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Arthurs JR, Martin Lillie CM, Master Z, Shapiro SA. The Direct to Consumer Stem Cell Market and the Role of Primary Care Providers in Correcting Misinformation. J Prim Care Community Health 2022; 13:21501319221121460. [PMID: 36112830 PMCID: PMC9476238 DOI: 10.1177/21501319221121460] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 08/05/2022] [Accepted: 08/09/2022] [Indexed: 11/22/2022] Open
Abstract
INTRODUCTION Direct to consumer stem cell and regenerative interventions (SCRIs) for various medical conditions have increased in popularity due to unmet medical needs and the promise of SCRIs to meet those needs. These interventions may have varying levels of safety and efficacy data and many lack sufficient scientific data to be marketed. The direct to consumer SCRI industry has received significant attention due to potential physical, economic, and emotional harms to patients. Patients may seek the counsel of their primary care providers when considering stem cell therapy for their condition. METHODS Here we describe strategies primary care providers can utilize when counseling patients. RESULTS Although we recommend constructing these discussions around individual patients' needs, one can utilize a general approach consisting of 4 parts. First, providers should recognize what information the patient is seeking and what is their understanding of stem cell and regenerative medicine. Next, providers should convey evidence-based information at the level of patients understanding so that they are aware of the risks, benefits, and descriptions of possible procedures. Throughout the conversations, attempts should be made to guide patients to a trusted resource that can provide additional information. Finally, providers should make an effort to address misinformation in a way that is nonjudgmental and patient-centered to make the patient feel safe and comfortable. CONCLUSION Effectively communicating risk information by primary care providers to patients is important given the harms reported from direct-to-consumer SCRIs. Correcting misinformation remains a priority when discussing SCRI's. Providers should strive to offer patients with additional resources such as the opportunity for consultation with a specialist or a consultation service dedicated to informing patients about regenerative medicine.
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Bioactive Polymeric Materials for the Advancement of Regenerative Medicine. J Funct Biomater 2021; 12:jfb12010014. [PMID: 33672492 PMCID: PMC8006220 DOI: 10.3390/jfb12010014] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/13/2021] [Accepted: 02/17/2021] [Indexed: 12/13/2022] Open
Abstract
Biopolymers are widely accepted natural materials in regenerative medicine, and further development of their bioactivities and discoveries on their composition/function relationships could greatly advance the field. However, a concise insight on commonly investigated biopolymers, their current applications and outlook of their modifications for multibioactivity are scarce. This review bridges this gap for professionals and especially freshmen in the field who are also interested in modification methods not yet in commercial use. A series of polymeric materials in research and development uses are presented as well as challenges that limit their efficacy in tissue regeneration are discussed. Finally, their roles in the regeneration of select tissues including the skin, bone, cartilage, and tendon are highlighted along with modifiable biopolymer moieties for different bioactivities.
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Chlan LL, Tofthagen C, Terzic A. The Regenerative Horizon: Opportunities for Nursing Research and Practice. J Nurs Scholarsh 2019; 51:651-660. [PMID: 31566894 PMCID: PMC6842049 DOI: 10.1111/jnu.12520] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/26/2019] [Indexed: 12/15/2022]
Abstract
Background Regenerative technologies aim to restore organ form and function. Technological advances in regenerative treatments have led to patients increasingly seeking these therapies. The readiness of nursing to fully contribute to this emerging healthcare field is uncertain. Purpose The goal of this discipline‐oriented overview is to enhance awareness in the nursing community regarding regenerative science, and to provide suggestions for nursing research contributions and practice implications. Methods Evolving and applied cutting‐edge therapies, such as regenerative immunotherapies with chimeric antigen receptor expressing T lymphocytes, are highlighted in the context of emerging opportunities for nurses in practice and research. Discussion Next generation nurses will increasingly be at the forefront of new therapies poised to make chronic illnesses curable, thus restoring health and function to diverse groups of individuals. Clinical Relevance The regenerative care model imposes on the nursing community the imperative to (a) increase research awareness; (a) educate, develop, and deploy a skilled nursing workforce; (c) integrate regenerative technologies into nursing practice; and (d) embrace the regenerative technologies horizon as a future in health care.
