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Lee W, Lin SL, Chiang CS, Chen JY, Chieng WW, Huang SR, Chang TY, Linju Yen B, Hung MC, Chang KC, Lee HT, Jeng LB, Shyu WC. Role of HIF-1α-Activated IL-22/IL-22R1/Bmi1 Signaling Modulates the Self-Renewal of Cardiac Stem Cells in Acute Myocardial Ischemia. Stem Cell Rev Rep 2024; 20:2194-2214. [PMID: 39264501 PMCID: PMC11554697 DOI: 10.1007/s12015-024-10774-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/06/2024] [Indexed: 09/13/2024]
Abstract
Impaired tissue regeneration negatively impacts on left ventricular (LV) function and remodeling after acute myocardial infarction (AMI). Little is known about the intrinsic regulatory machinery of ischemia-induced endogenous cardiac stem cells (eCSCs) self-renewing divisions after AMI. The interleukin 22 (IL-22)/IL-22 receptor 1 (IL-22R1) pathway has emerged as an important regulator of several cellular processes, including the self-renewal and proliferation of stem cells. However, whether the hypoxic environment could trigger the self-renewal of eCSCs via IL-22/IL-22R1 activation remains unknown. In this study, the upregulation of IL-22R1 occurred due to activation of hypoxia-inducible factor-1α (HIF-1α) under hypoxic and ischemic conditions. Systemic IL-22 administration not only attenuated cardiac remodeling, inflammatory responses, but also promoted eCSC-mediated cardiac repair after AMI. Unbiased RNA microarray analysis showed that the downstream mediator Bmi1 regulated the activation of CSCs. Therefore, the HIF-1α-induced IL-22/IL-22R1/Bmi1 cascade can modulate the proliferation and activation of eCSCs in vitro and in vivo. Collectively, investigating the HIF-1α-activated IL-22/IL-22R1/Bmi1 signaling pathway might offer a new therapeutic strategy for AMI via eCSC-induced cardiac repair.
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Affiliation(s)
- Wei Lee
- Cell Therapy Center, China Medical University Hospital (CMUH), Taichung, 404, Taiwan
| | - Syuan-Ling Lin
- Translational Medicine Research Center, CMUH, Taichung, 404, Taiwan
| | - Chih-Sheng Chiang
- Cell Therapy Center, China Medical University Hospital (CMUH), Taichung, 404, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University (CMU), Taichung, 404, Taiwan
- Neuroscience and Brain Disease Center and New Drug Development Center, CMU, Taichung, 404, Taiwan
| | - Jui-Yu Chen
- Translational Medicine Research Center, CMUH, Taichung, 404, Taiwan
| | - Wee-Wei Chieng
- Translational Medicine Research Center, CMUH, Taichung, 404, Taiwan
| | - Shu-Rou Huang
- Translational Medicine Research Center, CMUH, Taichung, 404, Taiwan
| | - Ting-Yu Chang
- Cell Therapy Center, China Medical University Hospital (CMUH), Taichung, 404, Taiwan
| | - B Linju Yen
- Regenerative Medicine Research Group, Institute of Cellular and System Medicine, National Health Research Institutes (NHRI), Zhunan, 350, Taiwan
| | - Mien-Chie Hung
- Graduate Institute of Biomedical Sciences and Research Centers for Cancer Biology and Molecular Medicine, CMU, Taichung, 404, Taiwan
| | - Kuan-Cheng Chang
- Division of Cardiovascular Medicine, Department of Medicine, CMUH, Taichung, 404, Taiwan
- School of Medicine, CMU, Taichung, 404, Taiwan
| | - Hsu-Tung Lee
- Department of Neurosurgery, Taichung Veterans General Hospital, Taichung, 404, Taiwan
| | - Long-Bin Jeng
- Cell Therapy Center, China Medical University Hospital (CMUH), Taichung, 404, Taiwan
- Organ Transplantation Center, CMUH, Taichung, 404, Taiwan
| | - Woei-Cherng Shyu
- Translational Medicine Research Center, CMUH, Taichung, 404, Taiwan.
- Graduate Institute of Biomedical Sciences, China Medical University (CMU), Taichung, 404, Taiwan.
- Neuroscience and Brain Disease Center and New Drug Development Center, CMU, Taichung, 404, Taiwan.
- Department of Neurology, CMUH, Taichung, 404, Taiwan.
- Department of Occupational Therapy, Asia University, No. 2, Yude Rd., North Dist, Taichung City, 404332, Taiwan.
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2
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Pampanella L, Petrocelli G, Forcellini F, Cruciani S, Ventura C, Abruzzo PM, Facchin F, Canaider S. Oxytocin, the Love Hormone, in Stem Cell Differentiation. Curr Issues Mol Biol 2024; 46:12012-12036. [PMID: 39590307 PMCID: PMC11592854 DOI: 10.3390/cimb46110713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/23/2024] [Accepted: 10/23/2024] [Indexed: 11/28/2024] Open
Abstract
Oxytocin (OXT) is a neurohypophysial nonapeptide that exerts its effects mainly through the oxytocin receptor (OXTR). Several studies have pointed out the role of OXT in the modulation of stem cell (SC) fate and properties. SCs are undifferentiated cells characterized by a remarkable ability to self-renew and differentiate into various cell types of the body. In this review, we focused on the role of OXT in SC differentiation. Specifically, we summarize and discuss the scientific research examining the effects of OXT on mesodermal SC-derived lineages, including cardiac, myogenic, adipogenic, osteogenic, and chondrogenic differentiation. The available studies related to the effects of OXT on SC differentiation provide little insights about the molecular mechanism mediated by the OXT-OXTR pathway. Further research is needed to fully elucidate these pathways to effectively modulate SC differentiation and develop potential therapeutic applications in regenerative medicine.
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Affiliation(s)
- Luca Pampanella
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.P.); (G.P.); (F.F.); (C.V.); (S.C.)
| | - Giovannamaria Petrocelli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.P.); (G.P.); (F.F.); (C.V.); (S.C.)
| | - Federica Forcellini
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.P.); (G.P.); (F.F.); (C.V.); (S.C.)
| | - Sara Cruciani
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy;
| | - Carlo Ventura
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.P.); (G.P.); (F.F.); (C.V.); (S.C.)
- National Laboratory of Molecular Biology and Stem Cell Bioengineering, National Institute of Biostructures and Biosystems (NIBB), Via di Corticella 183, 40129 Bologna, Italy
| | - Provvidenza Maria Abruzzo
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.P.); (G.P.); (F.F.); (C.V.); (S.C.)
| | - Federica Facchin
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.P.); (G.P.); (F.F.); (C.V.); (S.C.)
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Silvia Canaider
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (L.P.); (G.P.); (F.F.); (C.V.); (S.C.)
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Massarenti 9, 40138 Bologna, Italy
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3
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Inouye K, Yeganyan S, Kay K, Thankam FG. Programmed spontaneously beating cardiomyocytes in regenerative cardiology. Cytotherapy 2024; 26:790-796. [PMID: 38520412 DOI: 10.1016/j.jcyt.2024.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 03/07/2024] [Accepted: 03/08/2024] [Indexed: 03/25/2024]
Abstract
Stem cells have gained attention as a promising therapeutic approach for damaged myocardium, and there have been efforts to develop a protocol for regenerating cardiomyocytes (CMs). Certain cells have showed a greater aptitude for yielding beating CMs, such as induced pluripotent stem cells, embryonic stem cells, adipose-derived stromal vascular fraction cells and extended pluripotent stem cells. The approach for generating CMs from stem cells differs across studies, although there is evidence that Wnt signaling, chemical additives, electrical stimulation, co-culture, biomaterials and transcription factors triggers CM differentiation. Upregulation of Gata4, Mef2c and Tbx5 transcription factors has been correlated with successfully induced CMs, although Mef2c may potentially play a more prominent role in the generation of the beating phenotype, specifically. Regenerative research provides a possible candidate for cardiac repair; however, it is important to identify factors that influence their differentiation. Altogether, the spontaneously beating CMs would be monumental for regenerative research for cardiac repair.
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Affiliation(s)
- Keiko Inouye
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, USA
| | - Stephanie Yeganyan
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, USA
| | - Kaelen Kay
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, USA
| | - Finosh G Thankam
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, USA.
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4
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Cheng P, Rashad A, Gangrade A, Barros NRD, Khademhosseini A, Tam J, Varadarajan P, Agrawal DK, Thankam FG. Stem Cell-Derived Cardiomyocyte-Like Cells in Myocardial Regeneration. TISSUE ENGINEERING. PART B, REVIEWS 2024; 30:1-14. [PMID: 37294202 DOI: 10.1089/ten.teb.2023.0049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Myocardial infarction results in the significant loss of cardiomyocytes (CMs) due to the ischemic injury following coronary occlusion leading to impaired contractility, fibrosis, and ultimately heart failure. Stem cell therapy emerged as a promising regenerative strategy to replenish the otherwise terminally differentiated CM to restore cardiac function. Multiple strategies have been applied to successfully differentiate diverse stem cell populations into CM-like phenotypes characterized by the expression status of signature biomarkers and observable spontaneous contractions. This article discusses the current understanding and applications of various stem cell phenotypes to drive the differentiation machinery toward CM-like lineage. Impact Statement Ischemic heart disease (IHD) extensively affects a large proportion of the population worldwide. Unfortunately, current treatments for IHD are insufficient to restore cardiac effectiveness and functionality. A growing field in regenerative cardiology explores the potential for stem cell therapy following cardiovascular ischemic episodes. The thorough understanding regarding the potential and shortcomings of translational approaches to drive versatile stem cells to cardiomyocyte lineage paves the way for multiple opportunities for next-generation cardiac management.
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Affiliation(s)
- Pauline Cheng
- Department of Translational Research, Western University of Health Sciences, Pomona, California, USA
| | - Ahmad Rashad
- Terasaki Institute for Biomedical Innovation (TIBI), Los Angeles, California, USA
| | - Ankit Gangrade
- Terasaki Institute for Biomedical Innovation (TIBI), Los Angeles, California, USA
| | | | - Ali Khademhosseini
- Terasaki Institute for Biomedical Innovation (TIBI), Los Angeles, California, USA
| | - Jonathan Tam
- Department of Translational Research, Western University of Health Sciences, Pomona, California, USA
| | - Padmini Varadarajan
- University of California Riverside School of Medicine, Riverside, California, USA
| | - Devendra K Agrawal
- Department of Translational Research, Western University of Health Sciences, Pomona, California, USA
| | - Finosh G Thankam
- Department of Translational Research, Western University of Health Sciences, Pomona, California, USA
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5
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Buemann B. Does activation of oxytocinergic reward circuits postpone the decline of the aging brain? Front Psychol 2023; 14:1250745. [PMID: 38222845 PMCID: PMC10786160 DOI: 10.3389/fpsyg.2023.1250745] [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: 06/30/2023] [Accepted: 10/20/2023] [Indexed: 01/16/2024] Open
Abstract
Oxytocin supports reproduction by promoting sexual- and nursing behavior. Moreover, it stimulates reproductive organs by different avenues. Oxytocin is released to the blood from terminals of oxytocinergic neurons which project from the hypothalamus to the pituitary gland. Concomitantly, the dendrites of these neurons discharge oxytocin into neighboring areas of the hypothalamus. At this location it affects other neuroendocrine systems by autocrine and paracrine mechanisms. Moreover, sensory processing, affective functions, and reward circuits are influenced by oxytocinergic neurons that reach different sites in the brain. In addition to its facilitating impact on various aspects of reproduction, oxytocin is revealed to possess significant anti-inflammatory, restoring, and tranquilizing properties. This has been demonstrated both in many in-vivo and in-vitro studies. The oxytocin system may therefore have the capacity to alleviate detrimental physiological- and mental stress reactions. Thus, high levels of endogenous oxytocin may counteract inadequate inflammation and malfunctioning of neurons and supportive cells in the brain. A persistent low-grade inflammation increasing with age-referred to as inflammaging-may lead to a cognitive decline but may also predispose to neurodegenerative diseases such as Alzheimer's and Parkinson. Interestingly, animal studies indicate that age-related destructive processes in the body can be postponed by techniques that preserve immune- and stem cell functions in the hypothalamus. It is argued in this article that sexual activity-by its stimulating impact on the oxytocinergic activity in many regions of the brain-has the capacity to delay the onset of age-related cerebral decay. This may also postpone frailty and age-associated diseases in the body. Finally, oxytocin possesses neuroplastic properties that may be applied to expand sexual reward. The release of oxytocin may therefore be further potentiated by learning processes that involves oxytocin itself. It may therefore be profitable to raise the consciousness about the potential health benefits of sexual activity particularly among the seniors.
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Scalise M, Marino F, Salerno L, Amato N, Quercia C, Siracusa C, Filardo A, Chiefalo A, Pagano L, Misdea G, Salerno N, De Angelis A, Urbanek K, Viglietto G, Torella D, Cianflone E. Adult Multipotent Cardiac Progenitor-Derived Spheroids: A Reproducible Model of In Vitro Cardiomyocyte Commitment and Specification. Cells 2023; 12:1793. [PMID: 37443827 PMCID: PMC10341123 DOI: 10.3390/cells12131793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/16/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023] Open
Abstract
BACKGROUND Three-dimensional cell culture systems hold great promise for bridging the gap between in vitro cell-based model systems and small animal models to study tissue biology and disease. Among 3D cell culture systems, stem-cell-derived spheroids have attracted significant interest as a strategy to better mimic in vivo conditions. Cardiac stem cell/progenitor (CSC)-derived spheroids (CSs) provide a relevant platform for cardiac regeneration. METHODS We compared three different cell culture scaffold-free systems, (i) ultra-low attachment plates, (ii) hanging drops (both requiring a 2D/3D switch), and (iii) agarose micro-molds (entirely 3D), for CSC-derived CS formation and their cardiomyocyte commitment in vitro. RESULTS The switch from a 2D to a 3D culture microenvironment per se guides cell plasticity and myogenic differentiation within CS and is necessary for robust cardiomyocyte differentiation. On the contrary, 2D monolayer CSC cultures show a significant reduced cardiomyocyte differentiation potential compared to 3D CS culture. Forced aggregation into spheroids using hanging drop improves CS myogenic differentiation when compared to ultra-low attachment plates. Performing CS formation and myogenic differentiation exclusively in 3D culture using agarose micro-molds maximizes the cardiomyocyte yield. CONCLUSIONS A 3D culture system instructs CS myogenic differentiation, thus representing a valid model that can be used to study adult cardiac regenerative biology.
