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For: Urbanek K, Quaini F, Tasca G, Torella D, Castaldo C, Nadal-Ginard B, Leri A, Kajstura J, Quaini E, Anversa P. Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy. Proc Natl Acad Sci U S A 2003;100:10440-5. [PMID: 12928492 PMCID: PMC193580 DOI: 10.1073/pnas.1832855100] [Citation(s) in RCA: 372] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open

For:	Urbanek K, Quaini F, Tasca G, Torella D, Castaldo C, Nadal-Ginard B, Leri A, Kajstura J, Quaini E, Anversa P. Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy. Proc Natl Acad Sci U S A 2003;100:10440-5. [PMID: 12928492 PMCID: PMC193580 DOI: 10.1073/pnas.1832855100] [Citation(s) in RCA: 372] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open

Number

Cited by Other Article(s)

Lavin KM, Coen PM, Baptista LC, Bell MB, Drummer D, Harper SA, Lixandrão ME, McAdam JS, O’Bryan SM, Ramos S, Roberts LM, Vega RB, Goodpaster BH, Bamman MM, Buford TW. State of Knowledge on Molecular Adaptations to Exercise in Humans: Historical Perspectives and Future Directions. Compr Physiol 2022;12:3193-3279. [PMID: 35578962 PMCID: PMC9186317 DOI: 10.1002/cphy.c200033] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]

Affiliation(s)

Kaleen M. Lavin Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA Center for Human Health, Resilience, and Performance, Institute for Human and Machine Cognition, Pensacola, Florida, USA
Paul M. Coen Translational Research Institute for Metabolism and Diabetes, Advent Health, Orlando, Florida, USA Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA
Liliana C. Baptista Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA Department of Medicine, Division of Gerontology, Geriatrics and Palliative Care, The University of Alabama at Birmingham, Birmingham, Alabama, USA
Margaret B. Bell Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
Devin Drummer Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
Sara A. Harper Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA Department of Medicine, Division of Gerontology, Geriatrics and Palliative Care, The University of Alabama at Birmingham, Birmingham, Alabama, USA
Manoel E. Lixandrão Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
Jeremy S. McAdam Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
Samia M. O’Bryan Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
Sofhia Ramos Translational Research Institute for Metabolism and Diabetes, Advent Health, Orlando, Florida, USA Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA
Lisa M. Roberts Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA Department of Medicine, Division of Gerontology, Geriatrics and Palliative Care, The University of Alabama at Birmingham, Birmingham, Alabama, USA
Rick B. Vega Translational Research Institute for Metabolism and Diabetes, Advent Health, Orlando, Florida, USA Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA
Bret H. Goodpaster Translational Research Institute for Metabolism and Diabetes, Advent Health, Orlando, Florida, USA Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida, USA
Marcas M. Bamman Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA Department of Cell, Developmental, and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USA Center for Human Health, Resilience, and Performance, Institute for Human and Machine Cognition, Pensacola, Florida, USA
Thomas W. Buford Center for Exercise Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA Department of Medicine, Division of Gerontology, Geriatrics and Palliative Care, The University of Alabama at Birmingham, Birmingham, Alabama, USA

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Accelerated Growth, Differentiation, and Ploidy with Reduced Proliferation of Right Ventricular Cardiomyocytes in Children with Congenital Heart Defect Tetralogy of Fallot. Cells 2022;11:cells11010175. [PMID: 35011735 PMCID: PMC8750260 DOI: 10.3390/cells11010175] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 12/29/2021] [Accepted: 01/01/2022] [Indexed: 02/06/2023] Open

Wogksch MD, Goodenough CG, Finch ER, Partin RE, Ness KK. Physical activity and fitness in childhood cancer survivors: a scoping review. AGING AND CANCER 2021;2:112-128. [PMID: 35098147 PMCID: PMC8794406 DOI: 10.1002/aac2.12042] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 10/28/2021] [Indexed: 01/05/2023]

Abstract

BACKGROUND

Estimates indicate that nearly eight percent of the over 500,000 survivors of childhood cancer living in the United States are frail in their fourth and fifth decades of life, a phenotype typically seen in geriatric populations. Participation in regular physical activity to improve physical fitness in healthy and diseased populations reduces risk for frail health by increasing physiologic reserve. However, physical activity may not have the same effects on fitness in childhood cancer survivors as it does among their peers with no cancer history.

AIMS

This scoping review seeks to describe associations between physical activity, physical fitness, chronic disease, and mortality in childhood cancer survivors.

METHODS

Relevant literature was identified through a comprehensive search in the PubMed, Web of Science, CINAHL, and Cochrane databases. A narrative synthesis was performed on observational studies that had physical activity or physical fitness clearly defined and compared with chronic disease outcomes.

RESULTS

A total of 595 studies were screened, and results from 11 studies are presented. Childhood cancer survivors who participate in regular physical activity have improved markers of cardiovascular health, decreased risk of overt cardiovascular disease, and decreased risk of all-cause mortality compared to survivors who are not physically active. Childhood cancer survivors who are physically fit have increased neurocognition, and decreased risk of all-cause mortality compared to survivor's who are not fit. The differential effects of physical activity on fitness and health among childhood cancer survivors when compared to peers is potentially related to treatment exposures that damage cardiovascular tissue and impact regenerative potential.

CONCLUSION

Research is needed to determine the optimal timing, frequency, intensity, and duration of physical activity necessary to optimize fitness in childhood cancer survivors.