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Affiliation(s)
- Linda L Chlan
- Theta XI and Zeta, Associate Dean for Nursing Research, Professor of Nursing, Mayo Clinic, Rochester, MN, USA
| | - Cindy Tofthagen
- Delta Beta at Large, Nurse Scientist, Mayo Clinic, Jacksonville, FL, USA
| | - Andre Terzic
- Professor of Medicine and Director, Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA
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Cai JY, Zhang L, Chen J, Chen SY. Kartogenin and Its Application in Regenerative Medicine. Curr Med Sci 2019; 39:16-20. [PMID: 30868486 DOI: 10.1007/s11596-019-1994-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 12/04/2018] [Indexed: 01/28/2023]
Abstract
Regenerative medicine refers to the possibility of replacing aged/damaged cells with genetically similar young and functional cells to restore or establish normal function. Kartogenin (KGN), a small heterocyclic, drug-like compound was discovered in 2012, which is strongly associated with regenerative medicine. KGN has been applied in many regenerative fields, including cartilage regeneration and protection, tendon-bone healing, wound healing, and limb development. KGN could facilitate cartilage repair, promote formation of cartilage-like transition zone in tendon-bone junctions, stimulate collagen synthesis for wound healing, and regulate limb development in a coordinated manner. Considering the related mechanism, filamin A/CBFβ/RUNX1, Ihh, and TGFβ/Smad pathways have been reported to involve KGN. Therefore, KGN is proven a promising agent in regenerative medicine; however, studies conducted on the effect of KGN are limited to date and not convictive for long-term use. Further studies are recommended to explore the long-term effect and potential molecular mechanisms of KGN. Our investigations may motivate researchers to expand its applications in different forms and fields.
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Affiliation(s)
- Jiang-Yu Cai
- Department of Sports Medicine, Fudan University, Shanghai, 200040, China
| | - Li Zhang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Jun Chen
- Department of Sports Medicine, Fudan University, Shanghai, 200040, China
| | - Shi-Yi Chen
- Department of Sports Medicine, Fudan University, Shanghai, 200040, China.
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Shapiro SA, Smith CG, Arthurs JR, Master Z. Preparing regenerative therapies for clinical application: proposals for responsible translation. Regen Med 2019; 14:77-84. [DOI: 10.2217/rme-2018-0163] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Shane A Shapiro
- Department of Orthopedic Surgery, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
- Mayo Clinic Center for Regenerative Medicine, 200 First Street, SW, Rochester, MN 55905, USA
| | - Cambray G Smith
- Biomedical Ethics Research Program, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, USA
| | - Jennifer R Arthurs
- Mayo Clinic Center for Regenerative Medicine, 200 First Street, SW, Rochester, MN 55905, USA
| | - Zubin Master
- Mayo Clinic Center for Regenerative Medicine, 200 First Street, SW, Rochester, MN 55905, USA
- Biomedical Ethics Research Program, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, USA
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Functional Role of Circular RNA in Regenerative Medicine. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1087:299-308. [PMID: 30259376 DOI: 10.1007/978-981-13-1426-1_24] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Every year, millions of people around the world suffer from different forms of tissue trauma. Regenerative medicine refers to therapy that replaces the injured organ or cells. Stem cells are the frontiers and hotspots of current regenerative medicine research. Circular RNAs (circRNAs) are essential for the early development of many species. It was found that they could guide stem cell differentiation through interacting with certain microRNAs (miRNAs). Based on this concept, it is meaningful to look into how circRNAs influence stem cells and its role in regenerative medicine. In this chapter we will discuss the functional roles of circRNAs in the prevention, repair, or progression of chronic diseases, through the communication between stem cells.