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Affiliation(s)
- Mariangela Scalise
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (M.S.); (F.M.); (L.S.); (A.C.); (G.M.); (N.S.); (G.V.)
| | - Fabiola Marino
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (M.S.); (F.M.); (L.S.); (A.C.); (G.M.); (N.S.); (G.V.)
| | - Luca Salerno
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (M.S.); (F.M.); (L.S.); (A.C.); (G.M.); (N.S.); (G.V.)
| | - Nunzia Amato
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (N.A.); (C.Q.); (C.S.); (A.F.); (L.P.)
| | - Claudia Quercia
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (N.A.); (C.Q.); (C.S.); (A.F.); (L.P.)
| | - Chiara Siracusa
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (N.A.); (C.Q.); (C.S.); (A.F.); (L.P.)
| | - Andrea Filardo
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (N.A.); (C.Q.); (C.S.); (A.F.); (L.P.)
| | - Antonio Chiefalo
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (M.S.); (F.M.); (L.S.); (A.C.); (G.M.); (N.S.); (G.V.)
| | - Loredana Pagano
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (N.A.); (C.Q.); (C.S.); (A.F.); (L.P.)
| | - Giuseppe Misdea
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (M.S.); (F.M.); (L.S.); (A.C.); (G.M.); (N.S.); (G.V.)
| | - Nadia Salerno
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (M.S.); (F.M.); (L.S.); (A.C.); (G.M.); (N.S.); (G.V.)
| | - Antonella De Angelis
- Department of Experimental Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy;
| | - Konrad Urbanek
- Department of Molecular Medicine and Medical Biotechnology, Federico II University, 88121 Naples, Italy;
| | - Giuseppe Viglietto
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (M.S.); (F.M.); (L.S.); (A.C.); (G.M.); (N.S.); (G.V.)
| | - Daniele Torella
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy; (M.S.); (F.M.); (L.S.); (A.C.); (G.M.); (N.S.); (G.V.)
| | - Eleonora Cianflone
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy; (N.A.); (C.Q.); (C.S.); (A.F.); (L.P.)
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7
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Petrocelli G, Abruzzo PM, Pampanella L, Tassinari R, Marini S, Zamagni E, Ventura C, Facchin F, Canaider S. Oxytocin Modulates Osteogenic Commitment in Human Adipose-Derived Stem Cells. Int J Mol Sci 2023; 24:10813. [PMID: 37445991 DOI: 10.3390/ijms241310813] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 06/23/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Human adipose-derived stem cells (hASCs) are commonly harvested in minimally invasive contexts with few ethical concerns, and exhibit self-renewal, multi-lineage differentiation, and trophic signaling that make them attractive candidates for cell therapy approaches. The identification of natural molecules that can modulate their biological properties is a challenge for many researchers. Oxytocin (OXT) is a neurohypophyseal hormone that plays a pivotal role in the regulation of mammalian behavior, and is involved in health and well-being processes. Here, we investigated the role of OXT on hASC proliferation, migratory ability, senescence, and autophagy after a treatment of 72 h; OXT did not affect hASC proliferation and migratory ability. Moreover, we observed an increase in SA-β-galactosidase activity, probably related to the promotion of the autophagic process. In addition, the effects of OXT were evaluated on the hASC differentiation ability; OXT promoted osteogenic differentiation in a dose-dependent manner, as demonstrated by Alizarin red staining and gene/protein expression analysis, while it did not affect or reduce adipogenic differentiation. We also observed an increase in the expression of autophagy marker genes at the beginning of the osteogenic process in OXT-treated hASCs, leading us to hypothesize that OXT could promote osteogenesis in hASCs by modulating the autophagic process.
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Affiliation(s)
- Giovannamaria Petrocelli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Provvidenza Maria Abruzzo
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Luca Pampanella
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | | | - Serena Marini
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Elena Zamagni
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", 40138 Bologna, Italy
| | - Carlo Ventura
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
- National Laboratory of Molecular Biology and Stem Cell Bioengineering of the National Institute of Biostructures and Biosystems (NIBB) c/o Eldor Lab, Via Corticella 183, 40129 Bologna, Italy
| | - Federica Facchin
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Silvia Canaider
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
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Bryl R, Nawrocki MJ, Jopek K, Kaczmarek M, Bukowska D, Antosik P, Mozdziak P, Zabel M, Dzięgiel P, Kempisty B. Transcriptomic Characterization of Genes Regulating the Stemness in Porcine Atrial Cardiomyocytes during Primary In Vitro Culture. Genes (Basel) 2023; 14:1223. [PMID: 37372403 PMCID: PMC10297922 DOI: 10.3390/genes14061223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/01/2023] [Accepted: 06/02/2023] [Indexed: 06/29/2023] Open
Abstract
Heart failure remains a major cause of death worldwide. There is a need to establish new management options as current treatment is frequently suboptimal. Clinical approaches based on autologous stem cell transplant is potentially a good alternative. The heart was long considered an organ unable to regenerate and renew. However, several reports imply that it may possess modest intrinsic regenerative potential. To allow for detailed characterization of cell cultures, whole transcriptome profiling was performed after 0, 7, 15, and 30 days of in vitro cell cultures (IVC) from the right atrial appendage and right atrial wall utilizing microarray technology. In total, 4239 differentially expressed genes (DEGs) with ratio > abs |2| and adjusted p-value ≤ 0.05 for the right atrial wall and 4662 DEGs for the right atrial appendage were identified. It was shown that a subset of DEGs, which have demonstrated some regulation of expression levels with the duration of the cell culture, were enriched in the following GO BP (Gene Ontology Biological Process) terms: "stem cell population maintenance" and "stem cell proliferation". The results were validated by RT-qPCR. The establishment and detailed characterization of in vitro culture of myocardial cells may be important for future applications of these cells in heart regeneration processes.
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Affiliation(s)
- Rut Bryl
- Section of Regenerative Medicine and Cancer Research, Natural Sciences Club, Faculty of Biology, Adam Mickiewicz University, Poznań, 61-614 Poznan, Poland;
| | - Mariusz J. Nawrocki
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland;
| | - Karol Jopek
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland;
| | - Mariusz Kaczmarek
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, 61-866 Poznan, Poland;
- Gene Therapy Laboratory, Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Centre, 61-866 Poznan, Poland
| | - Dorota Bukowska
- Department of Diagnostics and Clinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland;
| | - Paweł Antosik
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland;
| | - Paul Mozdziak
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA;
- Physiology Graduate Faculty, North Carolina State University, Raleigh, NC 27695, USA
| | - Maciej Zabel
- Department of Human Morphology and Embryology, Division of Histology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland; (M.Z.); (P.D.)
- Division of Anatomy and Histology, University of Zielona Góra, 65-046 Zielona Góra, Poland
| | - Piotr Dzięgiel
- Department of Human Morphology and Embryology, Division of Histology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland; (M.Z.); (P.D.)
| | - Bartosz Kempisty
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland;
- Physiology Graduate Faculty, North Carolina State University, Raleigh, NC 27695, USA
- Department of Human Morphology and Embryology, Division of Anatomy, Wroclaw Medical University, 50-367 Wroclaw, Poland
- Department of Obstetrics and Gynaecology, University Hospital and Masaryk University, 62500 Brno, Czech Republic
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9
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Wang J, An M, Haubner BJ, Penninger JM. Cardiac regeneration: Options for repairing the injured heart. Front Cardiovasc Med 2023; 9:981982. [PMID: 36712238 PMCID: PMC9877631 DOI: 10.3389/fcvm.2022.981982] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 12/29/2022] [Indexed: 01/13/2023] Open
Abstract
Cardiac regeneration is one of the grand challenges in repairing injured human hearts. Numerous studies of signaling pathways and metabolism on cardiac development and disease pave the way for endogenous cardiomyocyte regeneration. New drug delivery approaches, high-throughput screening, as well as novel therapeutic compounds combined with gene editing will facilitate the development of potential cell-free therapeutics. In parallel, progress has been made in the field of cell-based therapies. Transplantation of human pluripotent stem cell (hPSC)-derived cardiomyocytes (hPSC-CMs) can partially rescue the myocardial defects caused by cardiomyocyte loss in large animals. In this review, we summarize current cell-based and cell-free regenerative therapies, discuss the importance of cardiomyocyte maturation in cardiac regenerative medicine, and envision new ways of regeneration for the injured heart.
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Affiliation(s)
- Jun Wang
- Department of Medical Genetics, Life Sciences Institute, The University of British Columbia, Vancouver, BC, Canada
| | - Meilin An
- Department of Medical Genetics, Life Sciences Institute, The University of British Columbia, Vancouver, BC, Canada
| | - Bernhard Johannes Haubner
- Department of Internal Medicine III (Cardiology and Angiology), Innsbruck Medical University, Innsbruck, Austria
- Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland
| | - Josef M. Penninger
- Department of Medical Genetics, Life Sciences Institute, The University of British Columbia, Vancouver, BC, Canada
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences, VBC – Vienna BioCenter, Vienna, Austria
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10
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Seara FAC, Maciel L, Kasai-Brunswick TH, Nascimento JHM, Campos-de-Carvalho AC. Extracellular Vesicles and Cardiac Aging. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1418:33-56. [PMID: 37603271 DOI: 10.1007/978-981-99-1443-2_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/22/2023]
Abstract
Global population aging is a major challenge to health and socioeconomic policies. The prevalence of diseases progressively increases with aging, with cardiovascular disease being the major cause of mortality among elderly people. The allostatic overload imposed by the accumulation of cardiac senescent cells has been suggested to play a pivotal role in the aging-related deterioration of cardiovascular function. Senescent cells exhibit intrinsic disorders and release a senescence-associated secretory phenotype (SASP). Most of these SASP compounds and damaged molecules are released from senescent cells by extracellular vesicles (EVs). Once secreted, these EVs can be readily incorporated by recipient neighboring cells and elicit cellular damage or otherwise can promote extracellular matrix remodeling. This has been associated with the development of cardiac dysfunction, fibrosis, and vascular calcification, among others. The molecular signature of these EVs is highly variable and might provide important information for the development of aging-related biomarkers. Conversely, EVs released by the stem and progenitor cells can exert a rejuvenating effect, raising the possibility of future anti-aging therapies.
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Affiliation(s)
- Fernando A C Seara
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- Department of Physiological Sciences, Institute of Health and Biological Sciences, Federal Rural University of Rio de Janeiro, Seropédica, Brazil
| | - Leonardo Maciel
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- Federal University of Rio de Janeiro, Campus Professor Geraldo, Duque de Caxias, Brazil
| | - Tais Hanae Kasai-Brunswick
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- National Center of Structural Biology and Bioimaging, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Jose H M Nascimento
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
- Laboratory of Cardiac Electrophysiology, Carlos Chagas Filho Institute of Biophysics, Health Sciences Centre, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
| | - Antonio C Campos-de-Carvalho
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- National Center of Structural Biology and Bioimaging, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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11
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Kanda M, Nagai T, Kondo N, Matsuura K, Akazawa H, Komuro I, Kobayashi Y. Pericardial Grafting of Cardiac Progenitor Cells in Self-Assembling Peptide Scaffold Improves Cardiac Function After Myocardial Infarction. Cell Transplant 2023; 32:9636897231174078. [PMID: 37191272 PMCID: PMC10192947 DOI: 10.1177/09636897231174078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/03/2023] [Accepted: 04/19/2023] [Indexed: 05/17/2023] Open
Abstract
Many studies have explored cardiac progenitor cell (CPC) therapy for heart disease. However, optimal scaffolds are needed to ensure the engraftment of transplanted cells. We produced a three-dimensional hydrogel scaffold (CPC-PRGmx) in which high-viability CPCs were cultured for up to 8 weeks. CPC-PRGmx contained an RGD peptide-conjugated self-assembling peptide with insulin-like growth factor-1 (IGF-1). Immediately after creating myocardial infarction (MI), we transplanted CPC-PRGmx into the pericardial space on to the surface of the MI area. Four weeks after transplantation, red fluorescent protein-expressing CPCs and in situ hybridization analysis in sex-mismatched transplantations revealed the engraftment of CPCs in the transplanted scaffold (which was cellularized with host cells). The average scar area of the CPC-PRGmx-treated group was significantly smaller than that of the non-treated group (CPC-PRGmx-treated group = 46 ± 5.1%, non-treated MI group = 59 ± 4.5%; p < 0.05). Echocardiography showed that the transplantation of CPC-PRGmx improved cardiac function and attenuated cardiac remodeling after MI. The transplantation of CPCs-PRGmx promoted angiogenesis and inhibited apoptosis, compared to the untreated MI group. CPCs-PRGmx secreted more vascular endothelial growth factor than CPCs cultured on two-dimensional dishes. Genetic fate mapping revealed that CPC-PRGmx-treated mice had more regenerated cardiomyocytes than non-treated mice in the MI area (CPC-PRGmx-treated group = 0.98 ± 0.25%, non-treated MI group = 0.25 ± 0.04%; p < 0.05). Our findings reveal the therapeutic potential of epicardial-transplanted CPC-PRGmx. Its beneficial effects may be mediated by sustainable cell viability, paracrine function, and the enhancement of de novo cardiomyogenesis.