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Chu X, Wang M, Qiu X, Huang Y, Li T, Otieno E, Li N, Luo L, Xiao X. Strategies for constructing pluripotent stem cell- and progenitor cell-derived three-dimensional cardiac micro-tissues. J Biomed Mater Res A 2021;110:488-503. [PMID: 34397148 DOI: 10.1002/jbm.a.37298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 07/31/2021] [Accepted: 08/04/2021] [Indexed: 12/15/2022]

Koohsarian P, Talebi A, Rahnama MA, Zomorrod MS, Kaviani S, Jalili A. Reviewing the role of cardiac exosomes in myocardial repair at a glance. Cell Biol Int 2021;45:1352-1363. [PMID: 33289229 DOI: 10.1002/cbin.11515] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 11/14/2020] [Accepted: 11/28/2020] [Indexed: 12/11/2022]

Carresi C, Scicchitano M, Scarano F, Macrì R, Bosco F, Nucera S, Ruga S, Zito MC, Mollace R, Guarnieri L, Coppoletta AR, Gliozzi M, Musolino V, Maiuolo J, Palma E, Mollace V. The Potential Properties of Natural Compounds in Cardiac Stem Cell Activation: Their Role in Myocardial Regeneration. Nutrients 2021;13:275. [PMID: 33477916 PMCID: PMC7833367 DOI: 10.3390/nu13010275] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 01/07/2021] [Accepted: 01/12/2021] [Indexed: 12/12/2022] Open

Abstract

Cardiovascular diseases (CVDs), which include congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, and many other cardiac disorders, cause about 30% of deaths globally; representing one of the main health problems worldwide. Among CVDs, ischemic heart diseases (IHDs) are one of the major causes of morbidity and mortality in the world. The onset of IHDs is essentially due to an unbalance between the metabolic demands of the myocardium and its supply of oxygen and nutrients, coupled with a low regenerative capacity of the heart, which leads to great cardiomyocyte (CM) loss; promoting heart failure (HF) and myocardial infarction (MI). To date, the first strategy recommended to avoid IHDs is prevention in order to reduce the underlying risk factors. In the management of IHDs, traditional therapeutic options are widely used to improve symptoms, attenuate adverse cardiac remodeling, and reduce early mortality rate. However, there are no available treatments that aim to improve cardiac performance by replacing the irreversible damaged cardiomyocytes (CMs). Currently, heart transplantation is the only treatment being carried out for irreversibly damaged CMs. Hence, the discovery of new therapeutic options seems to be necessary. Interestingly, recent experimental evidence suggests that regenerative stem cell medicine could be a useful therapeutic approach to counteract cardiac damage and promote tissue regeneration. To this end, researchers are tasked with answering one main question: how can myocardial regeneration be stimulated? In this regard, natural compounds from plant extracts seem to play a particularly promising role. The present review will summarize the recent advances in our knowledge of stem cell therapy in the management of CVDs; focusing on the main properties and potential mechanisms of natural compounds in stimulating and activating stem cells for myocardial regeneration.

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Affiliation(s)

Cristina Carresi Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
Miriam Scicchitano Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
Federica Scarano Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
Roberta Macrì Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
Francesca Bosco Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
Saverio Nucera Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
Stefano Ruga Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
Maria Caterina Zito Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
Rocco Mollace Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
Lorenza Guarnieri Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
Anna Rita Coppoletta Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
Micaela Gliozzi Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
Vincenzo Musolino Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
Jessica Maiuolo Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
Ernesto Palma Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.) Nutramed S.c.a.r.l., Complesso Ninì Barbieri, Roccelletta di Borgia, 88100 Catanzaro, Italy
Vincenzo Mollace Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.) Nutramed S.c.a.r.l., Complesso Ninì Barbieri, Roccelletta di Borgia, 88100 Catanzaro, Italy

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The Future of Direct Cardiac Reprogramming: Any GMT Cocktail Variety? Int J Mol Sci 2020;21:ijms21217950. [PMID: 33114756 PMCID: PMC7663133 DOI: 10.3390/ijms21217950] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/21/2020] [Accepted: 10/22/2020] [Indexed: 12/13/2022] Open

Abstract

Direct cardiac reprogramming has emerged as a novel therapeutic approach to treat and regenerate injured hearts through the direct conversion of fibroblasts into cardiac cells. Most studies have focused on the reprogramming of fibroblasts into induced cardiomyocytes (iCMs). The first study in which this technology was described, showed that at least a combination of three transcription factors, GATA4, MEF2C and TBX5 (GMT cocktail), was required for the reprogramming into iCMs in vitro using mouse cells. However, this was later demonstrated to be insufficient for the reprogramming of human cells and additional factors were required. Thereafter, most studies have focused on implementing reprogramming efficiency and obtaining fully reprogrammed and functional iCMs, by the incorporation of other transcription factors, microRNAs or small molecules to the original GMT cocktail. In this respect, great advances have been made in recent years. However, there is still no consensus on which of these GMT-based varieties is best, and robust and highly reproducible protocols are still urgently required, especially in the case of human cells. On the other hand, apart from CMs, other cells such as endothelial and smooth muscle cells to form new blood vessels will be fundamental for the correct reconstruction of damaged cardiac tissue. With this aim, several studies have centered on the direct reprogramming of fibroblasts into induced cardiac progenitor cells (iCPCs) able to give rise to all myocardial cell lineages. Especially interesting are reports in which multipotent and highly expandable mouse iCPCs have been obtained, suggesting that clinically relevant amounts of these cells could be created. However, as of yet, this has not been achieved with human iCPCs, and exactly what stage of maturity is appropriate for a cell therapy product remains an open question. Nonetheless, the major concern in regenerative medicine is the poor retention, survival, and engraftment of transplanted cells in the cardiac tissue. To circumvent this issue, several cell pre-conditioning approaches are currently being explored. As an alternative to cell injection, in vivo reprogramming may face fewer barriers for its translation to the clinic. This approach has achieved better results in terms of efficiency and iCMs maturity in mouse models, indicating that the heart environment can favor this process. In this context, in recent years some studies have focused on the development of safer delivery systems such as Sendai virus, Adenovirus, chemical cocktails or nanoparticles. This article provides an in-depth review of the in vitro and in vivo cardiac reprograming technology used in mouse and human cells to obtain iCMs and iCPCs, and discusses what challenges still lie ahead and what hurdles are to be overcome before results from this field can be transferred to the clinical settings.

