Cellular cardiomyoplasty

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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. [1] 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. [2] 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 (February 2012), 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. [3] Yet the SCIPIO trial "was recently called into question". [4] [5] Harvard University is "now investigating the integrity of some of the data". [4] The Lancet recently published a non-specific ‘Expression of concern’ about the paper. [6] Subsequently, another preclinical study also raised doubts on the rationale behind using this special kind of cell, [7] as it was found that the special cells only have a minimal ability in generating new cardiomyocytes. [8] Some specialists therefore now raise concerns to continue. [8]

Contents

Progenitor cell lines

To date, the ideal progenitor cells have not been found or created. With the goal of recreating human tissue, the use of embryonic stem cells (ESC) was the initial logical choice. These pluripotent cells can conceptually give rise to any somatic cell line in the human body and while animal studies have shown restoration of cardiac function, immunologic rejection issues and teratoma formation have rendered ESC's a high risk. [9] [10]

Human-induced pluripotent stem cells (iPSCs) are a cell line derived from somatic cells which have been induced through a combination of transcription factors. The iPSC line is very similar or identical to ESCs in many regards and also shows great promise in cardiac potential. [11] This cell line, however, is also less than ideal in that this cell type has been unable to mature into a homogeneous cell culture, making it immunogenic and teratogenic. [12] A third cell line that shows great promise and has no known safety concerns is the adult stem cell derived from bone marrow or from cardiac tissue explants. It has been shown in several studies that adult stem cells do have cardiogenic potential. [13] [14] [15]

Future direction

Presently, the success of adult stem cells in regenerating human myocardium is just a fraction of what it could be. Three major challenges have been observed. Adult stem cells exhibit a minimal[ clarification needed ] commitment to engraft into the damaged myocardium, they have low survival rates and they have limited proliferation. [16] The positive effects observed in clinical trials today are a result of the work of donated stem cells that persist in the damaged myocardium for just days to weeks after delivery. Clearly, if cell survival is prolonged, these effects could be greatly enhanced.[ citation needed ] This is where a majority of research is being done today and several methodologies hold great promise. [17] [18]

Related Research Articles

<span class="mw-page-title-main">Stem cell</span> Undifferentiated biological cells that can differentiate into specialized cells

In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell in a cell lineage. They are found in both embryonic and adult organisms, but they have slightly different properties in each. They are usually distinguished from progenitor cells, which cannot divide indefinitely, and precursor or blast cells, which are usually committed to differentiating into one cell type.

Transdifferentiation, also known as lineage reprogramming, is the process in which one mature somatic cell is transformed into another mature somatic cell without undergoing an intermediate pluripotent state or progenitor cell type. It is a type of metaplasia, which includes all cell fate switches, including the interconversion of stem cells. Current uses of transdifferentiation include disease modeling and drug discovery and in the future may include gene therapy and regenerative medicine. The term 'transdifferentiation' was originally coined by Selman and Kafatos in 1974 to describe a change in cell properties as cuticle producing cells became salt-secreting cells in silk moths undergoing metamorphosis.

<span class="mw-page-title-main">Cardiac muscle</span> Muscular tissue of heart in vertebrates

Cardiac muscle is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of the heart. The cardiac muscle (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 cardiac muscle cells joined by intercalated discs, and encased by collagen fibers and other substances that form the extracellular matrix.

<span class="mw-page-title-main">Embryonic stem cell</span> Type of pluripotent blastocystic stem cell

Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre-implantation embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consist of 50–150 cells. Isolating the inner cell mass (embryoblast) using immunosurgery results in destruction of the blastocyst, a process which raises ethical issues, including whether or not embryos at the pre-implantation stage have the same moral considerations as embryos in the post-implantation stage of development.

<span class="mw-page-title-main">Embryoid body</span> Three-dimensional aggregate of pluripotent stem cells

Embryoid bodies (EBs) are three-dimensional aggregates formed by pluripotent stem cells. These include embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC)

<span class="mw-page-title-main">Cell therapy</span> 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.

<span class="mw-page-title-main">Adult stem cell</span> Multipotent stem cell in the adult body

Adult stem cells are undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells, they can be found in juvenile, adult animals, and humans, unlike embryonic stem cells.

<span class="mw-page-title-main">Stem-cell line</span> Culture of stem cells that can be propagated indefinitely

A stem cell line is a group of stem cells that is cultured in vitro and can be propagated indefinitely. Stem cell lines are derived from either animal or human tissues and come from one of three sources: embryonic stem cells, adult stem cells, or induced pluripotent stem cells. They are commonly used in research and regenerative medicine.