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Zhang NK, Cao Y, Zhu ZM, Zheng N, Wang L, Xu XH, Gao LR. Activation of Endogenous Cardiac Stem Cells by Apelin-13 in Infarcted Rat Heart. Cell Transplant 2016; 25:1645-1652. [PMID: 26924778 DOI: 10.3727/096368916x691123] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Our previous study demonstrated that the apelin-APJ pathway contributed to myocardial regeneration and functional recovery after bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation during the differentiation of BM-MSCs into cardiomyogenic cells in acute myocardial infarction (AMI) rat models. However, the underlying mechanisms by which apelin promotes cardiac repair and functional recovery have not been completely clarified. In the present study, we investigated whether apelin could mobilize and activate endogenous cardiac stem cells and progenitors, thereby mediating regeneration and repair of the myocardium after AMI in rat models. Six-week-old male Sprague-Dawley rats underwent AMI and received apelin-13 (200 ng, n = 10) or an equivalent volume of saline by intramyocardial injection (n = 10); there was also a sham operation group (n = 8). Proliferation of endogenous cardiac stem cells was analyzed by immunofluorescence staining in rat infarcted myocardium, and heart function was evaluated by echocardiography at 28 days after apelin-13 injection. Treatment with apelin-13 led to a significant increase of Ki-67+-c-kit+/Sca-1+/Flk-1+ endogenous cardiac stem or progenitor cells in the border zone and infarct zone of rat hearts at 28 days after myocardial infarction (MI). Significant increases in the expression of c-kit, Sca-1, and Flk-1 on both levels of transcription and translation were confirmed by real-time polymerase chain reaction (RT-PCR) and Western blot. Treatment of apelin-13 also resulted in a significant reduction of infarct size and improvement of cardiac function post-MI. We conclude that apelin-13 is able to enhance mobilization, survival, and proliferation of endogenous myocardial stem cells in the injured heart, providing a novel mechanistic explanation for how apelin-13 might repair the heart and improve cardiac function. Thus, apelin-13 or pharmacological agonists of the APJ receptor could act as novel therapies for heart regeneration.
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Affiliation(s)
- Ning Kun Zhang
- Center of Cardiology, Navy General Hospital, Beijing, China
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Terzic A, Pfenning MA, Gores GJ, Harper CM. Regenerative Medicine Build-Out. Stem Cells Transl Med 2015; 4:1373-9. [PMID: 26537392 PMCID: PMC4675513 DOI: 10.5966/sctm.2015-0275] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 10/23/2015] [Indexed: 01/20/2023] Open
Abstract
UNLABELLED Regenerative technologies strive to boost innate repair processes and restitute normative impact. Deployment of regenerative principles into practice is poised to usher in a new era in health care, driving radical innovation in patient management to address the needs of an aging population challenged by escalating chronic diseases. There is urgency to design, execute, and validate viable paradigms for translating and implementing the science of regenerative medicine into tangible health benefits that provide value to stakeholders. A regenerative medicine model of care would entail scalable production and standardized application of clinical grade biotherapies supported by comprehensive supply chain capabilities that integrate sourcing and manufacturing with care delivery. Mayo Clinic has rolled out a blueprint for discovery, translation, and application of regenerative medicine therapies for accelerated adoption into the standard of care. To establish regenerative medical and surgical service lines, the Mayo Clinic model incorporates patient access, enabling platforms and delivery. Access is coordinated through a designated portal, the Regenerative Medicine Consult Service, serving to facilitate patient/provider education, procurement of biomaterials, referral to specialty services, and/or regenerative interventions, often in clinical trials. Platforms include the Regenerative Medicine Biotrust and Good Manufacturing Practice facilities for manufacture of clinical grade products for cell-based, acellular, and/or biomaterial applications. Care delivery leverages dedicated interventional suites for provision of regenerative services. Performance is tracked using a scorecard system to inform decision making. The Mayo Clinic roadmap exemplifies an integrated organization in the discovery, development, and delivery of regenerative medicine within a growing community of practice at the core of modern health care. SIGNIFICANCE Regenerative medicine is at the vanguard of health care poised to offer solutions for many of today's incurable diseases. Accordingly, there is a pressing need to develop, deploy, and demonstrate a viable framework for rollout of a regenerative medicine model of care. Translation of regenerative medicine principles into practice is feasible, yet clinical validity and utility must be established to ensure approval and adoption. Standardized and scaled-up regenerative products and services across medical and surgical specialties must in turn achieve a value-added proposition, advancing intended outcome beyond current management strategies.