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Aguayo-Cerón KA, Calzada-Mendoza CC, Méndez-Bolaina E, Romero-Nava R, Ocharan-Hernández ME. The regulatory effect of bromocriptine on cardiac hypertrophy by prolactin and D2 receptor modulation. Clin Exp Hypertens 2020;42:675-679. [PMID: 32478610 DOI: 10.1080/10641963.2020.1772814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]

Nishimura K, Oydanich M, Zhang J, Babici D, Fraidenraich D, Vatner DE, Vatner SF. Rats are protected from the stress of chronic pressure overload compared with mice. Am J Physiol Regul Integr Comp Physiol 2020;318:R894-R900. [PMID: 32209023 DOI: 10.1152/ajpregu.00370.2019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]

Barreto S, Hamel L, Schiatti T, Yang Y, George V. Cardiac Progenitor Cells from Stem Cells: Learning from Genetics and Biomaterials. Cells 2019;8:E1536. [PMID: 31795206 PMCID: PMC6952950 DOI: 10.3390/cells8121536] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 11/20/2019] [Accepted: 11/21/2019] [Indexed: 02/07/2023] Open

Davis DR. Paracrine Heart Repair Comes of Age. Can J Cardiol 2019;35:1278-1280. [PMID: 31601411 DOI: 10.1016/j.cjca.2019.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 07/07/2019] [Accepted: 07/07/2019] [Indexed: 11/29/2022] Open

Finan A, Demion M, Sicard P, Guisiano M, Bideaux P, Monceaux K, Thireau J, Richard S. Prolonged elevated levels of c-kit+ progenitor cells after a myocardial infarction by beta 2 adrenergic receptor priming. J Cell Physiol 2019;234:18283-18296. [PMID: 30912139 DOI: 10.1002/jcp.28461] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 02/12/2019] [Accepted: 02/14/2019] [Indexed: 12/23/2022]

Lee TM, Harn HJ, Chiou TW, Chuang MH, Chen CH, Chuang CH, Lin PC, Lin SZ. Remote transplantation of human adipose-derived stem cells induces regression of cardiac hypertrophy by regulating the macrophage polarization in spontaneously hypertensive rats. Redox Biol 2019;27:101170. [PMID: 31164286 PMCID: PMC6859583 DOI: 10.1016/j.redox.2019.101170] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Revised: 03/04/2019] [Accepted: 03/12/2019] [Indexed: 12/16/2022] Open

Abstract

Left ventricular hypertrophy (LVH) in hypertension has prognostic significance on cardiovascular mortality and morbidity. Recently, we have shown that n-butylidenephthalide (BP) improves human adipose-derived stem cell (hADSC) engraftment via attenuated reactive oxygen species (ROS) production. This prompted us to investigate whether remote transplantation of BP-pretreated hADSCs confers attenuated LVH at an established phase of hypertension. Male spontaneously hypertensive rats (SHRs) aged 12 weeks were randomly allocated to receive right hamstring injection of vehicle, clinical-grade hADSCs, and BP-preconditioned hADSCs for 8 weeks. As compared with untreated SHRs, naïve hADSCs decreased the ratio of LV weight to tibia, cardiomyocyte cell size, and collagen deposition independent of hemodynamic changes. These changes were accompanied by attenuated myocardial ROS production and increased p-STAT3 levels. Compared with naïve hADSCs, BP-preconditioned hADSCs provided a further decrease of ROS and LVH and an increase of local hADSC engraftment, STAT3 phosphorylation, STAT3 activity, STAT3 nuclear translocation, myocardial IL-10 levels, and the percentage of M2 macrophage infiltration. SIN-1 or S3I-201 reversed the effects of BP-preconditioned ADSCs increase on myocardial IL-10 levels. Furthermore, SIN-1 abolished the phosphorylation of STAT3, whereas superoxide levels were not affected following the inhibition of STAT3. Our results highlighted the feasibility of remote transplantation of hADSCs can be considered as an alternative procedure to reverse cardiac hypertrophy even at an established phase of hypertension. BP-pretreated hADSCs polarize macrophages into M2 immunoregulatory cells more efficiently than naïve hADSCs via ROS/STAT3 pathway.

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Hypertension was associated with left ventricular hypertrophy.

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Compared with untreated SHRs, naïve hADSCs injected at the right hamstring decreased LV mass and cardiomyocyte cell size.

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BP-preconditioned ADSCs provided a further increase of the M2 macrophage infiltration.

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The beneficial effects of BP-preconditioned stem cell administration can be abolished by exogenous SIN-1 or 3SI-201.

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Remote transplantation of hADSCs can be considered as an alternative procedure to reverse cardiac hypertrophy.

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Adult Cardiac Stem Cell Aging: A Reversible Stochastic Phenomenon? OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019;2019:5813147. [PMID: 30881594 PMCID: PMC6383393 DOI: 10.1155/2019/5813147] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Accepted: 11/08/2018] [Indexed: 12/17/2022]

Abstract

Aging is by far the dominant risk factor for the development of cardiovascular diseases, whose prevalence dramatically increases with increasing age reaching epidemic proportions. In the elderly, pathologic cellular and molecular changes in cardiac tissue homeostasis and response to injury result in progressive deteriorations in the structure and function of the heart. Although the phenotypes of cardiac aging have been the subject of intense study, the recent discovery that cardiac homeostasis during mammalian lifespan is maintained and regulated by regenerative events associated with endogenous cardiac stem cell (CSC) activation has produced a crucial reconsideration of the biology of the adult and aged mammalian myocardium. The classical notion of the adult heart as a static organ, in terms of cell turnover and renewal, has now been replaced by a dynamic model in which cardiac cells continuously die and are then replaced by CSC progeny differentiation. However, CSCs are not immortal. They undergo cellular senescence characterized by increased ROS production and oxidative stress and loss of telomere/telomerase integrity in response to a variety of physiological and pathological demands with aging. Nevertheless, the old myocardium preserves an endogenous functionally competent CSC cohort which appears to be resistant to the senescent phenotype occurring with aging. The latter envisions the phenomenon of CSC ageing as a result of a stochastic and therefore reversible cell autonomous process. However, CSC aging could be a programmed cell cycle-dependent process, which affects all or most of the endogenous CSC population. The latter would infer that the loss of CSC regenerative capacity with aging is an inevitable phenomenon that cannot be rescued by stimulating their growth, which would only speed their progressive exhaustion. The resolution of these two biological views will be crucial to design and develop effective CSC-based interventions to counteract cardiac aging not only improving health span of the elderly but also extending lifespan by delaying cardiovascular disease-related deaths.

