Methods for Delivering Stem Cells for Regeneration of Heart Tissue after Myocardial Infarction

Myocardial infarction (MI) results in irreversible loss of cardiomyocytes (CMs) and can often lead to heart failure. Due to the minimal regeneration capacity of the myocardium, novel therapeutic techniques are needed.

Myocardial infarction is a leading cause of morbidity and mortality worldwide and is the main cause of heart failure. It can be caused by obstruction of coronary arteries leading to reduced supply of blood flow to the heart muscle.  

Current standard therapies are largely palliative measures that aim to reduce remodeling and mitigate the risk of further complications. 

Cell transplantation, also known as cardiomyoplasty, is an emerging technology with the potential to regenerate functioning contractile tissue with the goals of regenerating myocytes at the site of injury, stimulating revascularization to reverse ischemia, and preventing harmful pathological remodeling. 

New Study on Methods of Stem Cells Delivering 

A new study published in the Journal of Stem Cell Research performed a review of the delivery methods and what studies have shown with the use of each of them. 

Intravenous (IV) Injection

Intravenous infusion of stem cells has been studied as a potential technique for treating post-MI patients and is appreciated for its simplicity and non-invasive nature. Studies have shown that stem cells intravenously introduced into the bloodstream are attracted to the injured tissue and are capable of engraftment into the ischemic myocardium.

Studies using MSCs and infarct rat models, myogenesis and angiogenesis were induced in the infarct area, some improvement was seen in left ventricular function as well as a decrease in infarct size. Researchers believe that the improvement in heart function is due primarily to paracrine effects stimulation surrounding viable muscle cells and increasing endogenous levels of vascular epithelial growth factors (VEGFs) rather than proliferation and regeneration of the injected cells themselves. 

Improvements in cardiac arrhythmias and LV function were seen in patients at the 12-month follow-up. According to studies the optimal cell concentration that should be injected to maximize engraftment and retention has to be at least 1 million MSCs/kg.

Intracoronary (IC) Artery Injection

This method provides a more direct method of delivery of cells into the myocardial region than allowed by IV injection. The cells are delivered via the coronary artery using an over-the-wire balloon catheter. It is a relatively non-invasive procedure, resulting in little to no damage upon engraftment. 

Trials have shown that there are no delayed threats following treatment and the positive effects of improved contractility and reduced infarct size were maintained beyond the first months. However, there was no significant improvement in ejection fraction. 

Intramyocardial (IM) Injection

The intramyocardial injection is the most direct, precise, and accurate approach to stem cell introduction into infarcted myocardium. This method does not require homing or mobilization mechanisms and is more site-specific, resulting in less systemic engraftment. Cells can be introduced directly into the myocardium by surgical administration or catheter-based administration for surgically high-risk patients.

In a study by Luciano C. Amado et. al., MSCs were safely and effectively delivered to a region of damaged myocardium in a pig model. This resulted in improved ejection fraction and a dramatic reduction of infarct size.

One disadvantage of IM injection is that is relatively invasive and could potentially result in myocardial perforation at the site of injection, causing acute inflammation, which can also result in leakage of cells from the injection site, leading to a decrease in overall engraftment. 

Biomaterial Scaffolds

Engineered tissue transplantation is a novel solution to these problems that aims to enhance cell adherence by providing a physical scaffold for the cells.

The implantation of MSC-seeded cellulose patches directly onto the surface of the affected heart region demonstrated improved cellular retention and survival, allowing for potential restoration of the dilated left ventricle and improved cardiac function in a rat model. 

However, when the scaffold degrades, the spaces previously occupied by the biodegradable polymers are often replaced by large quantities of extracellular matrix (ECM), forming a tissue with a low cell density. Also, long-term exposure to scaffold transplantation, inflammation, and foreign body reactions can occur. 

Cell Sheet Technology

To address issues associated with biodegradable scaffolds, scaffold-free cell sheet technology has emerged. Cells were cultured with the temperature-responsive polymer poly-N-isopropylacrylamide (PIPAAm). This polymer exists in a hydrophobic state at 32°C and in a hydrophilic state below 32°C. 

Numerous studies have shown that cell sheet technology can improve LV function, increase neovascularization, and decrease fibrosis and remodeling in MI models. 

Cell sheet technology appears to be one of the most promising novel therapeutic techniques as it has the potential to overcome the major obstacles presented with cell injection and bioscaffold engineering.

Mesenchymal Stem Cell-Derived Cell Sheets 

Mesenchymal stem cells (MSCs) are multipotent cells that have the ability to differentiate into CMs at low rates in vivo, as well as osteoblasts, chondrocytes, and adipocytes. The two primary sources of MSCs are bone marrow and adipose tissue.

Studies involving MSC-derived cell sheets have resulted in enhanced regional wall motion, prevented remodeling, reversal of wall thinning, accelerated angiogenesis, and high proliferation and survival rates.

Conclusions of the Study

Cell sheets composed of skeletal myoblasts, mesenchymal stem cells, and pluripotent stem cells have proven to be of the greatest interest for engraftment into infarcted myocardium. 

Further studies are needed in order to determine the most effective delivery method and cell type. Also, long-term studies are needed to establish the long-term effectiveness of the therapies. 

Stem Cell Therapy at ZignaGenix 

At our clinic, we use high doses of mesenchymal stem cells derived from the umbilical cord Wharton’s jelly and use the intravenous delivery method for cardiovascular disease. This delivery method is non-invasive and simple, and studies have shown that when MSCs are injected intravenously into the bloodstream they are attracted to the injured tissue and are capable of engraftment into the heart tissue. 

The studies have also shown that one of the ways that MSCs help improve heart tissue damage is by a paracrine effect, by stimulating surrounding viable muscle cells and increasing levels of different factors, such as vascular epithelial growth factor (VEGF). 

Source:

S Samantha, Gallicchio VS. (2021) Cell Therapy and Methods of Stem Cell Delivery for Regeneration of Heart Tissue Following Myocardial Infarction. J Stem Cell Res. 2(2):1-10.

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