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Affiliation(s)
- Masato Kanda
- Department of Cardiovascular Medicine,
Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Toshio Nagai
- Department of Cardiology, Chemotherapy
Research Institute, KAKEN Hospital, International University of Health and Welfare,
Ichikawa-shi, Japan
| | - Naomichi Kondo
- Department of Cardiovascular Medicine,
Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Katsuhisa Matsuura
- Institute of Advanced Biomedical
Engineering and Science, Tokyo Women’s Medical University, Tokyo, Japan
- Department of Cardiology, Tokyo Women’s
Medical University, Tokyo, Japan
| | - Hiroshi Akazawa
- Department of Cardiovascular Medicine,
Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Issei Komuro
- Department of Cardiovascular Medicine,
Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoshio Kobayashi
- Department of Cardiovascular Medicine,
Graduate School of Medicine, Chiba University, Chiba, Japan
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12
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Höving AL, Schmidt KE, Kaltschmidt B, Kaltschmidt C, Knabbe C. The Role of Blood-Derived Factors in Protection and Regeneration of Aged Tissues. Int J Mol Sci 2022; 23:ijms23179626. [PMID: 36077021 PMCID: PMC9455681 DOI: 10.3390/ijms23179626] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/17/2022] [Accepted: 08/19/2022] [Indexed: 12/02/2022] Open
Abstract
Tissue regeneration substantially relies on the functionality of tissue-resident endogenous adult stem cell populations. However, during aging, a progressive decline in organ function and regenerative capacities impedes endogenous repair processes. Especially the adult human heart is considered as an organ with generally low regenerative capacities. Interestingly, beneficial effects of systemic factors carried by young blood have been described in diverse organs including the heart, brain and skeletal muscle of the murine system. Thus, the interest in young blood or blood components as potential therapeutic agents to target age-associated malignancies led to a wide range of preclinical and clinical research. However, the translation of promising results from the murine to the human system remains difficult. Likewise, the establishment of adequate cellular models could help to study the effects of human blood plasma on the regeneration of human tissues and particularly the heart. Facing this challenge, this review describes the current knowledge of blood plasma-mediated protection and regeneration of aging tissues. The current status of preclinical and clinical research examining blood borne factors that act in stem cell-based tissue maintenance and regeneration is summarized. Further, examples of cellular model systems for a more detailed examination of selected regulatory pathways are presented.
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Affiliation(s)
- Anna L. Höving
- Heart and Diabetes Centre NRW, Institute for Laboratory and Transfusion Medicine, Ruhr-University Bochum, 32545 Bad Oeynhausen, Germany
- Department of Cell Biology, Faculty of Biology, Bielefeld University, 33615 Bielefeld, Germany
- Correspondence:
| | - Kazuko E. Schmidt
- Heart and Diabetes Centre NRW, Institute for Laboratory and Transfusion Medicine, Ruhr-University Bochum, 32545 Bad Oeynhausen, Germany
- Department of Cell Biology, Faculty of Biology, Bielefeld University, 33615 Bielefeld, Germany
| | - Barbara Kaltschmidt
- AG Molecular Neurobiology, Faculty of Biology, Bielefeld University, 33615 Bielefeld, Germany
| | - Christian Kaltschmidt
- Department of Cell Biology, Faculty of Biology, Bielefeld University, 33615 Bielefeld, Germany
| | - Cornelius Knabbe
- Heart and Diabetes Centre NRW, Institute for Laboratory and Transfusion Medicine, Ruhr-University Bochum, 32545 Bad Oeynhausen, Germany
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13
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Buemann B. Oxytocin Release: A Remedy for Cerebral Inflammaging. Curr Aging Sci 2022; 15:218-228. [PMID: 35431008 DOI: 10.2174/1874609815666220414104832] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 12/22/2021] [Accepted: 02/11/2022] [Indexed: 06/14/2023]
Abstract
Oxytocin facilitates reproduction both by physiological and behavioral mechanisms. Oxytocinergic neurons emerging from the hypothalamus release oxytocin from the pituitary gland to the blood by axonal discharge to regulate reproductive organs. However, at the same time, oxytocin is secreted into neighboring areas of the hypothalamus from the dendrites of these neurons. Here, the peptide acts by autocrine and paracrine mechanisms to influence other neuroendocrine systems. Furthermore, oxytocinergic neurons project to many different locations in the brain, where they affect sensory processing, affective functions, and reward. Additional to its regulatory role, significant anti-inflammatory and restoring effects of oxytocin have been reported from many invivo and in-vitro studies. The pervasive property of the oxytocin system may enable it generally to dampen stress reactions both peripherally and centrally, and protect neurons and supportive cells from inadequate inflammation and malfunctioning. Animal experiments have documented the importance of preserving immune- and stem cell functions in the hypothalamus to impede age-related destructive processes of the body. Sexual reward has a profound stimulating impact on the oxytocinergic activity, and the present article therefore presents the hypothesis that frequent sexual activity and gratigying social experiance may postpone the onset of frailty and age-associated diseases by neural protection from the bursts of oxytocin. Furthermore, suggestions are given how the neuroplastic properties of oxytocin may be utilized to enhance sexual reward by learning processes in order to further reinforce the release of this peptide.
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Affiliation(s)
- Benjamin Buemann
- Retired. Copenhagen, Denmark. Previous Affiliation: Research Department of Human Nutrition, The Royal Veterinary and Agricultural University, Copenhagen, Denmark
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14
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Salerno N, Salerno L, Marino F, Scalise M, Chiefalo A, Panuccio G, De Angelis A, Cianflone E, Urbanek K, Torella D. Myocardial regeneration protocols towards the routine clinical scenario: An unseemly path from bench to bedside. EClinicalMedicine 2022; 50:101530. [PMID: 35799845 PMCID: PMC9253597 DOI: 10.1016/j.eclinm.2022.101530] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 05/31/2022] [Accepted: 06/06/2022] [Indexed: 12/11/2022] Open
Abstract
UNLABELLED Heart failure secondary to cardiomyocyte loss and/or dysfunction is the number one killer worldwide. The field of myocardial regeneration with its far-reaching primary goal of cardiac remuscularization and its hard-to-accomplish translation from bench to bedside, has been filled with ups and downs, steps forward and steps backward, controversies galore and, unfortunately, scientific scandals. Despite the present morass in which cardiac remuscularization is stuck in, the search for clinically effective regenerative approaches remains keenly active. Starting with a concise overview of the still highly debated regenerative capacity of the adult mammalian heart, we focus on the main interventions, that have reached or are close to clinical use, critically discussing key findings, successes, and failures. Finally, some promising and innovative approaches for myocardial repair/regeneration still at the pre-clinical stage are discussed to offer a holistic view on the future of myocardial repair/regeneration for the prevention/management of heart failure in the clinical scenario. FUNDING This research was funded by Grants from the Ministry of University and Research PRIN2015 2015ZTT5KB_004; PRIN2017NKB2N4_005; PON-AIM - 1829805-2.
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Affiliation(s)
- Nadia Salerno
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100, Catanzaro, Italy
| | - Luca Salerno
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100, Catanzaro, Italy
| | - Fabiola Marino
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100, Catanzaro, Italy
| | - Mariangela Scalise
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100, Catanzaro, Italy
| | - Antonio Chiefalo
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100, Catanzaro, Italy
| | - Giuseppe Panuccio
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100, Catanzaro, Italy
| | - Antonella De Angelis
- Department of Experimental Medicine, University of Campania “L. Vanvitelli”, 80138 Naples, Italy
| | - Eleonora Cianflone
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100, Catanzaro, Italy
| | - Konrad Urbanek
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100, Catanzaro, Italy
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, 80125, Naples, Italy
| | - Daniele Torella
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100, Catanzaro, Italy
- Corresponding author.
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15
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Mendoza A, Karch J. Keeping the beat against time: Mitochondrial fitness in the aging heart. FRONTIERS IN AGING 2022; 3:951417. [PMID: 35958271 PMCID: PMC9360554 DOI: 10.3389/fragi.2022.951417] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 06/30/2022] [Indexed: 11/21/2022]
Abstract
The process of aging strongly correlates with maladaptive architectural, mechanical, and biochemical alterations that contribute to the decline in cardiac function. Consequently, aging is a major risk factor for the development of heart disease, the leading cause of death in the developed world. In this review, we will summarize the classic and recently uncovered pathological changes within the aged heart with an emphasis on the mitochondria. Specifically, we describe the metabolic changes that occur in the aging heart as well as the loss of mitochondrial fitness and function and how these factors contribute to the decline in cardiomyocyte number. In addition, we highlight recent pharmacological, genetic, or behavioral therapeutic intervention advancements that may alleviate age-related cardiac decline.
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Affiliation(s)
- Arielys Mendoza
- Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, United States
- Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, United States
| | - Jason Karch
- Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, United States
- Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, United States
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16
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Omatsu-Kanbe M, Fukunaga R, Mi X, Matsuura H. Atypically Shaped Cardiomyocytes (ACMs): The Identification, Characterization and New Insights into a Subpopulation of Cardiomyocytes. Biomolecules 2022; 12:biom12070896. [PMID: 35883452 PMCID: PMC9313223 DOI: 10.3390/biom12070896] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/17/2022] [Accepted: 06/24/2022] [Indexed: 02/01/2023] Open
Abstract
In the adult mammalian heart, no data have yet shown the existence of cardiomyocyte-differentiable stem cells that can be used to practically repair the injured myocardium. Atypically shaped cardiomyocytes (ACMs) are found in cultures of the cardiomyocyte-removed fraction obtained from cardiac ventricles from neonatal to aged mice. ACMs are thought to be a subpopulation of cardiomyocytes or immature cardiomyocytes, most closely resembling cardiomyocytes due to their spontaneous beating, well-organized sarcomere and the expression of cardiac-specific proteins, including some fetal cardiac gene proteins. In this review, we focus on the characteristics of ACMs compared with ventricular myocytes and discuss whether these cells can be substitutes for damaged cardiomyocytes. ACMs reside in the interstitial spaces among ventricular myocytes and survive under severely hypoxic conditions fatal to ventricular myocytes. ACMs have not been observed to divide or proliferate, similar to cardiomyocytes, but they maintain their ability to fuse with each other. Thus, it is worthwhile to understand the role of ACMs and especially how these cells perform cell fusion or function independently in vivo. It may aid in the development of new approaches to cell therapy to protect the injured heart or the clarification of the pathogenesis underlying arrhythmia in the injured heart.
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17
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Li X, Wang X, He P, Bennett E, Haggard E, Ma J, Cai C. Mitochondrial Membrane Potential Identifies a Subpopulation of Mesenchymal Progenitor Cells to Promote Angiogenesis and Myocardial Repair. Cells 2022; 11:1713. [PMID: 35626749 PMCID: PMC9139404 DOI: 10.3390/cells11101713] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/18/2022] [Accepted: 05/19/2022] [Indexed: 12/10/2022] Open
Abstract
Identifying effective donor cells is one of obstacles that limits cell therapy for heart disease. In this study, we sorted a subpopulation of human mesenchymal progenitor cells (hMPCs) from the right atrial appendage using the low mitochondrial membrane potential. Compared to the non-sorted cells, hMPCs hold the capacity for stemness and enrich mesenchymal stem cell markers. The hMPCs display better ability for survival, faster proliferation, less production of reactive oxygen species (ROS), and greater release of cytoprotective cytokines. The hMPCs exhibit decreased expression of senescence genes and increased expression of anti-apoptotic and antioxidant genes. Intramyocardial injection of hMPCs into the infarcted heart resulted in increased left ventricular ejection fraction and reduced cardiac remodeling and infarct size in the group of animals receiving hMPCs. Both in vitro and in vivo studies indicated hMPCs have the potential to differentiate into endothelial cells and smooth muscle cells. Immunohistochemistry staining showed that cell therapy with hMPCs enhances cardiac vascular regeneration and cardiac proliferation, and decreases cardiac cell apoptosis, which is associated with the increased secretion of cytoprotective and pro-angiogenic cytokines. Overall, we discovered a subpopulation of human mesenchymal progenitor cells via their low mitochondrial membrane potential, which might provide an alternative donor cell source for cellular therapy for ischemic heart disease.
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Affiliation(s)
- Xiuchun Li
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (X.L.); (X.W.); (E.H.); (J.M.)
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY 12208, USA;
| | - Xiaoliang Wang
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (X.L.); (X.W.); (E.H.); (J.M.)
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY 12208, USA;
| | - Pan He
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY 12208, USA;
| | - Edward Bennett
- Division of Cardiothoracic Surgery, Albany Medical Center, Albany, NY 12208, USA;
| | - Erin Haggard
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (X.L.); (X.W.); (E.H.); (J.M.)
| | - Jianjie Ma
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (X.L.); (X.W.); (E.H.); (J.M.)
| | - Chuanxi Cai
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (X.L.); (X.W.); (E.H.); (J.M.)
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY 12208, USA;
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18
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MicroRNAs and exosomes: Cardiac stem cells in heart diseases. Pathol Res Pract 2021; 229:153701. [PMID: 34872024 DOI: 10.1016/j.prp.2021.153701] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 11/09/2021] [Accepted: 11/18/2021] [Indexed: 12/20/2022]
Abstract
Treating cardiovascular diseases with cardiac stem cells (CSCs) is a valid treatment among various stem cell-based therapies. With supplying the physiological need for cardiovascular cells as their main function, under pathological circumstances, CSCs can also reproduce the myocardial cells. Although studies have identified many of CSCs' functions, our knowledge of molecular pathways that regulate these functions is not complete enough. Either physiological or pathological studies have shown, stem cells proliferation and differentiation could be regulated by microRNAs (miRNAs). How miRNAs regulate CSC behavior is an interesting area of research that can help us study and control the function of these cells in vitro; an achievement that may be beneficial for patients with cardiovascular diseases. The secretome of stem and progenitor cells has been studied and it has been determined that exosomes are the main source of their secretion which are very small vesicles at the nanoscale and originate from endosomes, which are secreted into the extracellular space and act as key signaling organelles in intercellular communication. Mesenchymal stem cells, cardiac-derived progenitor cells, embryonic stem cells, induced pluripotent stem cells (iPSCs), and iPSC-derived cardiomyocytes release exosomes that have been shown to have cardioprotective, immunomodulatory, and reparative effects. Herein, we summarize the regulation roles of miRNAs and exosomes in cardiac stem cells.