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Milasinovic D, Mohl W. Contemporary perspective on endogenous myocardial regeneration. World J Stem Cells 2015; 7:793-805. [PMID: 26131310 PMCID: PMC4478626 DOI: 10.4252/wjsc.v7.i5.793] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Revised: 03/01/2015] [Accepted: 04/20/2015] [Indexed: 02/06/2023] Open
Abstract
Considering the complex nature of the adult heart, it is no wonder that innate regenerative processes, while maintaining adequate cardiac function, fall short in myocardial jeopardy. In spite of these enchaining limitations, cardiac rejuvenation occurs as well as restricted regeneration. In this review, the background as well as potential mechanisms of endogenous myocardial regeneration are summarized. We present and analyze the available evidence in three subsequent steps. First, we examine the experimental research data that provide insights into the mechanisms and origins of the replicating cardiac myocytes, including cell populations referred to as cardiac progenitor cells (i.e., c-kit+ cells). Second, we describe the role of clinical settings such as acute or chronic myocardial ischemia, as initiators of pathways of endogenous myocardial regeneration. Third, the hitherto conducted clinical studies that examined different approaches of initiating endogenous myocardial regeneration in failing human hearts are analyzed. In conclusion, we present the evidence in support of the notion that regaining cardiac function beyond cellular replacement of dysfunctional myocardium via initiation of innate regenerative pathways could create a new perspective and a paradigm change in heart failure therapeutics. Reinitiating cardiac morphogenesis by reintroducing developmental pathways in the adult failing heart might provide a feasible way of tissue regeneration. Based on our hypothesis “embryonic recall”, we present first supporting evidence on regenerative impulses in the myocardium, as induced by developmental processes.
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Närhi MO, Nordström K. Regulation of cell-based therapeutic products intended for human applications in the EU. Regen Med 2014; 9:327-51. [PMID: 24935044 DOI: 10.2217/rme.14.10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
AIMS Recent developments in the field of cell-based therapeutic products (CBTPs) have forced the EU to revise its legislation on therapeutic products by enacting several new legal instruments. In this study, we investigate how CBTPs are regulated and what determines their regulatory classification. Furthermore, we compare the regulatory burden between CBTPs in different product categories. MATERIALS & METHODS Product categories covering CBTPs were identified and characteristics critical for the regulatory classification of a CBTP were determined in each category. The effect of the critical characteristics on the classification was evaluated by constructing a decision tree that covers all possible combinations of the critical characteristics. Differences in the regulatory burden between CBTPs were evaluated by comparing regulations crucial for placing a therapeutic product on the EU market between the product categories. RESULTS Regulation of CBTPs has been divided between the main product categories of the EU legal framework for therapeutic products on the basis of the characteristics of the cells that the CBTPs contain. The regulatory burden is lowest for CBTPs regulated as blood, cells or tissues, and highest for CBTPs regulated as medicinal products. CONCLUSION CBTPs exist in all product categories of the EU legal framework for therapeutic products. However, the current framework does not cover all possible CBTPs. Furthermore, our results indicate that the regulatory burden of a CBTP is related to the risk it may pose to the health and safety of recipients.