Stem-cell therapy uses stem cells to treat or prevent a disease or condition. As of 2024, the only FDA-approved therapy using stem cells is hematopoietic stem cell transplantation. This usually takes the form of a bone marrow or peripheral blood stem cell transplantation, but the cells can also be derived from umbilical cord blood. Research is underway to develop various sources for stem cells as well as to apply stem-cell treatments for neurodegenerative diseases and conditions such as diabetes and heart disease.

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.

<span class="mw-page-title-main">Induced pluripotent stem cell</span> Pluripotent stem cell generated directly from a somatic cell

Induced pluripotent stem cells are a type of pluripotent stem cell that can be generated directly from a somatic cell. The iPSC technology was pioneered by Shinya Yamanaka and Kazutoshi Takahashi in Kyoto, Japan, who together showed in 2006 that the introduction of four specific genes, collectively known as Yamanaka factors, encoding transcription factors could convert somatic cells into pluripotent stem cells. Shinya Yamanaka was awarded the 2012 Nobel Prize along with Sir John Gurdon "for the discovery that mature cells can be reprogrammed to become pluripotent."

In cardiology neocardiogenesis is the homeostatic regeneration, repair and renewal of sections of malfunctioning adult cardiovascular tissue. This includes a combination of cardiomyogenesis and angiogenesis.

<span class="mw-page-title-main">Cell potency</span> Ability of a cell to differentiate into other cell types

Cell potency is a cell's ability to differentiate into other cell types. The more cell types a cell can differentiate into, the greater its potency. Potency is also described as the gene activation potential within a cell, which like a continuum, begins with totipotency to designate a cell with the most differentiation potential, pluripotency, multipotency, oligopotency, and finally unipotency.

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 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.

Directed differentiation is a bioengineering methodology at the interface of stem cell biology, developmental biology and tissue engineering. It is essentially harnessing the potential of stem cells by constraining their differentiation in vitro toward a specific cell type or tissue of interest. Stem cells are by definition pluripotent, able to differentiate into several cell types such as neurons, cardiomyocytes, hepatocytes, etc. Efficient directed differentiation requires a detailed understanding of the lineage and cell fate decision, often provided by developmental biology.

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.

<span class="mw-page-title-main">Milica Radisic</span> Serbian Canadian tissue engineer

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.

Cardiomyocyte proliferation refers to the ability of cardiac muscle cells to progress through the cell cycle and continue to divide. Traditionally, cardiomyocytes were believed to have little to no ability to proliferate and regenerate after birth. Although other types of cells, such as gastrointestinal epithelial cells, can proliferate and differentiate throughout life, cardiac tissue contains little intrinsic ability to proliferate, as adult human cells arrest in the cell cycle. However, a recent paradigm shift has occurred. Recent research has demonstrated that human cardiomyocytes do proliferate to a small extent for the first two decades of life. Also, cardiomyocyte proliferation and regeneration has been demonstrated to occur in various neonatal mammals in response to injury in the first week of life. Current research aims to further understand the biological mechanism underlying cardiomyocyte proliferation in hopes to turn this capability back on in adults in order to combat heart disease.