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19
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Kasai-Brunswick TH, Carvalho AB, Campos de Carvalho AC. Stem cell therapies in cardiac diseases: Current status and future possibilities. World J Stem Cells 2021; 13:1231-1247. [PMID: 34630860 PMCID: PMC8474720 DOI: 10.4252/wjsc.v13.i9.1231] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 07/26/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular diseases represent the world’s leading cause of death. In this heterogeneous group of diseases, ischemic cardiomyopathies are the most devastating and prevalent, estimated to cause 17.9 million deaths per year. Despite all biomedical efforts, there are no effective treatments that can replace the myocytes lost during an ischemic event or progression of the disease to heart failure. In this context, cell therapy is an emerging therapeutic alternative to treat cardiovascular diseases by cell administration, aimed at cardiac regeneration and repair. In this review, we will cover more than 30 years of cell therapy in cardiology, presenting the main milestones and drawbacks in the field and signaling future challenges and perspectives. The outcomes of cardiac cell therapies are discussed in three distinct aspects: The search for remuscularization by replacement of lost cells by exogenous adult cells, the endogenous stem cell era, which pursued the isolation of a progenitor with the ability to induce heart repair, and the utilization of pluripotent stem cells as a rich and reliable source of cardiomyocytes. Acellular therapies using cell derivatives, such as microvesicles and exosomes, are presented as a promising cell-free therapeutic alternative.
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Affiliation(s)
- Tais Hanae Kasai-Brunswick
- National Center of Structural Biology and Bioimaging, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Adriana Bastos Carvalho
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Antonio Carlos Campos de Carvalho
- National Center of Structural Biology and Bioimaging, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
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20
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Fanni D, Gerosa C, Loddo C, Castagnola M, Fanos V, Zaffanello M, Faa G. Stem/progenitor cells in fetuses and newborns: overview of immunohistochemical markers. CELL REGENERATION (LONDON, ENGLAND) 2021; 10:22. [PMID: 34219203 PMCID: PMC8255250 DOI: 10.1186/s13619-021-00084-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 04/12/2021] [Indexed: 12/26/2022]
Abstract
Microanatomy of the vast majority of human organs at birth is characterized by marked differences as compared to adult organs, regarding their architecture and the cell types detectable at histology. In preterm neonates, these differences are even more evident, due to the lower level of organ maturation and to ongoing cell differentiation. One of the most remarkable finding in preterm tissues is the presence of huge amounts of stem/progenitor cells in multiple organs, including kidney, brain, heart, adrenals, and lungs. In other organs, such as liver, the completely different burden of cell types in preterm infants is mainly related to the different function of the liver during gestation, mainly focused on hematopoiesis, a function that is taken by bone marrow after birth. Our preliminary studies showed that the antigens expressed by stem/progenitors differ significantly from one organ to the next. Moreover, within each developing human tissue, reactivity for different stem cell markers also changes during gestation, according with the multiple differentiation steps encountered by each progenitor during development. A better knowledge of stem/progenitor cells of preterms will allow neonatologists to boost preterm organ maturation, favoring the differentiation of the multiple cells types that characterize each organ in at term neonates.
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Affiliation(s)
- D Fanni
- Division of Pathology, University Hospital San Giovanni Di Dio, via Ospedale, 54, Cagliari, Italy.,Department of Biology, College of Science and Technology, Temple University, Phidelphia, USA
| | - C Gerosa
- Division of Pathology, University Hospital San Giovanni Di Dio, via Ospedale, 54, Cagliari, Italy.,Department of Biology, College of Science and Technology, Temple University, Phidelphia, USA
| | - C Loddo
- Neonatal Intensive Care Unit, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy
| | - M Castagnola
- Laboratory of Biochemistry and Metabolomics, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - V Fanos
- Neonatal Intensive Care Unit, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy
| | - M Zaffanello
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Piazzale Stefani, 1, I-37126, Verona, Italy.
| | - G Faa
- Division of Pathology, University Hospital San Giovanni Di Dio, via Ospedale, 54, Cagliari, Italy.,Department of Biology, College of Science and Technology, Temple University, Phidelphia, USA
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21
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Kiuchi S, Usami A, Shimoyama T, Otsuka F, Suzuki S, Ono K. Generation of cardiomyocytes by atrioventricular node cells in long-term cultures. Biochem Biophys Rep 2021; 26:101018. [PMID: 34095551 PMCID: PMC8166639 DOI: 10.1016/j.bbrep.2021.101018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 05/06/2021] [Accepted: 05/06/2021] [Indexed: 11/08/2022] Open
Abstract
Turnover of cardiac pacemaker cells may occur during the lifetime of the body, and we recently raised the hypothesis that specialized cardiac cells have in common the potential to generate cardiomyocytes from fibroblasts. To examine this hypothesis, we analyzed the ability of atrioventricular node cells (AVNCs) to generate functional cardiomyocytes in long-term culture. AVNCs were isolated from adult guinea pig hearts and cultured for up to three weeks. Under phase-contrast microscopic observation over time, it was found that within a week, a number of fibroblasts gathered around the AVNCs and formed cell clusters, and thereafter the cell clusters started to beat spontaneously. The nascent cell clusters expanded their area gradually by three weeks in culture and expressed specific cardiac genes and proteins. Maturation of newly formed cardiomyocytes seems to be slow in cultures of AVNCs compared with those of sinoatrial node cells. Stimulation of muscarinic receptors with acetylcholine induced a beating rate decrease which was blocked by atropine, and activation of adenylate cyclase activity with forskolin increased the beat rate, while stimulation of beta adrenoceptors by isoproterenol had no effect. These results indicate that AVNCs form a cluster of cells with properties of functional cardiomyocytes and provide evidence to support the hypothesis.
Atrioventricular node cells formed spontaneously beating cell clusters in culture. The cell clusters expressed specific cardiac genes and proteins. The properties of the cell clusters depended on their spontaneous beating rate. Specialized cardiac cells may in common have the ability to generate cardiomyocytes.
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Affiliation(s)
- Shigeki Kiuchi
- Laboratory of Molecular Physiology and Pharmacology, Faculty of Pharma-Sciences, Teikyo University, Itabashi-Ku, Tokyo, 173-8605, Japan
| | - Akino Usami
- Laboratory of Molecular Physiology and Pharmacology, Faculty of Pharma-Sciences, Teikyo University, Itabashi-Ku, Tokyo, 173-8605, Japan
| | - Tae Shimoyama
- Laboratory of Molecular Environmental Health, Faculty of Pharma-Sciences, Teikyo University, Itabashi-Ku, Tokyo, 173-8605, Japan
| | - Fuminori Otsuka
- Laboratory of Molecular Environmental Health, Faculty of Pharma-Sciences, Teikyo University, Itabashi-Ku, Tokyo, 173-8605, Japan
| | - Shigeto Suzuki
- Laboratory of Molecular Physiology and Pharmacology, Faculty of Pharma-Sciences, Teikyo University, Itabashi-Ku, Tokyo, 173-8605, Japan
| | - Kageyoshi Ono
- Laboratory of Molecular Physiology and Pharmacology, Faculty of Pharma-Sciences, Teikyo University, Itabashi-Ku, Tokyo, 173-8605, Japan
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22
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Mesenchymal Stem Cells for Cardiac Regeneration: from Differentiation to Cell Delivery. Stem Cell Rev Rep 2021; 17:1666-1694. [PMID: 33954876 DOI: 10.1007/s12015-021-10168-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/12/2021] [Indexed: 12/20/2022]
Abstract
Mesenchymal stem cells (MSCs) are so far the most widely researched stem cells in clinics and used as an experimental cellular therapy module, particularly in cardiac regeneration and repair. Ever since the discovery of cardiomyogenesis induction in MSCs, a wide variety of differentiation protocols have been extensively used in preclinical models. However, pre differentiated MSC-derived cardiomyocytes have not been used in clinical trials; highlighting discrepancies and limitations in its use as a source of derived cardiomyocytes for transplantation to improve the damaged heart function. Therefore, this review article focuses on the strategies used to derive cardiomyocytes-like cells from MSCs isolated from three widely used tissue sources and their differentiation efficiencies. We have further discussed the role of MSCs in inducing angiogenesis as a cellular precursor to endothelial cells and its secretory aspects including exosomes. We have then discussed the strategies used for delivering cells in the damaged heart and how its retention plays a critical role in the overall outcome of the therapy. We have also conversed about the scope of the local and systemic modes of delivery of MSCs and the application of biomaterials to improve the overall delivery efficacy and function. We have finally discussed the advantages and limitations of cell delivery to the heart and the future scope of MSCs in cardiac regenerative therapy.
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23
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Nomura S, Komuro I. Precision medicine for heart failure based on molecular mechanisms: The 2019 ISHR Research Achievement Award Lecture. J Mol Cell Cardiol 2021; 152:29-39. [PMID: 33275937 DOI: 10.1016/j.yjmcc.2020.11.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 11/02/2020] [Accepted: 11/24/2020] [Indexed: 10/22/2022]
Abstract
Heart failure is a leading cause of death, and the number of patients with heart failure continues to increase worldwide. To realize precision medicine for heart failure, its underlying molecular mechanisms must be elucidated. In this review summarizing the "The Research Achievement Award Lecture" of the 2019 XXIII ISHR World Congress held in Beijing, China, we would like to introduce our approaches for investigating the molecular mechanisms of cardiac hypertrophy, development, and failure, as well as discuss future perspectives.
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Affiliation(s)
- Seitaro Nomura
- Department of Cardiovascular Medicine, The University of Tokyo, Japan
| | - Issei Komuro
- Department of Cardiovascular Medicine, The University of Tokyo, Japan.
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24
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A Concise Review on Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Personalized Regenerative Medicine. Stem Cell Rev Rep 2020; 17:748-776. [PMID: 33098306 DOI: 10.1007/s12015-020-10061-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/16/2020] [Indexed: 02/07/2023]
Abstract
The induced pluripotent stem cells (iPSCs) are derived from somatic cells by using reprogramming factors such as Oct4, Sox2, Klf4, and c-Myc (OSKM) or Oct4, Sox2, Nanog and Lin28 (OSNL). They resemble embryonic stem cells (ESCs) and have the ability to differentiate into cell lineage of all three germ-layer, including cardiomyocytes (CMs). The CMs can be generated from iPSCs by inducing embryoid bodies (EBs) formation and treatment with activin A, bone morphogenic protein 4 (BMP4), and inhibitors of Wnt signaling. However, these iPSC-derived CMs are a heterogeneous population of cells and require purification and maturation to mimic the in vivo CMs. The matured CMs can be used for various therapeutic purposes in regenerative medicine by cardiomyoplasty or through the development of tissue-engineered cardiac patches. In recent years, significant advancements have been made in the isolation of iPSC and their differentiation, purification, and maturation into clinically usable CMs. Newer small molecules have also been identified to substitute the reprogramming factors for iPSC generation as well as for direct differentiation of somatic cells into CMs without an intermediary pluripotent state. This review provides a concise update on the generation of iPSC-derived CMs and their application in personalized cardiac regenerative medicine. It also discusses the current limitations and challenges in the application of iPSC-derived CMs. Graphical abstract.
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25
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McKay EC, Counts SE. Oxytocin Receptor Signaling in Vascular Function and Stroke. Front Neurosci 2020; 14:574499. [PMID: 33071746 PMCID: PMC7544744 DOI: 10.3389/fnins.2020.574499] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 08/31/2020] [Indexed: 12/13/2022] Open
Abstract
The oxytocin receptor (OXTR) is a G protein-coupled receptor with a diverse repertoire of intracellular signaling pathways, which are activated in response to binding oxytocin (OXT) and a similar nonapeptide, vasopressin. This review summarizes the cell and molecular biology of the OXTR and its downstream signaling cascades, particularly focusing on the vasoactive functions of OXTR signaling in humans and animal models, as well as the clinical applications of OXTR targeting cerebrovascular accidents.
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Affiliation(s)
- Erin C McKay
- Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, United States.,Neuroscience Program, Michigan State University, East Lansing, MI, United States
| | - Scott E Counts
- Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, United States.,Neuroscience Program, Michigan State University, East Lansing, MI, United States.,Department of Family Medicine, Michigan State University, Grand Rapids, MI, United States.,Hauenstein Neurosciences Center, Mercy Health Saint Mary's Hospital, Grand Rapids, MI, United States.,Michigan Alzheimer's Disease Research Center, Ann Arbor, MI, United States
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26
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Jankowski M, Broderick TL, Gutkowska J. The Role of Oxytocin in Cardiovascular Protection. Front Psychol 2020; 11:2139. [PMID: 32982875 PMCID: PMC7477297 DOI: 10.3389/fpsyg.2020.02139] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 07/30/2020] [Indexed: 12/13/2022] Open
Abstract
The beneficial effects of oxytocin on infarct size and functional recovery of the ischemic reperfused heart are well documented. The mechanisms for this cardioprotection are not well defined. Evidence indicates that oxytocin treatment improves cardiac work, reduces apoptosis and inflammation, and increases scar vascularization. Oxytocin-mediated cytoprotection involves the production of cGMP stimulated by local release of atrial natriuretic peptide and synthesis of nitric oxide. Treatment with oxytocin reduces the expression of proinflammatory cytokines and reduces immune cell infiltration. Oxytocin also stimulates differentiation stem cells to cardiomyocyte lineages as well as generation of endothelial and smooth muscle cells, promoting angiogenesis. The beneficial actions of oxytocin may include the increase in glucose uptake by cardiomyocytes, reduction in cardiomyocyte hypertrophy, decrease in oxidative stress, and mitochondrial protection of several cell types. In cardiac and cellular models of ischemia and reperfusion, acute administration of oxytocin at the onset of reperfusion enhances cardiomyocyte viability and function by activating Pi3K and Akt phosphorylation and downstream cellular signaling. Reperfusion injury salvage kinase and signal transducer and activator of transcription proteins cardioprotective pathways are involved. Oxytocin is cardioprotective by reducing the inflammatory response and improving cardiovascular and metabolic function. Because of its pleiotropic nature, this peptide demonstrates a clear potential for the treatment of cardiovascular pathologies. In this review, we discuss the possible cellular mechanisms of action of oxytocin involved in cardioprotection.
