target cells, allowing the EV to be internalized [37]. Together with these previous findings and the results from the present study, HA-iMSC-EVs have potential as a novel cell-free therapeutic option for MI.
Conventionally, most preclinical/clinical investigations on cell therapy for heart diseases have used single-dose delivery, mostly due to the technical difficulties of repeated administration and high lethality [74]. However, EVs lack some of the risks associated with cell-based therapies due to their low immunogenicity, minimal embolism risk, and biocompatibility. Furthermore, EVs can be delivered to the heart via various delivery routes, including intravenous, intracoronary and intramyocardial administration [75]. In the present study, we compared the therapeutic effects of HA-iMSC-EVs administered via various regime (i.e., delivery routes, dosages, and schedules). TTC/Evan’s blue staining showed that the infarct size was significantly reduced by HA-iMSC-EVs compared to that in the vehicle-treated animals, regardless of the delivery route. However, bioluminescence imaging revealed that most of the intravenously injected HA-iMSC-EVs were localized in off-target organs, including the brain, lungs, liver, and kidneys. Therefore, we decided to administer HA-iMSC-EVs via intramyocardial route to reduce the localization and possible side effects in non-cardiac tissues. We also tried to identify whether the repeated injection of HA-iMSC-EVs, considering clinically feasible platforms, could improve cardiac functions in comparison with single injection. However, we found that the repeated injection of HA-iMSC-EVs did not significantly improve systolic and diastolic cardiac functions. In histologic analysis, only capillary densities in the border zone and percent fibrosis of LV wall were significantly improved in the high (20 mg/kg) dose of repeated injection of HA-iMSC-EVs. Considering that the repeated injection of 10 mg/kg of HA-iMSC-EVs didn’t improve capillary densities and percent fibrosis compared with those of single injection of 20 mg/kg of HA-iMSC-EVs, we can infer that (1) the therapeutic concentration of 20 mg/kg in single injection group was set too higher than expected, and (2) the time point of secondary injection (at day 7 after the first one) may not be sufficient to reverse the inflammation and fibrosis, resulting in reduced dose-dependency in some functional parameters. Thus, we are planning to conduct further studies to investigate optimal applications such as HA-iMSC-EVs concentration and dose intervals, in order to enhance the HA-iMSC-EVs treatment regime.
Conclusion
HA-iMSC-EVs improve cardiac repair via multiple cellular mechanisms including promoting capillary growth and attenuating tissue necrosis after MI. This strategy has potential to become an alternative option for cell-free therapeutics for cardiac repair.
Availability of data and materials
The materials can be provided upon request via email to the corresponding author.
Abbreviations
- AAR:
-
Area at risk
- ADSC:
-
Adipose-derived stem cells
- ATC:
-
Anatomical therapeutic chemical
- ATP:
-
Adenosine triphosphate
- CCK-8:
-
Cell counting cell kit 8
- cTnT:
-
Cardiac troponin T
- DAMP:
-
Danger-associated molecular patterns
- ECM:
-
Extracellular matrix
- EDPVR:
-
End-diastolic pressure–volume relationship
- EF:
-
Ejection fraction
- ESPVR:
-
End-systolic pressure–volume relationship
- EVs:
-
Extracellular vesicles
- FS:
-
Fractional shortening
- HA:
-
Hyaluronic acid
- HUVECs:
-
Human umbilical venous endothelial cells
- I/R:
-
Ischemic reperfusion
- IFN-γ:
-
Interferon-gamma
- IHD:
-
Ischemic heart disease
- IL-13:
-
Interleukin 13
- IL-1β:
-
Interleukin-1 beta
- IL-4:
-
Interleukin 4
- IM:
-
Intramyocardial
- iMSCs:
-
Induced mesenchymal stem cells
- iPSC-CM:
-