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Ross M, Lithgow H, Hayes L, Florida-James G. Potential Cellular and Biochemical Mechanisms of Exercise and Physical Activity on the Ageing Process. Subcell Biochem 2019;91:311-338. [PMID: 30888658 DOI: 10.1007/978-981-13-3681-2_12] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]

Scalise M, Marino F, Cianflone E, Mancuso T, Marotta P, Aquila I, Torella M, Nadal-Ginard B, Torella D. Heterogeneity of Adult Cardiac Stem Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019;1169:141-178. [PMID: 31487023 DOI: 10.1007/978-3-030-24108-7_8] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]

Abstract

Cardiac biology and heart regeneration have been intensively investigated and debated in the last 15 years. Nowadays, the well-established and old dogma that the adult heart lacks of any myocyte-regenerative capacity has been firmly overturned by the evidence of cardiomyocyte renewal throughout the mammalian life as part of normal organ cell homeostasis, which is increased in response to injury. Concurrently, reproducible evidences from independent laboratories have convincingly shown that the adult heart possesses a pool of multipotent cardiac stem/progenitor cells (CSCs or CPCs) capable of sustaining cardiomyocyte and vascular tissue refreshment after injury. CSC transplantation in animal models displays an effective regenerative potential and may be helpful to treat chronic heart failure (CHF), obviating at the poor/modest results using non-cardiac cells in clinical trials. Nevertheless, the degree/significance of cardiomyocyte turnover in the adult heart, which is insufficient to regenerate extensive damage from ischemic and non-ischemic origin, remains strongly disputed. Concurrently, different methodologies used to detect CSCs in situ have created the paradox of the adult heart harboring more than seven different cardiac progenitor populations. The latter was likely secondary to the intrinsic heterogeneity of any regenerative cell agent in an adult tissue but also to the confusion created by the heterogeneity of the cell population identified by a single cell marker used to detect the CSCs in situ. On the other hand, some recent studies using genetic fate mapping strategies claimed that CSCs are an irrelevant endogenous source of new cardiomyocytes in the adult. On the basis of these contradictory findings, here we critically reviewed the available data on adult CSC biology and their role in myocardial cell homeostasis and repair.

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Dergilev KV, Zubkova ЕS, Beloglazova IB, Menshikov МY, Parfyonova ЕV. Notch signal pathway - therapeutic target for regulation of reparative processes in the heart. TERAPEVT ARKH 2018;90:112-121. [PMID: 30701843 DOI: 10.26442/00403660.2018.12.000014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]

Cardiomyocyte cell cycle dynamics and proliferation revealed through cardiac-specific transgenesis of fluorescent ubiquitinated cell cycle indicator (FUCCI). J Mol Cell Cardiol 2018;127:154-164. [PMID: 30571978 DOI: 10.1016/j.yjmcc.2018.12.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 11/21/2018] [Accepted: 12/17/2018] [Indexed: 01/11/2023]

Abstract

RATIONALE

Understanding and manipulating the cardiomyocyte cell cycle has been the focus of decades of research, however the ultimate goal of activating mitotic activity in adult mammalian cardiomyocytes remains elusive and controversial. The relentless pursuit of controlling cardiomyocyte mitosis has been complicated and obfuscated by a multitude of indices used as evidence of cardiomyocyte cell cycle activity that lack clear identification of cardiomyocyte "proliferation" versus cell cycle progression, endoreplication, endomitosis, and even DNA damage. Unambiguous appreciation of the complexity of cardiomyocyte replication that avoids oversimplification and misinterpretation is desperately needed.

OBJECTIVE

Track cardiomyocyte cell cycle activity and authenticate fidelity of proliferation markers as indicators of de novo cardiomyogenesis in post-mitotic cardiomyocytes.

METHODS AND RESULTS

Cardiomyocytes expressing the FUCCI construct driven by the α-myosin heavy chain promoter were readily and uniformly detected through the myocardium of transgenic mice. Cardiomyocyte cell cycle activity peaks at postnatal day 2 and rapidly declines thereafter with almost all cardiomyocytes arrested at the G1/S cell cycle transition. Myocardial infarction injury in adult hearts prompts transient small increases in myocytes progressing through cell cycle without concurrent mitotic activity, indicating lack of cardiomyogenesis. In comparison, cardiomyogenic activity during early postnatal development correlated with coincidence of FUCCI and cKit⁺ cells that were undetectable in the adult myocardium.

CONCLUSIONS

Cardiomyocyte-specific expression of Fluorescence Ubiquitination-based Cell Cycle Indicators (FUCCI) reveals previously unappreciated aspects of cardiomyocyte cell cycle arrest and biological activity in postnatal development and in response to pathologic damage. Compared to many other methods and model systems, the FUCCI transgenic (FUCCI-Tg) mouse represents a valuable tool to unambiguously track cell cycle and proliferation of the entire cardiomyocyte population in the adult murine heart. FUCCI-Tg provides a desperately needed novel approach in the armamentarium of tools to validate cardiomyocyte proliferative activity that will reveal cell cycle progression, discriminate between cycle progression, DNA replication, and proliferation, and provide important insight for enhancing cardiomyocyte proliferation in the context of adult myocardial tissue.

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Michler RE. The role of stem cells in treating coronary artery disease in 2018. Indian J Thorac Cardiovasc Surg 2018;34:340-348. [PMID: 33060957 DOI: 10.1007/s12055-018-0739-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 08/24/2018] [Accepted: 08/27/2018] [Indexed: 11/27/2022] Open

Huang M, Liu J, Sheng Y, Lv Y, Yu J, Qi H, Di W, Lv S, Zhou S, Ding G. 11β-hydroxysteroid dehydrogenase type 1 inhibitor attenuates high-fat diet induced cardiomyopathy. J Mol Cell Cardiol 2018;125:106-116. [DOI: 10.1016/j.yjmcc.2018.10.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 09/06/2018] [Accepted: 10/02/2018] [Indexed: 12/29/2022]

Sayed A, Valente M, Sassoon D. Does cardiac development provide heart research with novel therapeutic approaches? F1000Res 2018;7. [PMID: 30450195 PMCID: PMC6221076 DOI: 10.12688/f1000research.15609.1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/24/2018] [Indexed: 01/04/2023] Open