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Affiliation(s)
- Marek Jankowski
- Cardiovascular Biochemistry Laboratory, University of Montreal Hospital Centre, Montreal, QC, Canada.,Department of Medicine, University of Montreal, Montreal, QC, Canada
| | - Tom L Broderick
- Laboratory of Diabetes and Exercise Metabolism, Department of Physiology, College of Graduate Studies, Midwestern University, Glendale, AZ, United States
| | - Jolanta Gutkowska
- Cardiovascular Biochemistry Laboratory, University of Montreal Hospital Centre, Montreal, QC, Canada.,Department of Medicine, University of Montreal, Montreal, QC, Canada
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27
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He L, Nguyen NB, Ardehali R, Zhou B. Heart Regeneration by Endogenous Stem Cells and Cardiomyocyte Proliferation: Controversy, Fallacy, and Progress. Circulation 2020; 142:275-291. [PMID: 32687441 DOI: 10.1161/circulationaha.119.045566] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Ischemic heart disease is the leading cause of death worldwide. Myocardial infarction results in an irreversible loss of cardiomyocytes with subsequent adverse remodeling and heart failure. Identifying new sources for cardiomyocytes and promoting their formation represents a goal of cardiac biology and regenerative medicine. Within the past decade, many types of putative cardiac stem cells (CSCs) have been reported to regenerate the injured myocardium by differentiating into new cardiomyocytes. Some of these CSCs have been translated from bench to bed with reported therapeutic effectiveness. However, recent basic research studies on stem cell tracing have begun to question their fundamental biology and mechanisms of action, raising serious concerns over the myogenic potential of CSCs. We review the history of different types of CSCs within the past decade and provide an update of recent cell tracing studies that have challenged the origin and existence of CSCs. In addition to the potential role of CSCs in heart regeneration, proliferation of preexisting cardiomyocytes has recently gained more attention. This review will also evaluate the methodologic and technical aspects of past and current studies on CSCs and cardiomyocyte proliferation, with emphasis on technical strengths, advantages, and potential limitations of research approaches. While our understanding of cardiomyocyte generation and regeneration continues to evolve, it is important to address the shortcomings and inaccuracies in this field. This is best achieved by embracing technological advancements and improved methods to label single cardiomyocytes/progenitors and accurately investigate their developmental potential and fate/lineage commitment.
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Affiliation(s)
- Lingjuan He
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China (L.H., B.Z.)
| | - Ngoc B Nguyen
- Division of Cardiology, Department of Internal Medicine, David Geffen School of Medicine (N.B.N., R.A.), University of California, Los Angeles.,Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (N.B.N., R.A.), University of California, Los Angeles
| | - Reza Ardehali
- Division of Cardiology, Department of Internal Medicine, David Geffen School of Medicine (N.B.N., R.A.), University of California, Los Angeles.,Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (N.B.N., R.A.), University of California, Los Angeles
| | - Bin Zhou
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China (L.H., B.Z.).,School of Life Science and Technology, ShanghaiTech University, Shanghai, China (B.Z.).,School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China (B.Z.).,Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China (B.Z.)
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28
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Japundžić-Žigon N, Lozić M, Šarenac O, Murphy D. Vasopressin & Oxytocin in Control of the Cardiovascular System: An Updated Review. Curr Neuropharmacol 2020; 18:14-33. [PMID: 31544693 PMCID: PMC7327933 DOI: 10.2174/1570159x17666190717150501] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 06/03/2019] [Accepted: 07/06/2019] [Indexed: 01/19/2023] Open
Abstract
Since the discovery of vasopressin (VP) and oxytocin (OT) in 1953, considerable knowledge has been gathered about their roles in cardiovascular homeostasis. Unraveling VP vasoconstrictor properties and V1a receptors in blood vessels generated powerful hemostatic drugs and drugs effective in the treatment of certain forms of circulatory collapse (shock). Recognition of the key role of VP in water balance via renal V2 receptors gave birth to aquaretic drugs found to be useful in advanced stages of congestive heart failure. There are still unexplored actions of VP and OT on the cardiovascular system, both at the periphery and in the brain that may open new venues in treatment of cardiovascular diseases. After a brief overview on VP, OT and their peripheral action on the cardiovascular system, this review focuses on newly discovered hypothalamic mechanisms involved in neurogenic control of the circulation in stress and disease.
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Affiliation(s)
| | - Maja Lozić
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Olivera Šarenac
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - David Murphy
- School of Clinical Sciences, University of Bristol, Bristol, United Kingdom
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29
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Cell-based therapies for the treatment of myocardial infarction: lessons from cardiac regeneration and repair mechanisms in non-human vertebrates. Heart Fail Rev 2020; 24:133-142. [PMID: 30421074 DOI: 10.1007/s10741-018-9750-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Ischemic cardiomyopathy is the cardiovascular condition with the highest impact on the Western population. In mammals (humans included), prolonged ischemia in the ventricular walls causes the death of cardiomyocytes (myocardial infarction, MI). The loss of myocardial mass is soon compensated by the formation of a reparative, non-contractile fibrotic scar that ultimately affects heart performance. Despite the enormous clinical relevance of MI, no effective therapy is available for the long-term treatment of this condition. Moreover, since the human heart is not able to undergo spontaneous regeneration, many researchers aim at designing cell-based therapies that allow for the substitution of dead cardiomyocytes by new, functional ones. So far, the majority of such strategies rely on the injection of different progenitor/stem cells to the infarcted heart. These cardiovascular progenitors, which are expected to differentiate into cardiomyocytes de novo, seldom give rise to new cardiac muscle. In this context, the most important challenge in the field is to fully disclose the molecular and cellular mechanisms that could promote active myocardial regeneration after cardiac damage. Accordingly, we suggest that such strategy should be inspired by the unique regenerative and reparative responses displayed by non-human animal models, from the restricted postnatal myocardial regeneration abilities of the murine heart to the full ventricular regeneration of some bony fishes (e.g., zebrafish). In this review article, we will discuss about current scientific approaches to study cardiac reparative and regenerative phenomena using animal models.
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30
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Thabassum Akhtar Iqbal S, Tirupathi Pichiah PB, Raja S, Arunachalam S. Paeonol Reverses Adriamycin Induced Cardiac Pathological Remodeling through Notch1 Signaling Reactivation in H9c2 Cells and Adult Zebrafish Heart. Chem Res Toxicol 2020; 33:312-323. [PMID: 31307187 DOI: 10.1021/acs.chemrestox.9b00093] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Adriamycin is a commonly prescribed chemotherapeutic drug for a wide range of cancers. Adriamycin causes cardiotoxicity as an adverse effect that limits its clinical application in cancer treatment. Several mechanisms have been proposed to explain the toxicity it causes in heart cells. Disruption of inherent cardiac repair mechanism is the least understood mechanism of Adriamycin-induced cardiotoxicity. Adriamycin induces pathological remodeling in cardiac cells by promoting apoptosis, hypertrophy, and fibrosis. We found that Adriamycin inhibited Notch1 in a time- and dose-dependent manner in H9c2 cells. We used Paeonol, a Notch1 activator, and analyzed the markers of apoptosis, hypertrophy, and fibrosis in H9c2 cells in vitro and in adult zebrafish heart in vivo as model systems to study Adriamycin-induced cardiotoxicity. Paeonol activated Notch1 signaling and expression of its downstream target genes effectively in the Adriamycin-treated condition in vitro and in vivo. Also we detected that Notch activation using Paeonol protected the cells from apoptosis, collagen deposition, and hypertrophy response using functional assays. We conclude that Adriamycin induced cardiotoxicity by promoting the pathological cardiac remodeling through inhibition of Notch1 signaling and that the Notch1 reactivation by Paeonol protected the cells and reversed the cardiotoxicity.
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Affiliation(s)
- Syeda Thabassum Akhtar Iqbal
- School of Bio-Sciences and Technology , Vellore Institute of Technology , Vellore , Tamilnadu PIN 632014 , India
| | | | - Sudhakaran Raja
- School of Bio-Sciences and Technology , Vellore Institute of Technology , Vellore , Tamilnadu PIN 632014 , India
| | - Sankarganesh Arunachalam
- Department of Biotechnology , Kalasalingam Academy of Research and Education , Krishnankoil , Virudhunagar, Tamilnadu PIN 626126 , India
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31
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Jeong HS, Park CY, Kim JH, Joo HJ, Choi SC, Choi JH, Lim IR, Park JH, Hong SJ, Lim DS. Cardioprotective effects of genetically engineered cardiac stem cells by spheroid formation on ischemic cardiomyocytes. Mol Med 2020; 26:15. [PMID: 32005100 PMCID: PMC6995053 DOI: 10.1186/s10020-019-0128-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Accepted: 12/12/2019] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Sca-1+ cardiac stem cells and their limited proliferative potential were major limiting factors for use in various studies. METHODS Therefore, the effects of sphere genetically engineered cardiac stem cells (S-GECS) inserted with telomerase reverse transcriptase (TERT) were investigated to examine cardiomyocyte survival under hypoxic conditions. GECS was obtained from hTERT-immortalized Sca-1+ cardiac stem cell (CSC) lines, and S-GECS were generated using poly-HEMA. RESULTS The optimal conditions for S-GECS was determined to be 1052 GECS cells/mm2 and a 48 h culture period to produce spheroids. Compared to adherent-GECS (A-GECS) and S-GECS showed significantly higher mRNA expression of SDF-1α and CXCR4. S-GECS conditioned medium (CM) significantly reduced the proportion of early and late apoptotic cardiomyoblasts during CoCl2-induced hypoxic injury; however, gene silencing via CXCR4 siRNA deteriorated the protective effects of S-GECS against hypoxic injury. As downstream pathways of SDF-1α/CXCR4, the Erk and Akt signaling pathways were stimulated in the presence of S-GECS CM. S-GECS transplantation into a rat acute myocardial infarction model improved cardiac function and reduced the fibrotic area. These cardioprotective effects were confirmed to be related with the SDF-1α/CXCR4 pathway. CONCLUSIONS Our findings suggest that paracrine factors secreted from transplanted cells may protect host cardiomyoblasts in the infarcted myocardium, contributing to beneficial left ventricle (LV) remodeling after acute myocardial infarction (AMI).
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Affiliation(s)
- Han Saem Jeong
- Department of Cardiology, Cardiovascular Center, Korea University College of Medicine, Seoul, Republic of Korea
| | - Chi-Yeon Park
- Department of Cardiology, Cardiovascular Center, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jong-Ho Kim
- Department of Cardiology, Cardiovascular Center, Korea University College of Medicine, Seoul, Republic of Korea
| | - Hyung Joon Joo
- Department of Cardiology, Cardiovascular Center, Korea University College of Medicine, Seoul, Republic of Korea
| | - Seung-Cheol Choi
- Department of Cardiology, Cardiovascular Center, Korea University College of Medicine, Seoul, Republic of Korea
| | - Ji-Hyun Choi
- Department of Cardiology, Cardiovascular Center, Korea University College of Medicine, Seoul, Republic of Korea
| | - I-Rang Lim
- Department of Cardiology, Cardiovascular Center, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jae Hyoung Park
- Department of Cardiology, Cardiovascular Center, Korea University College of Medicine, Seoul, Republic of Korea
| | - Soon Jun Hong
- Department of Cardiology, Cardiovascular Center, Korea University College of Medicine, Seoul, Republic of Korea
| | - Do-Sun Lim
- Department of Cardiology, Cardiovascular Center, Korea University College of Medicine, Seoul, Republic of Korea.
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32
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Witman N, Zhou C, Grote Beverborg N, Sahara M, Chien KR. Cardiac progenitors and paracrine mediators in cardiogenesis and heart regeneration. Semin Cell Dev Biol 2019; 100:29-51. [PMID: 31862220 DOI: 10.1016/j.semcdb.2019.10.011] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 10/13/2019] [Accepted: 10/21/2019] [Indexed: 12/17/2022]
Abstract
The mammalian hearts have the least regenerative capabilities among tissues and organs. As such, heart regeneration has been and continues to be the ultimate goal in the treatment against acquired and congenital heart diseases. Uncovering such a long-awaited therapy is still extremely challenging in the current settings. On the other hand, this desperate need for effective heart regeneration has developed various forms of modern biotechnologies in recent years. These involve the transplantation of pluripotent stem cell-derived cardiac progenitors or cardiomyocytes generated in vitro and novel biochemical molecules along with tissue engineering platforms. Such newly generated technologies and approaches have been shown to effectively proliferate cardiomyocytes and promote heart repair in the diseased settings, albeit mainly preclinically. These novel tools and medicines give somehow credence to breaking down the barriers associated with re-building heart muscle. However, in order to maximize efficacy and achieve better clinical outcomes through these cell-based and/or cell-free therapies, it is crucial to understand more deeply the developmental cellular hierarchies/paths and molecular mechanisms in normal or pathological cardiogenesis. Indeed, the morphogenetic process of mammalian cardiac development is highly complex and spatiotemporally regulated by various types of cardiac progenitors and their paracrine mediators. Here we discuss the most recent knowledge and findings in cardiac progenitor cell biology and the major cardiogenic paracrine mediators in the settings of cardiogenesis, congenital heart disease, and heart regeneration.
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Affiliation(s)
- Nevin Witman
- Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | - Chikai Zhou
- Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | - Niels Grote Beverborg
- Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Makoto Sahara
- Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Surgery, Yale University School of Medicine, CT, USA.
| | - Kenneth R Chien
- Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
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33
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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
Abstract
Cardiac Progenitor Cells (CPCs) show great potential as a cell resource for restoring cardiac function in patients affected by heart disease or heart failure. CPCs are proliferative and committed to cardiac fate, capable of generating cells of all the cardiac lineages. These cells offer a significant shift in paradigm over the use of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes owing to the latter's inability to recapitulate mature features of a native myocardium, limiting their translational applications. The iPSCs and direct reprogramming of somatic cells have been attempted to produce CPCs and, in this process, a variety of chemical and/or genetic factors have been evaluated for their ability to generate, expand, and maintain CPCs in vitro. However, the precise stoichiometry and spatiotemporal activity of these factors and the genetic interplay during embryonic CPC development remain challenging to reproduce in culture, in terms of efficiency, numbers, and translational potential. Recent advances in biomaterials to mimic the native cardiac microenvironment have shown promise to influence CPC regenerative functions, while being capable of integrating with host tissue. This review highlights recent developments and limitations in the generation and use of CPCs from stem cells, and the trends that influence the direction of research to promote better application of CPCs.