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Affiliation(s)
- Marko O Närhi
- Department of Biotechnology & Chemical Technology, Aalto University, School of Chemical Technology, Espoo, Finland
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Nadal-Ginard B, Ellison GM, Torella D. The cardiac stem cell compartment is indispensable for myocardial cell homeostasis, repair and regeneration in the adult. Stem Cell Res 2014; 13:615-30. [PMID: 24838077 DOI: 10.1016/j.scr.2014.04.008] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Revised: 02/24/2014] [Accepted: 04/18/2014] [Indexed: 02/07/2023] Open
Abstract
Resident cardiac stem cells in embryonic, neonatal and adult mammalian heart have been identified by different membrane markers and transcription factors. However, despite a flurry of publications no consensus has been reached on the identity and actual regenerative effects of the adult cardiac stem cells. Intensive research on the adult mammalian heart's capacity for self-renewal of its muscle cell mass has led to a consensus that new cardiomyocytes (CMs) are indeed formed throughout adult mammalian life albeit at a disputed frequency. The physiological significance of this renewal, the origin of the new CMs, and the rate of adult CM turnover are still highly debated. Myocyte replacement, particularly after injury, was originally attributed to differentiation of a stem cell compartment. More recently, it has been reported that CMs are mainly replaced by the division of pre-existing post-mitotic CMs. These latter results, if confirmed, would shift the target of regenerative therapy toward boosting mature CM cell-cycle re-entry. Despite this controversy, it is documented that the adult endogenous c-kit(pos) cardiac stem cells (c-kit(pos) eCSCs) participate in adaptations to myocardial stress, and, when transplanted into the myocardium, regenerate most cardiomyocytes and microvasculature lost in an infarct. Nevertheless, the in situ myogenic potential of adult c-kit(pos) cardiac cells has been questioned. To revisit the regenerative potential of c-kit(pos) eCSCs, we have recently employed experimental protocols of severe diffuse myocardial damage in combination with several genetic murine models and cell transplantation approaches showing that eCSCs are necessary and sufficient for CM regeneration, leading to complete cellular, anatomical, and functional myocardial recovery. Here we will review the available data on adult eCSC biology and their regenerative potential placing it in the context of the different claimed mechanisms of CM replacement. These data are in agreement with and have reinforced our view that most CMs are replaced by de novo CM formation through the activation, myogenic commitment and specification of the eCSC cohort.
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Affiliation(s)
- Bernardo Nadal-Ginard
- Department of Physiology, School of Biomedical Sciences, King's College, London, UK; Centre for Stem Cells & Regenerative Medicine, King's College, London, UK.
| | - Georgina M Ellison
- Department of Physiology, School of Biomedical Sciences, King's College, London, UK; Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro 88100, Italy; Centre for Stem Cells & Regenerative Medicine, King's College, London, UK
| | - Daniele Torella
- Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro 88100, Italy.
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Affiliation(s)
- Andre Terzic
- Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA
| | - Atta Behfar
- Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA
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Terzic A, Harper CM, Gores GJ, Pfenning MA. Regenerative Medicine Blueprint. Stem Cells Dev 2013; 22 Suppl 1:20-4. [DOI: 10.1089/scd.2013.0448] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Affiliation(s)
- Andre Terzic
- Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota
| | - C. Michel Harper
- Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota
| | - Gregory J. Gores
- Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota
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Matteson EL, Terzic A. Introduction to the Symposium on Regenerative Medicine. Mayo Clin Proc 2013; 88:645-6. [PMID: 23809314 DOI: 10.1016/j.mayocp.2013.04.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 04/12/2013] [Accepted: 04/22/2013] [Indexed: 02/08/2023]
Affiliation(s)
- Eric L Matteson
- Division of Rheumatology, Department of Medicine, and Division of Epidemiology, Department of Health Sciences Research.
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Terzic A, Nelson TJ. Regenerative medicine primer. Mayo Clin Proc 2013; 88:766-75. [PMID: 23809322 DOI: 10.1016/j.mayocp.2013.04.017] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Revised: 04/12/2013] [Accepted: 04/16/2013] [Indexed: 01/14/2023]
Abstract
The pandemic of chronic diseases, compounded by the scarcity of usable donor organs, mandates radical innovation to address the growing unmet needs of individuals and populations. Beyond life-extending measures that are often the last available option, regenerative strategies offer transformative solutions in treating degenerative conditions. By leveraging newfound knowledge of the intimate processes fundamental to organogenesis and healing, the emerging regenerative armamentarium aims to boost the aptitude of human tissues for self-renewal. Regenerative technologies strive to promote, augment, and reestablish native repair processes, restituting organ structure and function. Multimodal regenerative approaches incorporate transplant of healthy tissues into damaged environments, prompt the body to enact a regenerative response in damaged tissues, and use tissue engineering to manufacture new tissue. Stem cells and their products have a unique aptitude to form specialized tissues and promote repair signaling, providing active ingredients of regenerative regimens. Concomitantly, advances in materials science and biotechnology have unlocked additional prospects for growing tissue grafts and engineering organs. Translation of regenerative principles into practice is feasible and safe in the clinical setting. Regenerative medicine and surgery are, thus, poised to transit from proof-of-principle studies toward clinical validation and, ultimately, standardization, paving the way for next-generation individualized management algorithms.