Jara Avaca M, Gruh I. Bioengineered Cardiac Tissue Based on Human Stem Cells for Clinical Application. ADVANCES IN BIOCHEMICAL ENGINEERING/BIOTECHNOLOGY 2018;163:117-146. [PMID: 29218360 DOI: 10.1007/10_2017_24] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]

Michler RE. The current status of stem cell therapy in ischemic heart disease. J Card Surg 2018;33:520-531. [DOI: 10.1111/jocs.13789] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]

The mechanistic role of oxidative stress in cigarette smoke-induced cardiac stem cell dysfunction and prevention by ascorbic acid. Cell Biol Toxicol 2018;35:111-127. [DOI: 10.1007/s10565-018-9437-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 06/21/2018] [Indexed: 12/13/2022]

Broughton KM, Sussman MA. Enhancement Strategies for Cardiac Regenerative Cell Therapy: Focus on Adult Stem Cells. Circ Res 2018;123:177-187. [PMID: 29976686 PMCID: PMC6192710 DOI: 10.1161/circresaha.118.311207] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]

Li L, Wang Q, Yuan Z, Chen A, Liu Z, Wang Z, Li H. LncRNA-MALAT1 promotes CPC proliferation and migration in hypoxia by up-regulation of JMJD6 via sponging miR-125. Biochem Biophys Res Commun 2018;499:711-718. [PMID: 29605300 DOI: 10.1016/j.bbrc.2018.03.216] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 03/29/2018] [Indexed: 02/08/2023]

Gerisch M, Smettan J, Ebert S, Athelogou M, Brand-Saberi B, Spindler N, Mueller WC, Giri S, Bader A. Qualitative and Quantitative Analysis of Cardiac Progenitor Cells in Cases of Myocarditis and Cardiomyopathy. Front Genet 2018;9:72. [PMID: 29559994 PMCID: PMC5845648 DOI: 10.3389/fgene.2018.00072] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 02/16/2018] [Indexed: 11/24/2022] Open

Cardiac Progenitor Cells and the Interplay with Their Microenvironment. Stem Cells Int 2017;2017:7471582. [PMID: 29075298 PMCID: PMC5623801 DOI: 10.1155/2017/7471582] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 07/26/2017] [Indexed: 02/06/2023] Open

Regenerative Stem Cell Therapy Optimization via Tissue Engineering in Heart Failure with Reduced Ejection Fraction. Cardiovasc Eng Technol 2017;8:515-526. [DOI: 10.1007/s13239-017-0325-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Accepted: 07/31/2017] [Indexed: 12/30/2022]

Bianconi V, Sahebkar A, Kovanen P, Bagaglia F, Ricciuti B, Calabrò P, Patti G, Pirro M. Endothelial and cardiac progenitor cells for cardiovascular repair: A controversial paradigm in cell therapy. Pharmacol Ther 2017;181:156-168. [PMID: 28827151 DOI: 10.1016/j.pharmthera.2017.08.004] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]

Abstract

Stem cells have the potential to differentiate into cardiovascular cell lineages and to stimulate tissue regeneration in a paracrine/autocrine manner; thus, they have been extensively studied as candidate cell sources for cardiovascular regeneration. Several preclinical and clinical studies addressing the therapeutic potential of endothelial progenitor cells (EPCs) and cardiac progenitor cells (CPCs) in cardiovascular diseases have been performed. For instance, autologous EPC transplantation and EPC mobilization through pharmacological agents contributed to vascular repair and neovascularization in different animal models of limb ischemia and myocardial infarction. Also, CPC administration and in situ stimulation of resident CPCs have been shown to improve myocardial survival and function in experimental models of ischemic heart disease. However, clinical studies using EPC- and CPC-based therapeutic approaches have produced mixed results. In this regard, intracoronary, intra-myocardial or intramuscular injection of either bone marrow-derived or peripheral blood progenitor cells has improved pathological features of tissue ischemia in humans, despite modest or no clinical benefit has been observed in most cases. Also, the intriguing scientific background surrounding the potential clinical applications of EPC capture stenting is still waiting for a confirmatory proof. Moreover, clinical findings on the efficacy of CPC-based cell therapy in heart diseases are still very preliminary and based on small-size studies. Despite promising evidence, widespread clinical application of both EPCs and CPCs remains delayed due to several unresolved issues. The present review provides a summary of the different applications of EPCs and CPCs for cardiovascular cell therapy and underlies their advantages and limitations.

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Kanda P, Davis DR. Cellular mechanisms underlying cardiac engraftment of stem cells. Expert Opin Biol Ther 2017;17:1127-1143. [PMID: 28670973 DOI: 10.1080/14712598.2017.1346080] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]

Booth SA, Charchar FJ. Cardiac telomere length in heart development, function, and disease. Physiol Genomics 2017;49:368-384. [DOI: 10.1152/physiolgenomics.00024.2017] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open

The use and abuse of Cre/Lox recombination to identify adult cardiomyocyte renewal rate and origin. Pharmacol Res 2017;127:116-128. [PMID: 28655642 DOI: 10.1016/j.phrs.2017.06.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 06/19/2017] [Accepted: 06/21/2017] [Indexed: 11/20/2022]

Abstract

The adult mammalian heart, including the human, is unable to regenerate segmental losses after myocardial infarction. This evidence has been widely and repeatedly used up-to-today to suggest that the myocardium, contrary to most adult tissues, lacks an endogenous stem cell population or more specifically a bona-fide cardiomyocyte-generating progenitor cell of biological significance. In the last 15 years, however, the field has slowly evolved from the dogma that no new cardiomyocytes were produced from shortly after birth to the present consensus that new cardiomyocytes are formed throughout lifespan. This endogenous regenerative potential increases after various forms of injury. Nevertheless, the degree/significance and more importantly the origin of adult new cardiomyocytes remains strongly disputed. Evidence from independent laboratories has shown that the adult myocardium harbours bona-fide tissue-specific cardiac stem cells (CSCs). Their transplantation and in situ activation have demonstrated the CSCs regenerative potential and have been used to develop regeneration protocols which in pre-clinical tests have shown to be effective in the prevention and treatment of heart failure. Recent reports purportedly tracking the c-kit⁺CSC's fate using Cre/lox recombination in the mouse have challenged the existence and regenerative potential of the CSCs and have raised scepticism about their role in myocardial homeostasis and regeneration. The validity of these reports, however, is controversial because they failed to show that the experimental approach used is capable to both identify and tract the fate of the CSCs. Despite these serious shortcomings, in contraposition to the CSCs, these publications have proposed the proliferation of existing adult fully-matured cardiomyocytes as the relevant mechanism to explain cardiomyocyte renewal in the adult. This review critically ponders the available evidence showing that the adult mammalian heart possesses a definable myocyte-generating progenitor cell of biological significance. This endogenous regenerative potential is expected to provide the bases for novel approaches of myocardial repair in the near future.