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Affiliation(s)
- Sara Barreto
- Guy Hilton Research Centre, School of Pharmacy & Bioengineering, Keele University, Staffordshire ST4 7QB, UK; (S.B.); (T.S.); (Y.Y.)
| | | | - Teresa Schiatti
- Guy Hilton Research Centre, School of Pharmacy & Bioengineering, Keele University, Staffordshire ST4 7QB, UK; (S.B.); (T.S.); (Y.Y.)
| | - Ying Yang
- Guy Hilton Research Centre, School of Pharmacy & Bioengineering, Keele University, Staffordshire ST4 7QB, UK; (S.B.); (T.S.); (Y.Y.)
| | - Vinoj George
- Guy Hilton Research Centre, School of Pharmacy & Bioengineering, Keele University, Staffordshire ST4 7QB, UK; (S.B.); (T.S.); (Y.Y.)
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34
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Parrotta EI, Scalise S, Scaramuzzino L, Cuda G. Stem Cells: The Game Changers of Human Cardiac Disease Modelling and Regenerative Medicine. Int J Mol Sci 2019; 20:E5760. [PMID: 31744081 PMCID: PMC6888119 DOI: 10.3390/ijms20225760] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 11/08/2019] [Accepted: 11/14/2019] [Indexed: 12/12/2022] Open
Abstract
A comprehensive understanding of the molecular basis and mechanisms underlying cardiac diseases is mandatory for the development of new and effective therapeutic strategies. The lack of appropriate in vitro cell models that faithfully mirror the human disease phenotypes has hampered the understanding of molecular insights responsible of heart injury and disease development. Over the past decade, important scientific advances have revolutionized the field of stem cell biology through the remarkable discovery of reprogramming somatic cells into induced pluripotent stem cells (iPSCs). These advances allowed to achieve the long-standing ambition of modelling human disease in a dish and, more interestingly, paved the way for unprecedented opportunities to translate bench discoveries into new therapies and to come closer to a real and effective stem cell-based medicine. The possibility to generate patient-specific iPSCs, together with the new advances in stem cell differentiation procedures and the availability of novel gene editing approaches and tissue engineering, has proven to be a powerful combination for the generation of phenotypically complex, pluripotent stem cell-based cellular disease models with potential use for early diagnosis, drug screening, and personalized therapy. This review will focus on recent progress and future outcome of iPSCs technology toward a customized medicine and new therapeutic options.
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Affiliation(s)
- Elvira Immacolata Parrotta
- Department of Experimental and Clinical Medicine, Research Center for Advanced Biochemistry and Molecular Biology, University “Magna Graecia” of Catanzaro, 88100 Loc., Germaneto, Catanzaro, Italy; (S.S.); (L.S.); (G.C.)
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Cardiac Pacemaker Cells Generate Cardiomyocytes from Fibroblasts in Long-Term Cultures. Sci Rep 2019; 9:15174. [PMID: 31645588 PMCID: PMC6811548 DOI: 10.1038/s41598-019-51001-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 09/23/2019] [Indexed: 11/12/2022] Open
Abstract
Because cardiomyocyte generation is limited, the turnover of cardiomyocytes in adult heart tissues is much debated. We report here that cardiac pacemaker cells can generate cardiomyocytes from fibroblasts in vitro. Sinoatrial node cells (SANCs) were isolated from adult guinea pig hearts and were cultured at relatively low cell densities. Within a week, a number of fibroblast-like cells were observed to gather around SANCs, and these formed spontaneously beating clusters with cardiomyocyte structures. The clusters expressed genes and proteins that are characteristic of atrial cardiomyocytes. Pharmacological blocking of pacemaker currents inhibited generation of action potentials, and the spontaneous beating were ceased by physically destroying a few central cells. Inhibition of beating during culture also hampered the cluster formation. Moreover, purified guinea pig cardiac fibroblasts (GCFs) expressed cardiac-specific proteins in co-culture with SANCs or in SANC-preconditioned culture medium under electrical stimulation. These results indicate that SANCs can generate cardiomyocytes from cardiac fibroblasts through the influence of humoral factor(s) and electrophysiological activities followed by intracellular Ca2+ oscillations. This potential of SANCs to generate cardiomyocytes indicates a novel mechanism by which cardiomyocytes turns over in the vicinity of pacemaker cells and could be exploited in the development of strategies for cardiac regenerative therapy in adult hearts.
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Zhang L, Sultana N, Yan J, Yang F, Chen F, Chepurko E, Yang FC, Du Q, Zangi L, Xu M, Bu L, Cai CL. Cardiac Sca-1 + Cells Are Not Intrinsic Stem Cells for Myocardial Development, Renewal, and Repair. Circulation 2019; 138:2919-2930. [PMID: 30566018 DOI: 10.1161/circulationaha.118.035200] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND For more than a decade, Sca-1+ cells within the mouse heart have been widely recognized as a stem cell population with multipotency that can give rise to cardiomyocytes, endothelial cells, and smooth muscle cells in vitro and after cardiac grafting. However, the developmental origin and authentic nature of these cells remain elusive. METHODS Here, we used a series of high-fidelity genetic mouse models to characterize the identity and regenerative potential of cardiac resident Sca-1+ cells. RESULTS With these novel genetic tools, we found that Sca-1 does not label cardiac precursor cells during early embryonic heart formation. Postnatal cardiac resident Sca-1+ cells are in fact a pure endothelial cell population. They retain endothelial properties and exhibit minimal cardiomyogenic potential during development, normal aging and upon ischemic injury. CONCLUSIONS Our study provides definitive insights into the nature of cardiac resident Sca-1+ cells. The observations challenge the current dogma that cardiac resident Sca-1+ cells are intrinsic stem cells for myocardial development, renewal, and repair, and suggest that the mechanisms of transplanted Sca-1+ cells in heart repair need to be reassessed.
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Affiliation(s)
- Lu Zhang
- Riley Heart Research Center and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis (L. Zhang, F.Y., C.-L.C.).,Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute (L. Zhang, N.S., F.Y., C.-L.C.), Icahn School of Medicine at Mount Sinai, New York
| | - Nishat Sultana
- Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute (L. Zhang, N.S., F.Y., C.-L.C.), Icahn School of Medicine at Mount Sinai, New York.,Department of Medicine and Cardiovascular Research Center (N.S., E.C., L. Zangi), Icahn School of Medicine at Mount Sinai, New York
| | - Jianyun Yan
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, and Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Guangzhou, China (J.Y.)
| | - Fan Yang
- Riley Heart Research Center and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis (L. Zhang, F.Y., C.-L.C.).,Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute (L. Zhang, N.S., F.Y., C.-L.C.), Icahn School of Medicine at Mount Sinai, New York
| | - Fuxue Chen
- College of Life Sciences, Shanghai University, China (F.C.)
| | - Elena Chepurko
- Department of Medicine and Cardiovascular Research Center (N.S., E.C., L. Zangi), Icahn School of Medicine at Mount Sinai, New York
| | - Feng-Chun Yang
- Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, FL (F.-C.Y., Q.D., M.X.)
| | - Qinghua Du
- Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, FL (F.-C.Y., Q.D., M.X.)
| | - Lior Zangi
- Department of Medicine and Cardiovascular Research Center (N.S., E.C., L. Zangi), Icahn School of Medicine at Mount Sinai, New York
| | - Mingjiang Xu
- Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, FL (F.-C.Y., Q.D., M.X.)
| | - Lei Bu
- Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY (L.B.)
| | - Chen-Leng Cai
- Riley Heart Research Center and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis (L. Zhang, F.Y., C.-L.C.).,Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute (L. Zhang, N.S., F.Y., C.-L.C.), Icahn School of Medicine at Mount Sinai, New York
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Peng D, Yuan H, Liu T, Wang T, Reed-Maldonado AB, Kang N, Banie L, Wang G, Tang Y, He L, Lin G, Lue TF. Smooth Muscle Differentiation of Penile Stem/Progenitor Cells Induced by Microenergy Acoustic Pulses In Vitro. J Sex Med 2019; 16:1874-1884. [PMID: 31585805 DOI: 10.1016/j.jsxm.2019.08.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 08/08/2019] [Accepted: 08/19/2019] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Modulating tissue-resident stem and progenitor cells with a non-invasive, mechanobiological intervention is an optimal approach for tissue regeneration. Stem cell antigen-1 (Sca-1) has been identified as a stem cell marker within many organs but never within the penis. AIM To localize and isolate penile stem/progenitor cells (PSPCs) and to evaluate cellular differentiation after exposure to induction medium and microenergy acoustic pulse (MAP) therapy. METHODS Six male Sprague-Dawley rats were used to isolate PSPCs. Isolation was followed by stem cell characterization and differentiation assays. The PSPCs were then treated with MAP (0.033 mJ/mm2, 1 Hz) at various dosages (25, 50, 100, and 200 pulses) and for different durations (1, 2, 4, 6, or 8 hours) in vitro. MAIN OUTCOME MEASURE The PSPCs (Sca-1-positive cells) were isolated using the magnetic-activated cell sorting system. PSPC cellular differentiation was assessed after induction with induction medium and with MAP in vitro. Wnt/β-catenin signaling was also assayed. RESULTS The PSPCs were successfully localized within the penile subtunic and perisinusoidal spaces, and they were successfully isolated using magnetic-activated cell sorting. The stemness of the cells was confirmed by stem cell marker characterization and by multiple differentiation into smooth muscle cells, endothelial cells, adipocytes, and neurons. MAP-induced PSPCs differentiated into smooth muscle cells by activating the Wnt/β-catenin signaling pathway in a time- and dosage-dependent manner. CLINICAL IMPLICATIONS By modulating resident PSPCs, MAP may have utility in the treatment of erectile dysfunction (ED). STRENGTHS & LIMITATIONS This study provides solid evidence in support of microenergy therapies, including both MAP and low-intensity extracorporeal shock wave therapy, for the treatment of ED. Additional studies are needed and should include additional stem cells markers. Furthermore, studies exploring the underling mechanisms for PSPC activation and differentiation are required. CONCLUSION PSPCs were successfully identified, localized, and isolated. Additionally, MAP provoked PSPCs to differentiate into smooth muscle cells via the Wnt/β-catenin signaling pathway. As such, MAP provides a novel method for activating endogenous tissue-resident stem/progenitor cells and might facilitate stem cell regenerative therapy targeting ED. Peng D, Yuan H, Liu T, et al. Smooth Muscle Differentiation of Penile Stem/Progenitor Cells Induced by Microenergy Acoustic Pulses In Vitro. J Sex Med 2019; 16:1874-1884.
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Affiliation(s)
- Dongyi Peng
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA; Department of Urology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Huixing Yuan
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Tianshu Liu
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Tianyu Wang
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Amanda B Reed-Maldonado
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Ning Kang
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Lia Banie
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Guifang Wang
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Yuxin Tang
- Department of Urology, Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Leye He
- Department of Urology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Guiting Lin
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Tom F Lue
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA.
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Gorabi AM, Bianconi V, Pirro M, Banach M, Sahebkar A. Regulation of cardiac stem cells by microRNAs: State-of-the-art. Biomed Pharmacother 2019; 120:109447. [PMID: 31580971 DOI: 10.1016/j.biopha.2019.109447] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 09/05/2019] [Accepted: 09/06/2019] [Indexed: 12/27/2022] Open
Abstract
Stem cells have a therapeutic potential in various medical conditions. In cases without sufficient response to conventional drug treatments, stem cells represent a next generation therapeutic strategy in cardiovascular diseases. Cardiac stem cells (CSCs), among a wide variety of stem cell sources, have been identified as a valid option for stem cell-based therapy in cardiovascular diseases. CSCs mainly act as a cell source to supply the physiological need for cardiovascular cells. However, they have been demonstrated to reproduce the myocardial cells under pathological settings. Despite their roles and functions have somewhat been clarified, molecular pathways underlying the regulatory mechanisms of CSCs are still not fully elucidated. Several studies have recently shown that different microRNAs (miRNAs) play a substantial role in regulating and controlling both the physiological and pathological proliferation and differentiation of stem cells. MiRNAs are small non-coding RNA molecules that regulate gene expression and may undergo aberrant expression levels during pathological conditions. Understanding the way through which miRNAs regulate CSC behavior may open up new horizons in modulating these cells in vitro to devise sophisticated approaches for treating patients with cardiovascular diseases. In this review article, we tried to discuss available evidence about the role of miRNAs in regulating CSCs.
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Affiliation(s)
- Armita Mahdavi Gorabi
- Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Vanessa Bianconi
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - Matteo Pirro
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, Lodz, Poland; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
| | - Amirhossein Sahebkar
- Halal Research Center of IRI, FDA, Tehran, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Tassone NM, Li B, Patel MS, Devine MY, Firmiss PR, Gould AD, Kochan KS, Stubbee RA, Bowen DK, Dettman RW, Gong EM. Stem cell antigen/Ly6a protects against bladder fibrosis in mice. Am J Physiol Renal Physiol 2019; 317:F1503-F1512. [PMID: 31532245 DOI: 10.1152/ajprenal.00160.2019] [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: 12/21/2022] Open
Abstract
We have defined a population of stem cell antigen (Sca)-1+/CD34+/lin- mesenchymal stem cells in the mouse urinary bladder. These cells are reduced after partial bladder outlet obstruction (PO). To test the role of Sca-1 expressed by these cells, we analyzed bladders from Sca-1 knockout (KO) mice in both uninjured male mice and male mice subjected to PO. We found that loss of Sca-1 alone had little effect on bladder development or function but reduced the total number of mesenchymal stem cells by 30%. After PO, bladders from Sca-1-null KO male mice were larger, with more collagen and less muscle, than obstructed wild-type mice. Steady-state levels of caldesmon were significantly reduced and levels of fibroblast-specific protein 1 were significantly increased in Sca-1 KO mice compared with wild-type mice after PO. In investigating the effects of PO on cell proliferation, we found that loss of Sca-1 changed the timing of cell division in CD34+/lin-, collagen-producing, and smooth muscle cells. PO in combination with loss of Sca-1 drastically reduced the ability of CD34+/lin- cells to form colonies in vitro. Our findings therefore support the hypothesis that Sca-1 protects the bladder from fibrotic remodeling after obstruction, in part by influencing the proliferation of cells responding to the injury.
