Editorials
Adipose-Derived Regenerative Cells for Cardiovascular Regeneration – A Novel Therapy for the Cardiac Conduction System –
2015 Volume 79 Issue 12 Pages 2555-2556
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2015 Volume 79 Issue 12 Pages 2555-2556
The cardiac conduction system comprises the sino-atrial (SA) node, atrioventricular (AV) node, bundle of His, bundle branches and Purkinje fibers. Together these components function to send electrical signals to the heart muscle to control heart rate and contraction. When the cardiac conduction system falls into non-reversible insufficiency, as a result of ischemic heart disease, idiopathic fibrosis of the conduction system, and/or congenital heart disease, the heart cannot maintain efficient pump function. Cardiac conduction system insufficiency can present as either sick sinus syndrome (dysfunction of the SA node) or AV block (dysfunction of the AV node). Both conditions cause bradycardia and not only bring the symptoms of palpitation, dyspnea, and dizziness, but can also lead to heart failure or even sudden death.1
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Currently, implantation of a permanent pacemaker (PM) is the only intervention for the treatment of patients with a dysfunctional cardiac conduction system. The PM is a device that stimulates the electrical activity of cardiomyocytes in an effort to maintain efficient heart rhythm and synchronization of cardiac motion. Although implantation of a PM has been shown to improve mortality and morbidity,2 excessive implantation of PMs also brings economic and ethical concerns. For instance, the quality of life for patients is limited because of possible PM malfunction under the use of electromagnetic interference (EMI) devices such as cell phones, induction-heating cookers, computed tomography, and magnetic resonance imaging. Moreover, patients must undergo periodic surgeries to change the body of PMs, and/or to correct lead wire problems.3 There are also concerns of infection from the PM or even allergic reactions.
In this issue of the Journal, Takahashi et al4 demonstrate that cells derived from adult murine adipose tissues (AT) differentiated into spontaneously beating cells in vitro. Characterization of the cells revealed that they expressed the specific markers of pacemaker activity-related ion channels and gap-junction hemichannel connexins. More importantly, the implantation of AT-derived cells improved the AV conduction in an in-vivo AV block model. Finally, the authors show that brown AT-derived differentiated cells secrete a large amount of hepatocyte growth factor (HGF), suggesting a paracrine effect of AT-derived cells for cardiac conduction system regeneration (Figure).
Potential mechanisms of adipose tissue-derived regenerative cells (ADRCs) implantation for cardiac conduction system regeneration.
AT is not only an energy storage organ but also a source of stem/progenitor cells. AT-derived regenerative cells (ADRCs) have the potential to differentiate into bone, neuron, smooth muscle cells, and cardiomyocytes.5 Experimentally, Shiba et al recently reported that transplantation of ADRCs showed potential for not only improving cardiac function but also electrical stability in a rat model of myocardial infarction.6 There are also a number of animal studies demonstrating the ability of ADRCs to induce angiogenesis, lymphangiogenesis, reendothelialization and cardiac regeneration in the setting of peripheral artery disease (PAD),7 lymphedema,8 vascular injury,9 and ischemic heart disease.10 The PRECISE trial was the first-in-human trial involving myocardial injection of ADRCs for chronic ischemic heart failure.11 The APPOLO trial was designed to assess the safety and feasibility of intracoronary injection of ADRCs in patients with ST-elevation myocardial infarction.12 This pilot study reported its feasibility in 14 patients and was renewed as a randomized, placebo controlled, double-blind confirmatory study. Thus, ADRCs are a cell source that has been already used in clinical trials. Therefore, the safety of implantation of ADRCs, at least in the short term, is believed to be established by the clinical studies conducted so far.
Cell-based regenerative medicine began with the concept that reconstruction and/or replacement of damaged and dysfunctional organs could be achieved by new functional cells differentiating from transplanted stem/progenitor cells. The fact that ADRCs have a multi-lineage differentiation ability means they have the potential to differentiate into target functional cells by themselves and can contribute to the reconstruction/regeneration of a damaged dysfunctional organ by direct differentiation. However, many studies have shown that most of the implanted cells are washed out or excluded a few days after implantation. Additionally, the rate of engraftment is very low. Therefore, one of the main mechanisms of clinical cell-based regenerative medicine is considered to be a paracrine effect of the transplanted cells. Transplanted cells and/or the surrounding host tissues produce many growth factors, which are needed for tissue regeneration, and cytokines, which have antiinflammatory and antiapoptotic effects that improve the regenerating environment. We previously demonstrated that ADRCs under ischemic conditions produce multiple growth factors, such as VEGF, HGF, bFGF, and SDF-1, and also play a pivotal role in the antiinflammatory cross-talk against host inflammatory cells through the PGE2-EP2/4 axis.7 Therefore, implanted ADRCs improve damaged tissues via the release of multiple paracrine factors.
The clinical advantage of using ADRCs as a cell source for regenerative medicine is that it is relatively easy to collect enough cells without having to use an ex vivo culture step. This provides the option of using freshly isolated autologous cells in the short term. In other words, this advantage releases us from the potential problems of not having enough cells for transplantation, of allograft-related immune rejection, infection, and ethical considerations. Another advantage is the relatively minimally invasive approach to gathering and isolating ADRCs. This is a big benefit for high-risk patients. Taken together, ADRC can be thought of as one of the useful and suitable cell sources in regenerative medicine for clinical usage.
The effect of the current study by Takahashi et al on clinical medicine is the proposition of a novel strategy using ADRCs to create a biological pacemaker to improve AV conduction. However, there are some issues that need to be addressed before this therapy can be used clinically. First, there are questions about suitable cell numbers and delivery options. Second, the mechanism of action is still unclear. Third, we have to investigate and verify the safety and efficacy of ADRCs in larger animal models of AV block. It will probably take some time to address all these issues. Nevertheless, in the meantime, Takahashi et al have provided a novel treatment option for AV block that has the potential to release patients from the issues related to permanent PM implantation. If successful, this option would establish a new paradigm for the treatment of cardiac conduction system insufficiency.
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