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Stamm C, Liebold A, Steinhoff G, Strunk D. Stem Cell Therapy for Ischemic Heart Disease: Beginning or End of the Road? Cell Transplant 2017;15 Suppl 1:S47-56. [PMID: 16826795 DOI: 10.3727/000000006783982313] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open

Abstract Despite improvements in emergency treatment, myocardial infarction is often the beginning of a downward spiral leading to congestive heart failure. Other than heart transplantation, current therapeutic means aim at enabling the organism to survive with a heart that is working at a fraction of its original capacity. It is therefore no surprise that cardiac stem cell therapy has raised many hopes. However, neither the ideal source and type of stem cell nor the critical cell number and mode of application have been defined so far. Early reports on myocardial repair by adult bone marrow stem cells from rodent models promoted an unparalleled boost of clinical and experimental cell therapy studies. The phenomenon of stem/progenitor cell-induced angiogenesis in ischemic myocardium has ever since been reproduced by numerous groups in a variety of small and large animal models. Myogenesis, however, is an altogether different matter. Many of the initial clinical studies were fueled by the suggestion that early hematopoietic stem cells have a plasticity high enough to enable cross-lineage differentiation into cells of cardiomyocyte phenotype, but the initial enthusiasm has largely faded. The myogenic potential of stroma cell-derived mesenchymal stem cells is much better documented in animal models, but transfer to the clinical setting faces a variety of obstacles. In clinical pilot trials, we and others have demonstrated the feasibility and safety of administering progenitor cells derived from autologous bone marrow to the myocardium of patients with ischemic heart disease. Clinical efficacy data are still rare, but the few controlled trials that have been completed uniformly show a tendency towards better heart function in cell-treated patients. This review is an attempt to describe the scientific basis for cardiac cell therapy from the point of view of the clinician, focusing on problems that arise with beginning translation into the clinical setting. Collapse

Ellison-Hughes GM, Madeddu P. Exploring pericyte and cardiac stem cell secretome unveils new tactics for drug discovery. Pharmacol Ther 2017;171:1-12. [PMID: 27916652 PMCID: PMC5636619 DOI: 10.1016/j.pharmthera.2016.11.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]

Kannappan R, Matsuda A, Ferreira-Martins J, Zhang E, Palano G, Czarna A, Cabral-Da-Silva MC, Bastos-Carvalho A, Sanada F, Ide N, Rota M, Blasco MA, Serrano M, Anversa P, Leri A. p53 Modulates the Fate of Cardiac Progenitor Cells Ex Vivo and in the Diabetic Heart In Vivo. EBioMedicine 2017;16:224-237. [PMID: 28163043 PMCID: PMC5474510 DOI: 10.1016/j.ebiom.2017.01.028] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Revised: 01/20/2017] [Accepted: 01/20/2017] [Indexed: 12/01/2022] Open

Abstract

p53 is an important modulator of stem cell fate, but its role in cardiac progenitor cells (CPCs) is unknown. Here, we tested the effects of a single extra-copy of p53 on the function of CPCs in the presence of oxidative stress mediated by doxorubicin in vitro and type-1 diabetes in vivo. CPCs were obtained from super-p53 transgenic mice (p53-tg), in which the additional allele is regulated in a manner similar to the endogenous protein. Old CPCs with increased p53 dosage showed a superior ability to sustain oxidative stress, repair DNA damage and restore cell division. With doxorubicin, a larger fraction of CPCs carrying an extra-copy of the p53 allele recruited γH2A.X reestablishing DNA integrity. Enhanced p53 expression resulted in a superior tolerance to oxidative stress in vivo by providing CPCs with defense mechanisms necessary to survive in the milieu of the diabetic heart; they engrafted in regions of tissue injury and in three days acquired the cardiomyocyte phenotype. The biological advantage provided by the increased dosage of p53 in CPCs suggests that this genetic strategy may be translated to humans to increase cellular engraftment and growth, critical determinants of successful cell therapy for the failing heart.

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p53 improves the ability of CPCs to sustain oxidative stress.

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p53 promotes the restoration of DNA integrity and cell division.

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p53 enhances the engraftment of CPCs in the diabetic heart.

Ongoing clinical trials with autologous cardiac stem cells (CSCs) are faced with a critical limitation which is related to the modest amount of retained cells within the damaged myocardium. We have developed a strategy that overcomes in part this problem enhancing the number of CSCs able to engraft within the pathologic organ. Additionally, these genetically modified CSCs can be generated in large number, raising the possibility that multiple temporally distinct deliveries of cells can be introduced to restore the structural and functional integrity of the decompensated heart.

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Affiliation(s)

Ramaswamy Kannappan Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Alex Matsuda Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Cardiocentro Ticino Foundation, Swiss Institute for Regenerative Medicine (SIRM), Via Tesserete 48, 6900 Lugano, Switzerland
João Ferreira-Martins Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Eric Zhang Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Giorgia Palano Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Anna Czarna Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Cardiocentro Ticino Foundation, Swiss Institute for Regenerative Medicine (SIRM), Via Tesserete 48, 6900 Lugano, Switzerland
Mauricio Castro Cabral-Da-Silva Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Adriana Bastos-Carvalho Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Fumihiro Sanada Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Noriko Ide Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Marcello Rota Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Maria A Blasco Spanish National Cancer Research Centre (CNIO), Madrid E-28029, Spain
Manuel Serrano Spanish National Cancer Research Centre (CNIO), Madrid E-28029, Spain
Piero Anversa Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Cardiocentro Ticino Foundation, Swiss Institute for Regenerative Medicine (SIRM), Via Tesserete 48, 6900 Lugano, Switzerland
Annarosa Leri Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Cardiocentro Ticino Foundation, Swiss Institute for Regenerative Medicine (SIRM), Via Tesserete 48, 6900 Lugano, Switzerland.

