Neocardiogenesis

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In cardiology neocardiogenesis is the homeostatic regeneration, repair and renewal of sections of malfunctioning adult cardiovascular tissue. This includes a combination of cardiomyogenesis (the regeneration of cardiac muscle) and angiogenesis (the regeneration of blood vessels). [1]

Contents

Definition and scope

The term neocardiogenesis comes from cardiogenesis, which refers to the development of the heart in the embryo; neocardiogenesis, in turn, means the development of the heart in adults. The heart has mechanisms already in place that are responsible for small scale repair. However, these repair mechanisms are not sufficient for large scale repair, made necessary by events such as myocardial infarctions. Neocardiogenesis replaces dead cardiac muscle cells with living cells so that both the structure and function of the heart are maintained. This improves myocardial pumping of fluid around the body. [2]

Background

The human heart has been thought of as a postmitotic organ. Cardiomyocytes (muscle cells of the heart) were thought to be terminally differentiated cells that were irreplaceable and thus required to maintain cardiac function throughout life. However it is now known that the heart is able to regenerate new small vessels needed to repair an ischemic (lacking blood) myocardium. The belief that humans are born with a fixed number of cardiomyocytes, and that the growth of these cells was directly responsible for the growth of the heart, has also been disproven. [3] Reports of the heart's ability to repair itself have started to appear in peer reviewed journals [4] and a paper has been published that has shown the potential of bone marrow cells to regenerate myocardium (myogenesis). [5] Other studies into the regeneration of myocardium have reported evidence of angiogenesis, [6] although such studies have been found to contain discrepancies. [7]

It has been reported that improvement in heart contractility has occurred as a result of the induction of angiogenesis. [8] The results of these studies suggest that there is a possibility that, during neocardiogenesis, angiogenesis and myogenesis are interlinked and operate simultaneously in the process of cardiac regeneration. The possibility of such a linkage necessitates more research. There is also the need for a clearer definition of neocardiogenesis.[ citation needed ]

Mechanism

The activation of cardiac progenitor cells (a special type of stem cell with long telomeres located in the storage areas of the heart) and circulating stem cells induce cardiomyocytes to proliferate. These cells are activated by a mixture of transcriptional factors, genes, growth factors, receptors, the extracellular matrix and signalling pathways. The cells then move to affected areas where they can reverse some of the damage by generating a new population of cardiomyocytes. [9]

Clinical importance

The heart has the potential to repair itself when damaged using progenitor and stem cells. [10] Clinical trials have shown that heart muscle has not previously been able to regenerate itself. New noninvasive drugs, which may make this possible in humans, are required to induce the cardiac myocytes to proliferate. Studies have been done in an attempt to find such a treatment. [11]

Related Research Articles

Cardiac muscle Muscular tissue of heart

Cardiac muscle is one of three types of vertebrate muscles, with the other two being skeletal and smooth muscles. It is involuntary, striated muscle that constitutes the main tissue of the walls of the heart. The myocardium forms a thick middle layer between the outer layer of the heart wall and the inner layer, with blood supplied via the coronary circulation. It is composed of individual heart muscle cells (cardiomyocytes) joined together by intercalated discs, encased by collagen fibers and other substances that form the extracellular matrix.

Endocardium

The endocardium is the innermost layer of tissue that lines the chambers of the heart. Its cells are embryologically and biologically similar to the endothelial cells that line blood vessels. The endocardium also provides protection to the valves and heart chambers.

In cardiology, ventricular remodeling refers to changes in the size, shape, structure, and function of the heart. This can happen as a result of exercise or after injury to the heart muscle. The injury is typically due to acute myocardial infarction, but may be from a number of causes that result in increased pressure or volume, causing pressure overload or volume overload on the heart. Chronic hypertension, congenital heart disease with intracardiac shunting, and valvular heart disease may also lead to remodeling. After the insult occurs, a series of histopathological and structural changes occur in the left ventricular myocardium that lead to progressive decline in left ventricular performance. Ultimately, ventricular remodeling may result in diminished contractile (systolic) function and reduced stroke volume.

Cell therapy Therapy in which cellular material is injected into a patient

Cell therapy is a therapy in which viable cells are injected, grafted or implanted into a patient in order to effectuate a medicinal effect, for example, by transplanting T-cells capable of fighting cancer cells via cell-mediated immunity in the course of immunotherapy, or grafting stem cells to regenerate diseased tissues.

Cardiac muscle cell Muscle cells (myocytes) that make up the cardiac muscle

Cardiac muscle cells or cardiomyocytes are the muscle cells (myocytes) that make up the cardiac muscle. Each myocardial cell contains myofibrils, which are specialized organelles consisting of long chains of sarcomeres, the fundamental contractile units of muscle cells.