References

  1. ↑ Murry CE (2005). "Cell-Based Cardiac Repair: Reflections at the 10-Year Point". Circulation. 112 (20): 3174–83. doi: 10.1161/CIRCULATIONAHA.105.546218 . PMID   16286608.
  2. ↑ Traverse, JH; Ellis (Nov 2011). "Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: the LateTIME randomized trial". JAMA. 306 (19): 2110–9. doi:10.1001/jama.2011.1670. PMC   3600981 . PMID   22084195.
  3. ↑ Bolli, R; Chugh (Nov 2011). "Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial". Lancet. 378 (9806): 1847–57. doi:10.1016/S0140-6736(11)61590-0. PMC   3614010 . PMID   22088800. (Retracted, see doi:10.1016/S0140-6736(19)30542-2, PMID   30894259,  Retraction Watch . If this is an intentional citation to a retracted paper, please replace {{ retracted |...}} with {{ retracted |...|intentional=yes}}.)
  4. 1 2 Abbott, A (May 2014). "Doubts over heart stem-cell therapy". Nature. 509 (7498): 15–16. Bibcode:2014Natur.509...15A. doi: 10.1038/509015a . PMID   24784193.
  5. ↑ "Lancet Editors Raise More Questions About Prominent Harvard Stem Cell Researcher". Forbes .
  6. ↑ "Expression of concern: the SCIPIO trial". Lancet. 383 (9925): 1279. April 2014. doi:10.1016/S0140-6736(14)60608-5. PMC   5586533 . PMID   24725564.
  7. ↑ van Berlo, J; et al. (2014). "c-kit+ cells minimally contribute cardiomyocytes to the heart". Nature. 509 (7500): 337–341. Bibcode:2014Natur.509..337V. doi:10.1038/nature13309. PMC   4127035 . PMID   24805242.
  8. 1 2 "Preclinical Study Casts Doubt on Regenerative Ability of Special Cardiac Stem Cells - Journal News - TCTMD". Archived from the original on 2014-05-21. Retrieved 2014-05-20.
  9. ↑ Yang, L; Adler (May 2008). "Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population". Nature. 453 (7194): 524–528. Bibcode:2008Natur.453..524Y. doi:10.1038/nature06894. PMID   18432194. S2CID   205212998.
  10. ↑ Asano, T; Sasaki (2006). "In Vivo Tumor Formation from Primate Embryonic Stem Cells". Embryonic Stem Cell Protocols. Methods in Molecular Biology. Vol. 329. pp. 459–467. doi:10.1385/1-59745-037-5:459. ISBN   978-1-59745-037-9. PMID   16846010.
  11. ↑ Shiba, Y; Laflamme (2009). "Cardiac applications for human pluripotent stem cells". Current Pharmaceutical Design. 15 (24): 2791–806. doi:10.2174/138161209788923804. PMC   2901183 . PMID   19689350.
  12. ↑ Wu, SM; Hochedlinger, K. (June 2011). "Harnessing the potential of induced pluripotent stem cells for regenerative medicine". Nature Cell Biology. 13 (6): 497–505. doi:10.1038/ncb0511-497. PMC   3617981 . PMID   21540845.
  13. ↑ Beltrami, AP; Barlucchi, L.; Torella, D.; Baker, M.; Limana, F.; et al. (September 2003). "Adult cardiac stem cells are multipotent and support myocardial regeneration". Cell. 114 (6): 763–776. doi: 10.1016/S0092-8674(03)00687-1 . PMID   14505575.
  14. ↑ Smits, AM; van Vliet P; et al. (2009). "Human cardiomyocyte progenitor cells differentiate into functional mature cardiomyocytes: an in vitro model for studying human cardiac physiology and pathophysiology". Nature Protocols. 4 (2): 232–243. doi:10.1038/nprot.2008.229. PMID   19197267. S2CID   32174805.
  15. ↑ Fischer, KM; Cottage CT; Wu W; Din S; Gude NA; Avitabil D; Quijada P; Collins BL; Fransioli J; Sussman MA (Nov 2009). "Enhancement of myocardial regeneration through genetic engineering of cardiac progenitor cells expressing Pim-1 kinase". Circulation. 120 (21): 2077–2087. doi:10.1161/CIRCULATIONAHA.109.884403. PMC   2787902 . PMID   19901187.
  16. ↑ Mohsin, Sadia; Siddiqu S; Collins B; Sussman M (December 2011). "Empowering adult stem cells for myocardial regeneration". Circulation Research. 109 (12): 1415–1428. doi:10.1161/CIRCRESAHA.111.243071. PMC   3266718 . PMID   22158649.
  17. ↑ Pagani, Francis D; DerSimonian, Harout; Zawadzka, Agatha; Wetzel, Kristie; Edge, Albert SB; Jacoby, Douglas B; Dinsmore, Jonathan H; Wright, Susan; Aretz, Tom H; Eisen, Howard J; Aaronson, Keith D (2003). "Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans". Journal of the American College of Cardiology. 41 (5): 879–888. doi: 10.1016/S0735-1097(03)00081-0 . ISSN   0735-1097. PMID   12628737.
  18. ↑ Muller-Ehmsen, J; Whittaker P; Kloner RA; Dow JS; Sakoda T; Long TI; Laird PW; Kedes L. (Feb 2002). "Survival and development of neonatal rat cardiomyocytes transplanted into adult myocardium". J Mol Cell Cardiol. 34 (2): 107–116. doi:10.1006/jmcc.2001.1491. PMID   11851351.
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