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Wang Z, Schmull S, Zheng H, Shan J, Zou R, Xue S. Ascending Aortic Constriction Promotes Cardiomyocyte Proliferation in Neonatal Rats. Int Heart J 2017;58:264-270. [PMID: 28077821 DOI: 10.1536/ihj.16-234] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]

Shen L, Wang H, Bei Y, Cretoiu D, Cretoiu SM, Xiao J. Formation of New Cardiomyocytes in Exercise. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017;999:91-102. [DOI: 10.1007/978-981-10-4307-9_6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]

Luo L, Nishi K, Urata Y, Yan C, Hasan AS, Goto S, Kudo T, Li ZL, Li TS. Ionizing Radiation Impairs Endogenous Regeneration of Infarcted Heart: An In Vivo ¹⁸F-FDG PET/CT and ^99mTc-Tetrofosmin SPECT/CT Study in Mice. Radiat Res 2016;187:89-97. [PMID: 27922334 DOI: 10.1667/rr14543.1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]

Sukhacheva TV, Chudinovskikh YA, Eremeeva MV, Serov RA, Bockeria LA. Proliferative Potential of Cardiomyocytes in Hypertrophic Cardiomyopathy: Correlation with Myocardial Remodeling. Bull Exp Biol Med 2016;162:160-169. [PMID: 27882462 DOI: 10.1007/s10517-016-3566-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Indexed: 01/07/2023]

Pasipoularides A. Calcific Aortic Valve Disease: Part 2-Morphomechanical Abnormalities, Gene Reexpression, and Gender Effects on Ventricular Hypertrophy and Its Reversibility. J Cardiovasc Transl Res 2016;9:374-99. [PMID: 27184804 PMCID: PMC4992466 DOI: 10.1007/s12265-016-9695-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 05/03/2016] [Indexed: 02/07/2023]

Lazarowski AJ, García Rivello HJ, Vera Janavel GL, Cuniberti LA, Cabeza Meckert PM, Yannarelli GG, Mele A, Crottogini AJ, Laguens RP. Cardiomyocytes of Chronically Ischemic Pig Hearts Express the MDR-1 Gene-encoded P-glycoprotein. J Histochem Cytochem 2016;53:845-50. [PMID: 15995143 DOI: 10.1369/jhc.4a6542.2005] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open

Zhang L, Geng WR, Hu J, Chen XM, Shen YL, Wang LL, Jiang JP, Chen YY. Lipopolysaccharide pretreatment promotes cardiac stem cell migration through heat shock protein 90-dependent β-catenin activation. Life Sci 2016;153:132-40. [DOI: 10.1016/j.lfs.2016.04.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Revised: 04/06/2016] [Accepted: 04/14/2016] [Indexed: 12/14/2022]

Cameli M, Righini FM, Sparla S, Tacchini D, Dokollari A, Sassi CG, Di Tommaso C, Curci V, Censini S, Incampo E, Cassano F, Droandi G, Bernazzali S, Focardi M, Ietta F, Sartiani L, Romagnoli R, Marotta G, Mugelli A, Paulesu L, Sani G, Tanganelli P, Maccherini M, Mondillo S. First Evidence of Cardiac Stem Cells From the Left Ventricular Apical Tip in Patients With Left Ventricular Assist Device Implantation. Transplant Proc 2016;48:395-8. [PMID: 27109964 DOI: 10.1016/j.transproceed.2015.12.045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 12/30/2015] [Indexed: 02/02/2023]

Affiliation(s)

M Cameli Department of Cardiovascular Diseases, University of Siena, Siena, Italy.
F M Righini Department of Cardiovascular Diseases, University of Siena, Siena, Italy
S Sparla Department of Cardiovascular Diseases, University of Siena, Siena, Italy
D Tacchini Department of Pathological Anatomy, University of Siena, Siena, Italy
A Dokollari Department of Cardiac Surgery, University of Siena, Siena, Italy
C G Sassi Department of Cardiac Surgery, University of Siena, Siena, Italy
C Di Tommaso Department of Cardiovascular Diseases, University of Siena, Siena, Italy
V Curci Department of Cardiovascular Diseases, University of Siena, Siena, Italy
S Censini Department of Cardiovascular Diseases, University of Siena, Siena, Italy
E Incampo Department of Cardiovascular Diseases, University of Siena, Siena, Italy
F Cassano Department of Cardiovascular Diseases, University of Siena, Siena, Italy
G Droandi Department of Cardiac Surgery, University of Siena, Siena, Italy
S Bernazzali Department of Cardiac Surgery, University of Siena, Siena, Italy
M Focardi Department of Cardiovascular Diseases, University of Siena, Siena, Italy
F Ietta Department of Life Sciences, University of Siena, Siena, Italy
L Sartiani Department of NeuroFarBa, Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata, University of Florence, Florence, Italy
R Romagnoli Department of Life Sciences, University of Siena, Siena, Italy
G Marotta Department of Hematology, University of Siena, Siena, Italy
A Mugelli Department of NeuroFarBa, Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata, University of Florence, Florence, Italy
L Paulesu Department of Life Sciences, University of Siena, Siena, Italy
G Sani Department of Cardiac Surgery, University of Siena, Siena, Italy
P Tanganelli Department of Pathological Anatomy, University of Siena, Siena, Italy
M Maccherini Department of Cardiac Surgery, University of Siena, Siena, Italy
S Mondillo Department of Cardiovascular Diseases, University of Siena, Siena, Italy

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Cui J, Zhang F, Wang Y, Liu J, Ming X, Hou J, Lv B, Fang S, Yu B. Macrophage migration inhibitory factor promotes cardiac stem cell proliferation and endothelial differentiation through the activation of the PI3K/Akt/mTOR and AMPK pathways. Int J Mol Med 2016;37:1299-309. [PMID: 27035848 PMCID: PMC4829139 DOI: 10.3892/ijmm.2016.2542] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 03/16/2016] [Indexed: 01/05/2023] Open

