Bone marrow stem cells (BMSCs) are a promising strategy for cardiac regenerative therapy for myocardial infarction (MI). However, cell transplantation has to overcome a number of hurdles, such as cell quality control, clinical practicality, low cell retention/engraftment, and immune reactions when allogeneic cells are used. Bispecific antibodies (BsAbs) have been developed as potential agents in cancer immunotherapy but their application is sparse in cardiovascular diseases. In the present study, BsAbs are designed by chemical cycloaddition of F(ab′)2fragments from monoclonal anti‐CD34 and anti‐ cardiac myosin heavy chain (CMHC) antibodies, which specifically targets circulating CD34‐positive cells and injured cardiomyocytes simultaneously. It is hypothesized that intravenous administration of stem cell re‐directing (SCRD) BsAbs (anti‐CD34‐F(ab′)2–anti‐CMHC‐F(ab′)2) can home endogenous BMSCs to the injured heart for cardiac repair. The in vivo studies in a mouse model with heart ischemia/reperfusion (I/R) injury demonstrate the safety and therapeutic potency of SCRD BsAb, which supports cardiac recovery by reducing scarring, promoting angiomyogenesis, and boosting cardiac function.
Cardiovascular disease is the leading cause of mortality worldwide. While reperfusion therapy is vital for patient survival post‐heart attack, it also causes further tissue injury, known as myocardial ischemia/reperfusion (I/R) injury in clinical practice. Exploring ways to attenuate I/R injury is of clinical interest for improving post‐ischemic recovery. A platelet‐inspired nanocell (PINC) that incorporates both prostaglandin E2 (PGE2)‐modified platelet membrane and cardiac stromal cell‐secreted factors to target the heart after I/R injury is introduced. By taking advantage of the natural infarct‐homing ability of platelet membrane and the overexpression of PGE2receptors (EPs) in the pathological cardiac microenvironment after I/R injury, the PINCs can achieve targeted delivery of therapeutic payload to the injured heart. Furthermore, a synergistic treatment efficacy can be achieved by PINC, which combines the paracrine mechanism of cell therapy with the PGE2/EP receptor signaling that is involved in the repair and regeneration of multiple tissues. In a mouse model of myocardial I/R injury, intravenous injection of PINCs results in augmented cardiac function and mitigated heart remodeling, which is accompanied by the increase in cycling cardiomyocytes, activation of endogenous stem/progenitor cells, and promotion of angiogenesis. This approach represents a promising therapeutic delivery platform for treating I/R injury.
more » « less- NSF-PAR ID:
- 10462421
- Author(s) / Creator(s):
- ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; more »
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Advanced Functional Materials
- Volume:
- 29
- Issue:
- 4
- ISSN:
- 1616-301X
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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In the modern world, myocardial infarction is one of the most common cardiovascular diseases, which are responsible for around 18 million deaths every year or almost 32% of all deaths. Due to the detrimental effects of COVID-19 on the cardiovascular system, this rate is expected to increase in the coming years. Although there has been some progress in myocardial infarction treatment, translating pre-clinical findings to the clinic remains a major challenge. One reason for this is the lack of reliable and human representative healthy and fibrotic cardiac tissue models that can be used to understand the fundamentals of ischemic/reperfusion injury caused by myocardial infarction and to test new drugs and therapeutic strategies. In this review, we first present an overview of the anatomy of the heart and the pathophysiology of myocardial infarction, and then discuss the recent developments on pre-clinical infarct models, focusing mainly on the engineered three-dimensional cardiac ischemic/reperfusion injury and fibrosis models developed using different engineering methods such as organoids, microfluidic devices, and bioprinted constructs. We also present the benefits and limitations of emerging and promising regenerative therapy treatments for myocardial infarction such as cell therapies, extracellular vesicles, and cardiac patches. This review aims to overview recent advances in three-dimensional engineered infarct models and current regenerative therapeutic options, which can be used as a guide for developing new models and treatment strategies.more » « less
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Hydrogen sulfide (H2S) exhibits protective effects in cardiovascular disease such as myocardial ischemia/reperfusion (I/R) injury, cardiac hypertrophy, and atherosclerosis. Despite these findings, its mechanism of action remains elusive. Recent studies suggest that H2S can modulate protein activity through redox-based post-translational modifications of protein cysteine residues forming hydropersulfides (RSSH). Furthermore, emerging evidence indicates that reactive sulfur species, including RSSH and polysulfides, exhibit cardioprotective action. However, it is not clear yet whether there are any pharmacological differences in the use of H2S vs. RSSH and/or polysulfides. This study aims to examine the differing cardioprotective effects of distinct reactive sulfur species (RSS) such as H2S, RSSH, and dialkyl trisulfides (RSSSR) compared with canonical ischemic post-conditioning in the context of a Langendorff ex-vivo myocardial I/R injury model. For the first time, a side-by-side study has revealed that exogenous RSSH donation is a superior approach to maintain post-ischemic function and limit infarct size when compared with other RSS and mechanical post-conditioning. Our results also suggest that RSSH preserves mitochondrial respiration in H9c2 cardiomyocytes exposed to hypoxia-reoxygenation via inhibition of oxidative phosphorylation while preserving cell viability.more » « less
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