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      Challenges in identifying the best source of stem cells for cardiac regeneration therapy

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      Stem Cell Research & Therapy
      BioMed Central

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          Abstract

          The overall clinical cardiac regeneration experience suggests that stem cell therapy can be safely performed, but it also underlines the need for reproducible results for their effective use in a real-world scenario. One of the significant challenges is the identification and selection of the best suited stem cell type for regeneration therapy. Bone marrow mononuclear cells, bone marrow-derived mesenchymal stem cells, resident or endogenous cardiac stem cells, endothelial progenitor cells and induced pluripotent stem cells are some of the stem cell types which have been extensively tested for their ability to regenerate the lost myocardium. While most of these cell types are being evaluated in clinical trials for their safety and efficacy, results show significant heterogeneity in terms of efficacy. The enthusiasm surrounding regenerative medicine in the heart has been dampened by the reports of poor survival, proliferation, engraftment, and differentiation of the transplanted cells. Therefore, the primary challenge is to create clearcut evidence on what actually drives the improvement of cardiac function after the administration of stem cells. In this review, we provide an overview of different types of stem cells currently being considered for cardiac regeneration and discuss why associated factors such as practicality and difficulty in cell collection should also be considered when selecting the stem cells for transplantation. Next, we discuss how the experimental variables (type of disease, marker-based selection and use of different isolation techniques) can influence the study outcome. Finally, we provide an outline of the molecular and genetic approaches to increase the functional ability of stem cells before and after transplantation.

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          Most cited references84

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          Endothelial progenitor cells: characterization and role in vascular biology.

          Infusion of different hematopoietic stem cell populations and ex vivo expanded endothelial progenitor cells augments neovascularization of tissue after ischemia and contributes to reendothelialization after endothelial injury, thereby, providing a novel therapeutic option. However, controversy exists with respect to the identification and the origin of endothelial progenitor cells. Overall, there is consensus that endothelial progenitor cells can derive from the bone marrow and that CD133/VEGFR2 cells represent a population with endothelial progenitor capacity. However, increasing evidence suggests that there are additional bone marrow-derived cell populations (eg, myeloid cells, "side population" cells, and mesenchymal cells) and non-bone marrow-derived cells, which also can give rise to endothelial cells. The characterization of the different progenitor cell populations and their functional properties are discussed. Mobilization and endothelial progenitor cell-mediated neovascularization is critically regulated. Stimulatory (eg, statins and exercise) or inhibitory factors (risk factors for coronary artery disease) modulate progenitor cell levels and, thereby, affect the vascular repair capacity. Moreover, recruitment and incorporation of endothelial progenitor cells requires a coordinated sequence of multistep adhesive and signaling events including adhesion and migration (eg, by integrins), chemoattraction (eg, by SDF-1/CXCR4), and finally the differentiation to endothelial cells. This review summarizes the mechanisms regulating endothelial progenitor cell-mediated neovascularization and reendothelialization.
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            Adult cardiac stem cells are multipotent and support myocardial regeneration.

            The notion of the adult heart as terminally differentiated organ without self-renewal potential has been undermined by the existence of a subpopulation of replicating myocytes in normal and pathological states. The origin and significance of these cells has remained obscure for lack of a proper biological context. We report the existence of Lin(-) c-kit(POS) cells with the properties of cardiac stem cells. They are self-renewing, clonogenic, and multipotent, giving rise to myocytes, smooth muscle, and endothelial cells. When injected into an ischemic heart, these cells or their clonal progeny reconstitute well-differentiated myocardium, formed by blood-carrying new vessels and myocytes with the characteristics of young cells, encompassing approximately 70% of the ventricle. Thus, the adult heart, like the brain, is mainly composed of terminally differentiated cells, but is not a terminally differentiated organ because it contains stem cells supporting its regeneration. The existence of these cells opens new opportunities for myocardial repair.
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              Isolation and expansion of adult cardiac stem cells from human and murine heart.

              Cardiac myocytes have been traditionally regarded as terminally differentiated cells that adapt to increased work and compensate for disease exclusively through hypertrophy. However, in the past few years, compelling evidence has accumulated suggesting that the heart has regenerative potential. Recent studies have even surmised the existence of resident cardiac stem cells, endothelial cells generating cardiomyocytes by cell contact or extracardiac progenitors for cardiomyocytes, but these findings are still controversial. We describe the isolation of undifferentiated cells that grow as self-adherent clusters (that we have termed "cardiospheres") from subcultures of postnatal atrial or ventricular human biopsy specimens and from murine hearts. These cells are clonogenic, express stem and endothelial progenitor cell antigens/markers, and appear to have the properties of adult cardiac stem cells. They are capable of long-term self-renewal and can differentiate in vitro and after ectopic (dorsal subcutaneous connective tissue) or orthotopic (myocardial infarction) transplantation in SCID beige mouse to yield the major specialized cell types of the heart: myocytes (ie, cells demonstrating contractile activity and/or showing cardiomyocyte markers) and vascular cells (ie, cells with endothelial or smooth muscle markers).
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                Author and article information

                Contributors
                dixpa159@student.otago.ac.nz
                rajesh.katare@otago.ac.nz
                Journal
                Stem Cell Res Ther
                Stem Cell Res Ther
                Stem Cell Research & Therapy
                BioMed Central (London )
                1757-6512
                13 March 2015
                13 March 2015
                2015
                : 6
                : 1
                : 26
                Affiliations
                Department of Physiology, HeartOtago, Otago School of Medical Sciences, University of Otago, Dunedin, 9010 New Zealand
                Article
                10
                10.1186/s13287-015-0010-8
                4357059
                25886612
                41cb0336-3ff9-4a43-9e4f-74b607b1b3cc
                © Dixit and Katare; licensee BioMed Central. 2015

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 16 July 2014
                : 17 February 2015
                Categories
                Review
                Custom metadata
                © The Author(s) 2015

                Molecular medicine
                Molecular medicine

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