Månsson-Broberg A, Rodin S, Bulatovic I, Ibarra C, Löfling M, Genead R, Wärdell E, Felldin U, Granath C, Alici E, Le Blanc K, Smith CIE, Salašová A, Westgren M, Sundström E, Uhlén P, Arenas E, Sylvén C, Tryggvason K, Corbascio M, Simonson OE, Österholm C, Grinnemo KH. Wnt/β-Catenin Stimulation and Laminins Support Cardiovascular Cell Progenitor Expansion from Human Fetal Cardiac Mesenchymal Stromal Cells. Stem Cell Reports 2016;6:607-617. [PMID: 27052314 PMCID: PMC4834052 DOI: 10.1016/j.stemcr.2016.02.014] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 02/19/2016] [Accepted: 02/22/2016] [Indexed: 11/29/2022] Open

Affiliation(s)

Agneta Månsson-Broberg Division of Cardiology, Department of Medicine, Karolinska Institutet, 17177 Stockholm, Sweden
Sergey Rodin Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden
Ivana Bulatovic Division of Cardiothoracic Surgery and Anesthesiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden
Cristián Ibarra Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; Cardiovascular & Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca R&D, 43150 Mölndal, Sweden
Marie Löfling Division of Cardiothoracic Surgery and Anesthesiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden
Rami Genead Division of Cardiothoracic Surgery and Anesthesiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden
Eva Wärdell Division of Cardiology, Department of Medicine, Karolinska Institutet, 17177 Stockholm, Sweden
Ulrika Felldin Division of Cardiothoracic Surgery and Anesthesiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden
Carl Granath Division of Cardiothoracic Surgery and Anesthesiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden
Evren Alici Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 17177 Stockholm, Sweden; Cell Therapy Institute, Nova Southeastern University, Fort Lauderdale, FL 33314, USA
Katarina Le Blanc Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 17177 Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, 17177 Stockholm, Sweden
C I Edvard Smith Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, 17177 Stockholm, Sweden
Alena Salašová Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden
Magnus Westgren CLINTEC, Division of Obstetrics and Gynecology, Karolinska Institutet, Karolinska University Hospital, 17177 Stockholm, Sweden
Erik Sundström Division of Neurodegeneration, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Karolinska University Hospital, 17177 Stockholm, Sweden
Per Uhlén Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden
Ernest Arenas Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden
Christer Sylvén Division of Cardiology, Department of Medicine, Karolinska Institutet, 17177 Stockholm, Sweden
Karl Tryggvason Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; Duke-NUS Graduate Medical School, Durham, NC 27710, USA
Matthias Corbascio Division of Cardiothoracic Surgery and Anesthesiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden
Oscar E Simonson Division of Cardiothoracic Surgery and Anesthesiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden
Cecilia Österholm Division of Cardiothoracic Surgery and Anesthesiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden; Cell Therapy Institute, Nova Southeastern University, Fort Lauderdale, FL 33314, USA
Karl-Henrik Grinnemo Division of Cardiothoracic Surgery and Anesthesiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden; Cell Therapy Institute, Nova Southeastern University, Fort Lauderdale, FL 33314, USA.

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Pathological Left Ventricular Hypertrophy and Stem Cells: Current Evidence and New Perspectives. Stem Cells Int 2015;2016:5720758. [PMID: 26798360 PMCID: PMC4699040 DOI: 10.1155/2016/5720758] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 08/17/2015] [Accepted: 09/06/2015] [Indexed: 12/17/2022] Open

Kokkinopoulos I, Ishida H, Saba R, Coppen S, Suzuki K, Yashiro K. Cardiomyocyte differentiation from mouse embryonic stem cells using a simple and defined protocol. Dev Dyn 2015;245:157-65. [DOI: 10.1002/dvdy.24366] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 10/27/2015] [Accepted: 10/27/2015] [Indexed: 12/12/2022] Open

Zhang Y, Mignone J, MacLellan WR. Cardiac Regeneration and Stem Cells. Physiol Rev 2015;95:1189-204. [PMID: 26269526 DOI: 10.1152/physrev.00021.2014] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open

Finan A, Richard S. Stimulating endogenous cardiac repair. Front Cell Dev Biol 2015;3:57. [PMID: 26484341 PMCID: PMC4586501 DOI: 10.3389/fcell.2015.00057] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2015] [Accepted: 09/08/2015] [Indexed: 01/10/2023] Open

Abstract

The healthy adult heart has a low turnover of cardiac myocytes. The renewal capacity, however, is augmented after cardiac injury. Participants in cardiac regeneration include cardiac myocytes themselves, cardiac progenitor cells, and peripheral stem cells, particularly from the bone marrow compartment. Cardiac progenitor cells and bone marrow stem cells are augmented after cardiac injury, migrate to the myocardium, and support regeneration. Depletion studies of these populations have demonstrated their necessary role in cardiac repair. However, the potential of these cells to completely regenerate the heart is limited. Efforts are now being focused on ways to augment these natural pathways to improve cardiac healing, primarily after ischemic injury but in other cardiac pathologies as well. Cell and gene therapy or pharmacological interventions are proposed mechanisms. Cell therapy has demonstrated modest results and has passed into clinical trials. However, the beneficial effects of cell therapy have primarily been their ability to produce paracrine effects on the cardiac tissue and recruit endogenous stem cell populations as opposed to direct cardiac regeneration. Gene therapy efforts have focused on prolonging or reactivating natural signaling pathways. Positive results have been demonstrated to activate the endogenous stem cell populations and are currently being tested in clinical trials. A potential new avenue may be to refine pharmacological treatments that are currently in place in the clinic. Evidence is mounting that drugs such as statins or beta blockers may alter endogenous stem cell activity. Understanding the effects of these drugs on stem cell repair while keeping in mind their primary function may strike a balance in myocardial healing. To maximize endogenous cardiac regeneration, a combination of these approaches could ameliorate the overall repair process to incorporate the participation of multiple cellular players.

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