Cardiomyocytes derived from iPSC
- IV:
-
Intravenously
- LDH:
-
Lactate dehydrogenase
- LPS:
-
Lipopolysaccharides
- LV:
-
Left ventricular
- LVEDD:
-
Left ventricular end diastolic diameter
- LVEDV:
-
Left ventricular end diastolic volume
- LVEF:
-
Left ventricular ejection fraction
- LVESD:
-
Left ventricular end systolic diameter
- LVESV:
-
Left ventricular end systolic volume
- LVIDd:
-
Left ventricular internal diastolic dimension
- LVIDs:
-
Left ventricular internal systolic dimension
- MI:
-
Myocardial infarction
- MSCs:
-
Mesenchymal stem cells
- NLRP3:
-
NACHT, LRR, and PYD domain-containing protein 3
- NRCFs:
-
Neonatal rat cardiac fibroblasts
- NRCMs:
-
Neonatal rat cardiomyocytes
- NTA:
-
Nanoparticle tracing analysis
- PMA:
-
Phorbol 12-myristate 13-acete
- PV:
-
Pressure–volume
- ROS:
-
Reactive oxidative species
- SWT:
-
Septal wall thickness
- TEM:
-
Transmission electronic microscopy
- TGF-β:
-
Transforming growth factor- beta
- TTC:
-
2,3,5-Triphenyltetrazolium chloride
- VEGF:
-
Vascular endothelial growth factor
- WJ:
-
Wharton’s jelly
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Acknowledgements
The experimental scheme and process were created with BioRender.com.
Funding
This research was supported by the Korean Fund for Regenerative Medicine funded by the Ministry of Science and ICT, the Ministry of Health and Welfare (21C0708L1-13, Republic of Korea), and a National Research Foundation of Korea Grant funded by the Korean Government (NRF-2022R1A2C2009067, Republic of Korea).
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SYJ performed in vitro experiments and wrote the manuscript. BWP performed in vivo experiments and wrote the manuscript. JK performed in vitro experiments. SL, HY and JL performed analysis and prepared the experimental materials. SL, JHP, JK, WS, and KB performed in vivo experiment. JP analyzed the bioinformatics data and wrote the manuscript. HJP and SK supervised the study and wrote the manuscript. All authors read and approved the final manuscript.
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All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of The Catholic University of Korea (Approval date: 25 June 2021; Approval number: CUMC-2020–0063-03).
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Supplementary Information
Additional file 1: Fig S1.
Characterization of hiPSC-CM. a Characterization of hiPSC-CM was performed by flow cytometric analysis with cardiomyocyte markers including cardiac troponin T (cTnT), actinin alpha (α-actinin), alpha smooth muscle actin (α-SMA) and myosin light chain 2a (MLC2a). Fig S2. Protection effects of the HA-iMSC-EVs on primary neonatal rat cardiomyocyte. a-b EVs were treated to primary neonatal rat cardiomyocyte damaged with 500 μM of H2O2 for 2h. a Video were recorded for 15 seconds, and the beating area were marked yellow line. b After 48 h, relative viable cells were increased in EV-treated groups compared to PBS group. Mean ± SD, n= 3, **p < 0.01 vs PBS; ##p < 0.01 vs iMSC-EV. Fig S3. Heart rate during the cardiac function measurements. During cardiac ultrasound measurements, imaging was conducted on a temperature-controlled pad set at 40 degrees Celsius. Anesthesia was carefully administered using masks. Ultrasound system recorded M-mode images over a 3-second duration. Subsequently, heart rate calculations were derived from M-mode images captured at the 5-week time point. Mean ± SEM, n= 5.
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Jeong, SY., Park, BW., Kim, J. et al. Hyaluronic acid stimulation of stem cells for cardiac repair: a cell-free strategy for myocardial infarct. J Nanobiotechnol 22, 149 (2024). https://doi.org/10.1186/s12951-024-02410-x
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DOI: https://doi.org/10.1186/s12951-024-02410-x