Cardiomyoplasty is a surgical procedure in which healthy muscle from another part of the body is wrapped around the heart to provide support for the failing heart. Most often the latissimus dorsi muscle is used for this purpose. A special pacemaker is implanted to make the skeletal muscle contract. If cardiomyoplasty is successful and increased cardiac output is achieved, it usually acts as a bridging therapy, giving time for damaged myocardium to be treated in other ways, such as remodeling by cellular therapies.

Myocytolysis refers to a state of significant damage to cardiac myocytes, muscle cells of the heart, caused by myocardial strain. It was first described in medical literature by Schlesinger and Reiner in 1955. It is considered a type of cellular necrosis. Two types of myocytolysis have been defined: coagulative and colliquative.

mir-1 microRNA precursor family

The miR-1 microRNA precursor is a small micro RNA that regulates its target protein's expression in the cell. microRNAs are transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give products at ~22 nucleotides. In this case the mature sequence comes from the 3' arm of the precursor. The mature products are thought to have regulatory roles through complementarity to mRNA. In humans there are two distinct microRNAs that share an identical mature sequence, these are called miR-1-1 and miR-1-2.

Endothelial progenitor cell is a term that has been applied to multiple different cell types that play roles in the regeneration of the endothelial lining of blood vessels. Outgrowth endothelial cells are an EPC subtype committed to endothelial cell formation. Despite the history and controversy, the EPC in all its forms remains a promising target of regenerative medicine research.

<i>Geum japonicum</i> Species of flowering plant

Geum japonicum, known as Asian herb bennet, is a yellow-flowering perennial plant native to North America and East Asia, especially Japan. It may be synonymous with Geum macrophyllum, the North American flower. As a traditional herbal remedy it is known as an astringent and used in poultices. However, in recent years, the Thunberg variant has received attention for other possible medical uses.

Myocardial infarction complications may occur immediately following a heart attack, or may need time to develop. After an infarction, an obvious complication is a second infarction, which may occur in the domain of another atherosclerotic coronary artery, or in the same zone if there are any live cells left in the infarct.

A diagnosis of myocardial infarction is created by integrating the history of the presenting illness and physical examination with electrocardiogram findings and cardiac markers. A coronary angiogram allows visualization of narrowings or obstructions on the heart vessels, and therapeutic measures can follow immediately. At autopsy, a pathologist can diagnose a myocardial infarction based on anatomopathological findings.

Cellular cardiomyoplasty, or cell-based cardiac repair, is a new potential therapeutic modality in which progenitor cells are used to repair regions of damaged or necrotic myocardium. The ability of transplanted progenitor cells to improve function within the failing heart has been shown in experimental animal models and in some human clinical trials. In November 2011, a large group of collaborators at Minneapolis Heart Institute Foundation at Abbott Northwestern found no significant difference in left ventricular ejection fraction (LVEF) or other markers, between a group of patients treated with cellular cardiomyoplasty and a group of control patients. In this study, all patients were post MI, post percutaneous coronary intervention (PCI) and that infusion of progenitor cells occurred 2–3 weeks after intervention. In a study that is currently underway, however, more positive results were being reported: In the SCIPIO trial, patients treated with autologous cardiac stem cells post MI have been reported to be showing statistically significant increases in LVEF and reduction in infarct size over the control group at four months after implant. Positive results at the one-year mark are even more pronounced. Yet the SCIPIO trial "was recently called into question". Harvard University is "now investigating the integrity of some of the data". The Lancet recently published a non-specific ‘Expression of concern’ about the paper. Subsequently, another preclinical study also raised doubts on the rationale behind using this special kind of cell, as it was found that the special cells only have a minimal ability in generating new cardiomyocytes. Some specialists therefore now raise concerns to continue.

Heart nanotechnology is the "Engineering of functional systems at the molecular scale".

Endogenous cardiac stem cells (eCSCs) are tissue-specific stem progenitor cells harboured within the adult mammalian heart. It has to be noted that a scientific-misconduct scandal, involving Harvard professor Piero Anversa, might indicate that the heart stem cell concept be broken. Therefore, the following article should be read with caution, as it builds on Anversa's results.

Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease, as well as treatment for the damage that occurs to the heart after MI. After MI, the myocardium suffers from reperfusion injury which leads to death of cardiomyocytes and detrimental remodelling of the heart, consequently reducing proper cardiac function. Transfection of cardiac myocytes with human HGF reduces ischemic reperfusion injury after MI. The benefits of HGF therapy include preventing improper remodelling of the heart and ameliorating heart dysfunction post-MI.