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Affiliation(s)
- Nicholas M Tassone
- Pediatric Urology, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
| | - Belinda Li
- Department of Urology, Loyola University Health System, Maywood, Illinois
| | - Mehul S Patel
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Megan Y Devine
- Pediatric Urology, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
| | - Paula R Firmiss
- Pediatric Urology, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
| | - Andrew D Gould
- Pediatric Urology, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
| | - Kirsten S Kochan
- Pediatric Urology, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
| | - Reid A Stubbee
- Pediatric Urology, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
| | - Diana K Bowen
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Robert W Dettman
- Pediatric Urology, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.,Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Edward M Gong
- Pediatric Urology, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.,Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
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Deutsch MA, Doppler SA, Li X, Lahm H, Santamaria G, Cuda G, Eichhorn S, Ratschiller T, Dzilic E, Dreßen M, Eckart A, Stark K, Massberg S, Bartels A, Rischpler C, Gilsbach R, Hein L, Fleischmann BK, Wu SM, Lange R, Krane M. Reactivation of the Nkx2.5 cardiac enhancer after myocardial infarction does not presage myogenesis. Cardiovasc Res 2019; 114:1098-1114. [PMID: 29579159 DOI: 10.1093/cvr/cvy069] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 03/15/2018] [Indexed: 12/13/2022] Open
Abstract
Aims The contribution of resident stem or progenitor cells to cardiomyocyte renewal after injury in adult mammalian hearts remains a matter of considerable debate. We evaluated a cell population in the adult mouse heart induced by myocardial infarction (MI) and characterized by an activated Nkx2.5 enhancer element that is specific for multipotent cardiac progenitor cells (CPCs) during embryonic development. We hypothesized that these MI-induced cells (MICs) harbour cardiomyogenic properties similar to their embryonic counterparts. Methods and results MICs reside in the heart and mainly localize to the infarction area and border zone. Interestingly, gene expression profiling of purified MICs 1 week after infarction revealed increased expression of stem cell markers and embryonic cardiac transcription factors (TFs) in these cells as compared to the non-mycoyte cell fraction of adult hearts. A subsequent global transcriptome comparison with embryonic CPCs and fibroblasts and in vitro culture of MICs unveiled that (myo-)fibroblastic features predominated and that cardiac TFs were only expressed at background levels. Conclusions Adult injury-induced reactivation of a cardiac-specific Nkx2.5 enhancer element known to specifically mark myocardial progenitor cells during embryonic development does not reflect hypothesized embryonic cardiomyogenic properties. Our data suggest a decreasing plasticity of cardiac progenitor (-like) cell populations with increasing age. A re-expression of embryonic, stem or progenitor cell features in the adult heart must be interpreted very carefully with respect to the definition of cardiac resident progenitor cells. Albeit, the abundance of scar formation after cardiac injury suggests a potential to target predestinated activated profibrotic cells to push them towards cardiomyogenic differentiation to improve regeneration.
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Affiliation(s)
- Marcus-André Deutsch
- Department of Cardiovascular Surgery, German Heart Center Munich at the Technische Universität München, Lazarettstraße 36, 80636 Munich, Germany.,Department of Cardiovascular Surgery, German Heart Center, Insure (Institute for Translational Cardiac Surgery), Technische Universität München, Lothstraße 11, 80636 Munich, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Stefanie A Doppler
- Department of Cardiovascular Surgery, German Heart Center Munich at the Technische Universität München, Lazarettstraße 36, 80636 Munich, Germany.,Department of Cardiovascular Surgery, German Heart Center, Insure (Institute for Translational Cardiac Surgery), Technische Universität München, Lothstraße 11, 80636 Munich, Germany
| | - Xinghai Li
- Department of Cardiovascular Surgery, German Heart Center Munich at the Technische Universität München, Lazarettstraße 36, 80636 Munich, Germany.,Department of Cardiovascular Surgery, German Heart Center, Insure (Institute for Translational Cardiac Surgery), Technische Universität München, Lothstraße 11, 80636 Munich, Germany
| | - Harald Lahm
- Department of Cardiovascular Surgery, German Heart Center Munich at the Technische Universität München, Lazarettstraße 36, 80636 Munich, Germany.,Department of Cardiovascular Surgery, German Heart Center, Insure (Institute for Translational Cardiac Surgery), Technische Universität München, Lothstraße 11, 80636 Munich, Germany
| | - Gianluca Santamaria
- Stem Cell Laboratory, Department of Experimental and Clinical Medicine, Research Center of Advanced Biochemistry and Molecular Biology.,CIS (Centro Interdisciplinare Servizi), University 'Magna Graecia' of Catanzaro, Viale Europa, 88100 Catanzaro, Italy
| | - Giovanni Cuda
- Stem Cell Laboratory, Department of Experimental and Clinical Medicine, Research Center of Advanced Biochemistry and Molecular Biology
| | - Stefan Eichhorn
- Department of Cardiovascular Surgery, German Heart Center Munich at the Technische Universität München, Lazarettstraße 36, 80636 Munich, Germany.,Department of Cardiovascular Surgery, German Heart Center, Insure (Institute for Translational Cardiac Surgery), Technische Universität München, Lothstraße 11, 80636 Munich, Germany
| | - Thomas Ratschiller
- Department of Cardiothoracic and Vascular Surgery, Kepler University Hospital, 4021 Linz, Austria
| | - Elda Dzilic
- Department of Cardiovascular Surgery, German Heart Center Munich at the Technische Universität München, Lazarettstraße 36, 80636 Munich, Germany.,Department of Cardiovascular Surgery, German Heart Center, Insure (Institute for Translational Cardiac Surgery), Technische Universität München, Lothstraße 11, 80636 Munich, Germany
| | - Martina Dreßen
- Department of Cardiovascular Surgery, German Heart Center Munich at the Technische Universität München, Lazarettstraße 36, 80636 Munich, Germany.,Department of Cardiovascular Surgery, German Heart Center, Insure (Institute for Translational Cardiac Surgery), Technische Universität München, Lothstraße 11, 80636 Munich, Germany
| | - Annekathrin Eckart
- Medizinische Klinik und Poliklinik I, Ludwig-Maximilians-Universität, 81377 Munich, Germany
| | - Konstantin Stark
- DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.,Medizinische Klinik und Poliklinik I, Ludwig-Maximilians-Universität, 81377 Munich, Germany
| | - Steffen Massberg
- DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.,Medizinische Klinik und Poliklinik I, Ludwig-Maximilians-Universität, 81377 Munich, Germany
| | - Anna Bartels
- Nuklearmedizinische Klinik des Klinikums Rechts der Isar, Technische Universität München, 81675 Munich, Germany
| | - Christoph Rischpler
- DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.,Nuklearmedizinische Klinik des Klinikums Rechts der Isar, Technische Universität München, 81675 Munich, Germany
| | - Ralf Gilsbach
- Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Albertstraße 25, 79104 Freiburg, Germany
| | - Lutz Hein
- Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Albertstraße 25, 79104 Freiburg, Germany.,BIOSS Centre for Biological Signaling Studies, University of Freiburg, Schänzlestraße 18, 79104 Freiburg, Germany
| | - Bernd K Fleischmann
- Institute of Physiology I, Life and Brain Center, Medical Faculty, University of Bonn, 53105 Bonn, Germany
| | - Sean M Wu
- Division of Cardiovascular Medicine, Department of Medicine, Stanford Cardiovascular Institute, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA
| | - Rüdiger Lange
- Department of Cardiovascular Surgery, German Heart Center Munich at the Technische Universität München, Lazarettstraße 36, 80636 Munich, Germany.,Department of Cardiovascular Surgery, German Heart Center, Insure (Institute for Translational Cardiac Surgery), Technische Universität München, Lothstraße 11, 80636 Munich, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Markus Krane
- Department of Cardiovascular Surgery, German Heart Center Munich at the Technische Universität München, Lazarettstraße 36, 80636 Munich, Germany.,Department of Cardiovascular Surgery, German Heart Center, Insure (Institute for Translational Cardiac Surgery), Technische Universität München, Lothstraße 11, 80636 Munich, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
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Ferreira RR, Abreu RDS, Vilar-Pereira G, Degrave W, Meuser-Batista M, Ferreira NVC, da Cruz Moreira O, da Silva Gomes NL, Mello de Souza E, Ramos IP, Bailly S, Feige JJ, Lannes-Vieira J, de Araújo-Jorge TC, Waghabi MC. TGF-β inhibitor therapy decreases fibrosis and stimulates cardiac improvement in a pre-clinical study of chronic Chagas' heart disease. PLoS Negl Trop Dis 2019; 13:e0007602. [PMID: 31365537 PMCID: PMC6690554 DOI: 10.1371/journal.pntd.0007602] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 08/12/2019] [Accepted: 07/03/2019] [Indexed: 01/11/2023] Open
Abstract
TGF-β involvement in Chagas disease cardiomyopathy has been clearly demonstrated. The TGF-β signaling pathway is activated in the cardiac tissue of chronic phase patients and is associated with an increase in extracellular matrix protein expression. The aim of this study was to investigate the effect of GW788388, a selective inhibitor of TβR1/ALK5, on cardiac function in an experimental model of chronic Chagas' heart disease. To this end, C57BL/6 mice were infected with Trypanosoma cruzi (102 parasites from the Colombian strain) and treated orally with 3mg/kg GW788388 starting at 120 days post-infection (dpi), when 100% of the infected mice show cardiac damage, and following three distinct treatment schedules: i) single dose; ii) one dose per week; or iii) three doses per week during 30 days. The treatment with GW788388 improved several cardiac parameters: reduced the prolonged PR and QTc intervals, increased heart rate, and reversed sinus arrhythmia, and atrial and atrioventricular conduction disorders. At 180 dpi, 30 days after treatment interruption, the GW3x-treated group remained in a better cardiac functional condition. Further, GW788388 treatment reversed the loss of connexin-43 enriched intercellular plaques and reduced fibrosis of the cardiac tissue. Inhibition of the TGF-β signaling pathway reduced TGF-β/pSmad2/3, increased MMP-9 and Sca-1, reduced TIMP-1/TIMP-2/TIMP-4, and partially restored GATA-6 and Tbox-5 transcription, supporting cardiac recovery. Moreover, GW788388 administration did not modify cardiac parasite load during the infection but reduced the migration of CD3+ cells to the heart tissue. Altogether, our data suggested that the single dose schedule was not as effective as the others and treatment three times per week during 30 days seems to be the most effective strategy. The therapeutic effects of GW788388 are promising and suggest a new possibility to treat cardiac fibrosis in the chronic phase of Chagas' heart disease by TGF-β inhibitors.
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Affiliation(s)
- Roberto Rodrigues Ferreira
- Laboratório de Genômica Funcional e Bioinformática—Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro RJ, Brasil
| | - Rayane da Silva Abreu
- Laboratório de Genômica Funcional e Bioinformática—Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro RJ, Brasil
| | - Glaucia Vilar-Pereira
- Laboratório de Biologia das Interações—Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro RJ, Brasil
| | - Wim Degrave
- Laboratório de Genômica Funcional e Bioinformática—Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro RJ, Brasil
| | - Marcelo Meuser-Batista
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos—Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro RJ, Brasil
- Departamento de Anatomia Patológica e Citopatologia, Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brasil
| | - Nilma Valéria Caldeira Ferreira
- Departamento de Anatomia Patológica e Citopatologia, Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brasil
| | - Otacílio da Cruz Moreira
- Laboratório de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz (FIOCRUZ/RJ), Rio de Janeiro, Brazil
| | - Natália Lins da Silva Gomes
- Laboratório de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz (FIOCRUZ/RJ), Rio de Janeiro, Brazil
| | - Elen Mello de Souza
- Laboratório de Virologia Molecular—Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro RJ, Brasil
| | - Isalira P. Ramos
- UFRJ, Centro Nacional de Biologia Estrutural e Bioimagem, Rio de Janeiro, RJ, Brazil
| | - Sabine Bailly
- Université Grenoble-Alpes, Inserm, CEA, Biology of Cancer and Infection Laboratory, Grenoble, France
| | - Jean-Jacques Feige
- Université Grenoble-Alpes, Inserm, CEA, Biology of Cancer and Infection Laboratory, Grenoble, France
| | - Joseli Lannes-Vieira
- Laboratório de Biologia das Interações—Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro RJ, Brasil
| | - Tania C. de Araújo-Jorge
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos—Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro RJ, Brasil
| | - Mariana Caldas Waghabi
- Laboratório de Genômica Funcional e Bioinformática—Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro RJ, Brasil
- * E-mail:
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Reiss AB, Glass DS, Lam E, Glass AD, De Leon J, Kasselman LJ. Oxytocin: Potential to mitigate cardiovascular risk. Peptides 2019; 117:170089. [PMID: 31112739 DOI: 10.1016/j.peptides.2019.05.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 04/17/2019] [Accepted: 05/10/2019] [Indexed: 02/08/2023]
Abstract
Cardiovascular disease (CVD) remains the leading cause of death worldwide, despite multiple treatment options. In addition to elevated lipid levels, oxidative stress and inflammation are key factors driving atherogenesis and CVD. New strategies are required to mitigate risk and most urgently for statin-intolerant patients. The neuropeptide hormone oxytocin, synthesized in the brain hypothalamus, is worthy of consideration as a CVD ancillary treatment because it moderates factors directly linked to atherosclerotic CVD such as inflammation, weight gain, food intake and insulin resistance. Though initially studied for its contribution to parturition and lactation, oxytocin participates in social attachment and bonding, associative learning, memory and stress responses. Oxytocin has shown promise in animal models of atherosclerosis and in some human studies as well. A number of properties of oxytocin make it a candidate CVD treatment. Oxytocin not only lowers fat mass and cytokine levels, but also improves glucose tolerance, lowers blood pressure and relieves anxiety. Further, it has an important role in communication in the gut-brain axis that makes it a promising treatment for obesity and type 2 diabetes. Oxytocin acts through its receptor which is a class I G-protein-coupled receptor present in cells of the vascular system including the heart and arteries. While oxytocin is not used for heart disease at present, residual CVD risk remains in a substantial portion of patients despite multidrug regimens, leaving open the possibility of using the endogenous nonapeptide as an adjunct therapy. This review discusses the possible role for oxytocin in human CVD prevention and treatment.
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Affiliation(s)
- Allison B Reiss
- Department of Medicine and Research Institute, NYU Winthrop Hospital, Mineola NY 11501, USA.
| | - Daniel S Glass
- Department of Medicine and Research Institute, NYU Winthrop Hospital, Mineola NY 11501, USA
| | - Eric Lam
- Department of Medicine and Research Institute, NYU Winthrop Hospital, Mineola NY 11501, USA
| | - Amy D Glass
- Department of Medicine and Research Institute, NYU Winthrop Hospital, Mineola NY 11501, USA
| | - Joshua De Leon
- Department of Medicine and Research Institute, NYU Winthrop Hospital, Mineola NY 11501, USA
| | - Lora J Kasselman
- Department of Medicine and Research Institute, NYU Winthrop Hospital, Mineola NY 11501, USA
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Li C, Chang Y, Jia Y, Guo Z. A new structure from cardiac cells cultured in vitro: Cardiomyocyte-annulation of neonatal rats. J Cell Biochem 2019; 120:18533-18543. [PMID: 31245874 DOI: 10.1002/jcb.29175] [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: 03/25/2019] [Revised: 05/17/2019] [Accepted: 05/23/2019] [Indexed: 11/10/2022]
Abstract
To explore the formation, morphological characteristics, cell composition, and differentiation potential of cardiomyocyte annulation (cardio-annulation) during in vitro culture of cardiac cells. Cardiac cells were isolated and cultured. A live-cell imaging system was used to observe cardio-annulation. Cardiac troponin-T (cTnT) and vimentin were labeled with double immunofluorescence staining, and coexpressions of cTnT and connexin43 (Cx43), cTnT and nanog, c-kit and nanog, and c-kit and stem cell antigen (sca-1) were detected. The location of various types of cells within the cardio-annulation structure was observed. Adipogenic- and osteogenic-inducing fluids were used separately for in situ induction to detect the multidirectional differentiation potential of cells during the annulation process. After 3 to 6 days, cardiac cells migrated and formed an open or closed annulus with a diameter of 800 to 3500 μm. The annulus wall comprised the medial, middle, and lateral regions. The cells in the medial region were small, abundant, and laminated, while those in the middle region were larger with fewer layers, and those in the lateral region were less abundant, and loosely arranged in a single layer. Cardiomyocytes were distributed mainly on the surface of the medial region; nanog+ , c-kit+ , and sca-1+ cells were located mainly at the bottom of the annulus wall and fibroblasts were located mainly between these layers. The annulus cavity contained a large number of small, round cells, and telocytes. Cx43 was expressed in all cell types, and nanog, c-kit, and sca-1 were coexpressed in the cardio-annulation cells, which possess adipogenic and osteogenic differentiation potential. Cardio-annulation was discovered during an in vitro culture of cardiac cells. The structure contains cardiomyocytes, fibroblasts, telocytes, and abundant stem cells. These results provide insight into the relationship among cardiac cells in vitro.
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Affiliation(s)
- Cixia Li
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Yuqiao Chang
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Yangyang Jia
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Zhikun Guo
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
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Spontaneously Formed Spheroids from Mouse Compact Bone-Derived Cells Retain Highly Potent Stem Cells with Enhanced Differentiation Capability. Stem Cells Int 2019; 2019:8469012. [PMID: 31191686 PMCID: PMC6525826 DOI: 10.1155/2019/8469012] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 02/26/2019] [Accepted: 03/10/2019] [Indexed: 02/07/2023] Open
Abstract
The results from our recent study showed the presence of two distinct spheroid-forming mechanisms, i.e., spontaneous and mechanical. In this study, we focused on the spontaneously formed spheroids, and the character of spontaneously formed spheroids from mouse compact bone-derived cells (CBDCs) was explored. Cells from (C57BL/6J) mouse leg bones were isolated, and compact bone-derived cells were cultured after enzymatic digestion. Spontaneous spheroid formation was achieved on a culture plate with specific water contact angle as reported. The expression levels of embryonic stem cell markers were analyzed using immunofluorescence and quantitative reverse transcription polymerase chain reaction. Then, the cells from spheroids were induced into osteogenic and neurogenic lineages. The spontaneously formed spheroids from CBDCs were positive for ES cell markers such as SSEA1, Sox2, Oct4, and Nanog. Additionally, the expressions of fucosyltransferase 4/FUT4 (SSEA1), Sox2, and Nanog were significantly higher than those in monolayer cultured cells. The gene expression of mesenchymal stem cell markers was almost identical in both spheroids and monolayer-cultured cells, but the expression of Sca-1 was higher in spheroids. Spheroid-derived cells showed significantly higher osteogenic and neurogenic marker expression than monolayer-cultured cells after induction. Spontaneously formed spheroids expressed stem cell markers and showed enhanced osteogenic and neurogenic differentiation capabilities than cells from the conventional monolayer culture, which supports the superior stemness.
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Liu Y, Niu R, Li W, Lin J, Stamm C, Steinhoff G, Ma N. Therapeutic potential of menstrual blood-derived endometrial stem cells in cardiac diseases. Cell Mol Life Sci 2019; 76:1681-1695. [PMID: 30721319 PMCID: PMC11105669 DOI: 10.1007/s00018-019-03019-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 12/13/2018] [Accepted: 01/15/2019] [Indexed: 12/21/2022]
Abstract
Despite significant developments in medical and surgical strategies, cardiac diseases remain the leading causes of morbidity and mortality worldwide. Numerous studies involving preclinical and clinical trials have confirmed that stem cell transplantation can help improve cardiac function and regenerate damaged cardiac tissue, and stem cells isolated from bone marrow, heart tissue, adipose tissue and umbilical cord are the primary candidates for transplantation. During the past decade, menstrual blood-derived endometrial stem cells (MenSCs) have gradually become a promising alternative for stem cell-based therapy due to their comprehensive advantages, which include their ability to be periodically and non-invasively collected, their abundant source material, their ability to be regularly donated, their superior proliferative capacity and their ability to be used for autologous transplantation. MenSCs have shown positive therapeutic potential for the treatment of various diseases. Therefore, aside from a brief introduction of the biological characteristics of MenSCs, this review focuses on the progress being made in evaluating the functional improvement of damaged cardiac tissue after MenSC transplantation through preclinical and clinical studies. Based on published reports, we conclude that the paracrine effect, transdifferentiation and immunomodulation by MenSC promote both regeneration of damaged myocardium and improvement of cardiac function.
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Affiliation(s)
- Yanli Liu
- Stem Cell and Biotherapy Technology Research Center, College of Life Science and Technology, Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, 453003, People's Republic of China
- Institute of Chemistry and Biochemistry, Free University Berlin, 14195, Berlin, Germany
| | - Rongcheng Niu
- Stem Cell and Biotherapy Technology Research Center, College of Life Science and Technology, Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, 453003, People's Republic of China
| | - Wenzhong Li
- Institute of Chemistry and Biochemistry, Free University Berlin, 14195, Berlin, Germany.
| | - Juntang Lin
- Stem Cell and Biotherapy Technology Research Center, College of Life Science and Technology, Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, 453003, People's Republic of China.
| | - Christof Stamm
- Deutsches Herzzentrum Berlin (DHZB), Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health, Berlin, Germany
| | - Gustav Steinhoff
- Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Rostock, 18055, Rostock, Germany
| | - Nan Ma
- Institute of Chemistry and Biochemistry, Free University Berlin, 14195, Berlin, Germany
- Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Rostock, 18055, Rostock, Germany
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, 14513, Teltow, Germany
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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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Marino F, Scalise M, Cianflone E, Mancuso T, Aquila I, Agosti V, Torella M, Paolino D, Mollace V, Nadal-Ginard B, Torella D. Role of c-Kit in Myocardial Regeneration and Aging. Front Endocrinol (Lausanne) 2019; 10:371. [PMID: 31275242 PMCID: PMC6593054 DOI: 10.3389/fendo.2019.00371] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 05/24/2019] [Indexed: 12/15/2022] Open
Abstract
c-Kit, a type III receptor tyrosine kinase (RTK), is involved in multiple intracellular signaling whereby it is mainly considered a stem cell factor receptor, which participates in vital functions of the mammalian body, including the human. Furthermore, c-kit is a necessary yet not sufficient marker to detect and isolate several types of tissue-specific adult stem cells. Accordingly, c-kit was initially used as a marker to identify and enrich for adult cardiac stem/progenitor cells (CSCs) that were proven to be clonogenic, self-renewing and multipotent, being able to differentiate into cardiomyocytes, endothelial cells and smooth muscle cells in vitro as well as in vivo after myocardial injury. Afterwards it was demonstrated that c-kit expression labels a heterogenous cardiac cell population, which is mainly composed by endothelial cells while only a very small fraction represents CSCs. Furthermore, c-kit as a signaling molecule is expressed at different levels in this heterogenous c-kit labeled cardiac cell pool, whereby c-kit low expressers are enriched for CSCs while c-kit high expressers are endothelial and mast cells. This heterogeneity in cell composition and expression levels has been neglected in recent genetic fate map studies focusing on c-kit, which have claimed that c-kit identifies cells with robust endothelial differentiation potential but with minimal if not negligible myogenic commitment potential. However, modification of c-kit gene for Cre Recombinase expression in these Cre/Lox genetic fate map mouse models produced a detrimental c-kit haploinsufficiency that prevents efficient labeling of true CSCs on one hand while affecting the regenerative potential of these cells on the other. Interestingly, c-kit haploinsufficiency in c-kit-deficient mice causes a worsening myocardial repair after injury and accelerates cardiac aging. Therefore, these studies have further demonstrated that adult c-kit-labeled CSCs are robustly myogenic and that the adult myocardium relies on c-kit expression to regenerate after injury and to counteract aging effects on cardiac structure and function.
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Affiliation(s)
- Fabiola Marino
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
- Department of Health Sciences, Interregional Research Center on Food Safety and Health (IRC-FSH), University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Mariangela Scalise
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Eleonora Cianflone
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Teresa Mancuso
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Iolanda Aquila
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Valter Agosti
- Interdepartmental Center of Services (CIS) of Genomics, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Michele Torella
- Department of Cardiothoracic Sciences, University of Campania L. Vanvitelli, Naples, Italy
| | - Donatella Paolino
- Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Vincenzo Mollace
- Department of Health Sciences, Interregional Research Center on Food Safety and Health (IRC-FSH), University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Bernardo Nadal-Ginard
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
- StemCell OpCo, Madrid, Spain
| | - Daniele Torella
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
- *Correspondence: Daniele Torella
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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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Affiliation(s)
- Mariangela Scalise
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Fabiola Marino
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Eleonora Cianflone
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Teresa Mancuso
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Pina Marotta
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Iolanda Aquila
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Michele Torella
- Department of Cardiothoracic Surgery, University of Campania "L.Vanvitelli", Naples, Italy
| | - Bernardo Nadal-Ginard
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Daniele Torella
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
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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
Abstract
Embryonic heart progenitors arise at specific spatiotemporal periods that contribute to the formation of distinct cardiac structures. In mammals, the embryonic and fetal heart is hypoxic by comparison to the adult heart. In parallel, the cellular metabolism of the cardiac tissue, including progenitors, undergoes a glycolytic to oxidative switch that contributes to cardiac maturation. While oxidative metabolism is energy efficient, the glycolytic-hypoxic state may serve to maintain cardiac progenitor potential. Consistent with this proposal, the adult epicardium has been shown to contain a reservoir of quiescent cardiac progenitors that are activated in response to heart injury and are hypoxic by comparison to adjacent cardiac tissues. In this review, we discuss the development and potential of the adult epicardium and how this knowledge may provide future therapeutic approaches for cardiac repair.
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Affiliation(s)
- Angeliqua Sayed
- Cellular, Molecular, and Physiological Mechanisms of Heart Failure, Paris-Cardiovascular Research Center (PARCC), European Georges Pompidou Hospital (HEGP), INSERM U970, F-75737 Paris Cedex 15, Paris, France
| | - Mariana Valente
- Cellular, Molecular, and Physiological Mechanisms of Heart Failure, Paris-Cardiovascular Research Center (PARCC), European Georges Pompidou Hospital (HEGP), INSERM U970, F-75737 Paris Cedex 15, Paris, France
| | - David Sassoon
- Cellular, Molecular, and Physiological Mechanisms of Heart Failure, Paris-Cardiovascular Research Center (PARCC), European Georges Pompidou Hospital (HEGP), INSERM U970, F-75737 Paris Cedex 15, Paris, France
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50
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Taha MF, Javeri A, Karimipour M, Yamaghani MS. Priming with oxytocin and relaxin improves cardiac differentiation of adipose tissue-derived stem cells. J Cell Biochem 2018; 120:5825-5834. [PMID: 30362159 DOI: 10.1002/jcb.27868] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 09/20/2018] [Indexed: 11/07/2022]
Abstract
Previous studies have identified the heart as a source and a target tissue for oxytocin and relaxin hormones. These hormones play important roles in the regulation of cardiovascular function and repair of ischemic heart injury. In the current study, we examined the impact of oxytocin and relaxin on the development of cardiomyocytes from mesenchymal stem cells. For this purpose, mouse adipose tissue-derived stem cells (ADSCs) were treated with different concentrations of oxytocin or relaxin for 4 days. Three weeks after initiation of cardiac induction, differentiated ADSCs expressed cardiac-specific genes, Gata4, Mef2c, Nkx2.5, Tbx5, α- and β-Mhc, Mlc2v, Mlc2a and Anp, and cardiac proteins including connexin 43, desmin and α-actinin. 10 -7 M oxytocin and 50 ng/mL relaxin induced the maximum upregulation in the expression of cardiac markers. A combination of oxytocin and relaxin induced cardiomyocyte differentiation more potently than the individual factors. In our experiment, oxytocin-relaxin combination increased the population of cardiac troponin I-expressing cells to 6.84% as compared with 2.36% for the untreated ADSCs, 3.7% for oxytocin treatment and 3.41% for relaxin treatment groups. In summary, the results of this study indicated that oxytocin and relaxin hormones individually and in combination can improve cardiac differentiation of ADSCs, and treatment of the ADSCs and possibly other mesenchymal stem cells with these hormones may enhance their cardiogenic differentiation and survival after transplantation into the ischemic heart tissue.
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Affiliation(s)
- Masoumeh Fakhr Taha
- Department of Stem Cells and Regenerative Medicine, Institute for Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Arash Javeri
- Department of Stem Cells and Regenerative Medicine, Institute for Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Mojtaba Karimipour
- Department of Anatomy, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
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