Human engineered cardiac tissues (hECTs) are derived by experimental manipulation of pluripotent stem cells, such as human embryonic stem cells (hESCs) and, more recently, human induced pluripotent stem cells (hiPSCs) to differentiate into human cardiomyocytes. Interest in these bioengineered cardiac tissues has risen due to their potential use in cardiovascular research and clinical therapies. These tissues provide a unique in vitro model to study cardiac physiology with a species-specific advantage over cultured animal cells in experimental studies. hECTs also have therapeutic potential for in vivo regeneration of heart muscle. hECTs provide a valuable resource to reproduce the normal development of human heart tissue, understand the development of human cardiovascular disease (CVD), and may lead to engineered tissue-based therapies for CVD patients.

Regeneration in humans is the regrowth of lost tissues or organs in response to injury. This is in contrast to wound healing, or partial regeneration, which involves closing up the injury site with some gradation of scar tissue. Some tissues such as skin, the vas deferens, and large organs including the liver can regrow quite readily, while others have been thought to have little or no capacity for regeneration following an injury.

Annarosa Leri is a medical doctor and former associate professor at Harvard University. Along with former professor Piero Anversa, Leri was engaged in biomedical research at Brigham and Women’s Hospital in Boston, an affiliate of Harvard Medical School. Since at least 2003 Anversa and Leri had investigated the ability of the heart to regenerate damaged cells using cardiac stem cells.

Milica Radisic is a Serbian Canadian tissue engineer, academic and researcher. She is a Professor at the University of Toronto’s Institute of Biomaterials and Biomedical Engineering, and the Department of Chemical Engineering and Applied Chemistry. She co-founded TARA Biosystems and is a senior scientist at the Toronto General Hospital Research Institute.

References

  1. Zimmet, H. and Krum, H. 2008. "Using Adult Stem Cells to Treat Heart Failure- Fact or Fiction?" Heart, Lung and Circulation 17S:S48-S54.
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  3. Quaini F, Cigola E, Lagrasta C, Saccani G, Quaini E, Rossi C, Olivetti G and Anversa P. End-stage cardiac failure in humans is coupled with the induction of proliferating cell nuclear antigen and nuclear mitotic division in ventricular myocytes. Circ Res 1994;75:1050–1063.
  4. Beltrami AP, Urbanek K, Kajstura J, Yan SM, Finato N, Bussani R, Nadal-Ginard B, Silvestri F, Leri A, Beltrami CA and Anversa P. Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 2001;344:1750–1757.
  5. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li BS, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A and Anversa P. Bone marrow cells regenerate infarcted myocardium. Nature, 2001; 5:410 (6829):701-5.
  6. Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg RV, Kogler G and Wernet P. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002;106:1913-8.
  7. Francis, DP; Mielewczik, M; Zargaran, D; Cole, GD (Jun 26, 2013). "Autologous bone marrow-derived stem cell therapy in heart disease: Discrepancies and contradictions". International Journal of Cardiology. 168 (4): 3381–403. doi:10.1016/j.ijcard.2013.04.152. PMID   23830344. Archived from the original on July 21, 2013. Retrieved 21 July 2013.
  8. Kastrup, J. Jorgensen E, Ruck A, Tagil K, Glogar D, Ruzyllo W, Botker HE, Dudek D, Drvota V, Hesse B, Thuesen L, Blomberg P, Gyongyosi M and Sylven C. Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris: A randomized double-blind placebo-controlled study: the Euroinject One Trial. J. Am. Coll. Cardiol. 2005; 45, 982–988.
  9. Gonzalez A, Rota M, Nurzynska D, Misao Y, Tillmanns J, Ojaimi C, Padin-Iruegas ME, Muller P, Esposito G, Bearzi C, Vitale S, Dawn B, Sanganalmath SK, Baker M, Hintze TH, Bolli R, Urbanek K, Hosoda T, Anversa P, Kajstura J, Leri A. 2008. "Activation of cardiac progenitor cells reverses the failing heart senescent phenotype and prolongs lifespan." Journal of the American Heart Association. 102:597-606
  10. Gonzalez A, Rota M, Nurzynska D, Misao Y, Tillmanns J, Ojaimi C, Padin-Iruegas ME, Muller P, Esposito G, Bearzi C, Vitale S, Dawn B, Sanganalmath SK, Baker M, Hintze TH, Bolli R, Urbanek K, Hosoda T, Anversa P, Kajstura J, Leri A. 2008. "Activation of cardiac progenitor cells reverses the failing heart senescent phenotype and prolongs lifespan." Journal of the American Heart Association. 102:597-606
  11. Author unknown, 2008. Cardio Series Meta Report # MRCS-01: Neocardiogenesis Celebrating the Birth of Regenerative Cardiology Chapter 5 "The Change of Heart." Available from: http://www.metareports.net/chapter5.htm Archived 2012-02-20 at the Wayback Machine [Accessed 02/02/09]