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Affiliation(s)
- Andre Terzic
- Mayo Clinic Center for Regenerative Medicine, Mayo Clinic, Rochester, MN; Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, MN; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN; Department of Medical Genetics, Mayo Clinic, Rochester, MN.
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Bartunek J, Behfar A, Dolatabadi D, Vanderheyden M, Ostojic M, Dens J, El Nakadi B, Banovic M, Beleslin B, Vrolix M, Legrand V, Vrints C, Vanoverschelde JL, Crespo-Diaz R, Homsy C, Tendera M, Waldman S, Wijns W, Terzic A. Cardiopoietic stem cell therapy in heart failure: the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) multicenter randomized trial with lineage-specified biologics. J Am Coll Cardiol 2013; 61:2329-38. [PMID: 23583246 DOI: 10.1016/j.jacc.2013.02.071] [Citation(s) in RCA: 374] [Impact Index Per Article: 31.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Accepted: 02/05/2013] [Indexed: 02/08/2023]
Abstract
OBJECTIVES This study sought to evaluate the feasibility and safety of autologous bone marrow-derived and cardiogenically oriented mesenchymal stem cell therapy and to probe for signs of efficacy in patients with chronic heart failure. BACKGROUND In pre-clinical heart failure models, cardiopoietic stem cell therapy improves left ventricular function and blunts pathological remodeling. METHODS The C-CURE (Cardiopoietic stem Cell therapy in heart failURE) trial, a prospective, multicenter, randomized trial, was conducted in patients with heart failure of ischemic origin who received standard of care or standard of care plus lineage-specified stem cells. In the cell therapy arm, bone marrow was harvested and isolated mesenchymal stem cells were exposed to a cardiogenic cocktail. Derived cardiopoietic stem cells, meeting release criteria under Good Manufacturing Practice, were delivered by endomyocardial injections guided by left ventricular electromechanical mapping. Data acquisition and analysis were performed in blinded fashion. The primary endpoint was feasibility/safety at 2-year follow-up. Secondary endpoints included cardiac structure/function and measures of global clinical performance 6 months post-therapy. RESULTS Mesenchymal stem cell cocktail-based priming was achieved for each patient with the dose attained in 75% and delivery without complications in 100% of cases. There was no evidence of increased cardiac or systemic toxicity induced by cardiopoietic cell therapy. Left ventricular ejection fraction was improved by cell therapy (from 27.5 ± 1.0% to 34.5 ± 1.1%) versus standard of care alone (from 27.8 ± 2.0% to 28.0 ± 1.8%, p < 0.0001) and was associated with a reduction in left ventricular end-systolic volume (-24.8 ± 3.0 ml vs. -8.8 ± 3.9 ml, p < 0.001). Cell therapy also improved the 6-min walk distance (+62 ± 18 m vs. -15 ± 20 m, p < 0.01) and provided a superior composite clinical score encompassing cardiac parameters in tandem with New York Heart Association functional class, quality of life, physical performance, hospitalization, and event-free survival. CONCLUSIONS The C-CURE trial implements the paradigm of lineage guidance in cell therapy. Cardiopoietic stem cell therapy was found feasible and safe with signs of benefit in chronic heart failure, meriting definitive clinical evaluation. (C-Cure Clinical Trial; NCT00810238).
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Affiliation(s)
- Jozef Bartunek
- Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium.
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O'Gara PT, Kushner FG, Ascheim DD, Casey DE, Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX, Anderson JL, Jacobs AK, Halperin JL, Albert NM, Brindis RG, Creager MA, DeMets D, Guyton RA, Hochman JS, Kovacs RJ, Kushner FG, Ohman EM, Stevenson WG, Yancy CW. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2012; 127:e362-425. [PMID: 23247304 DOI: 10.1161/cir.0b013e3182742cf6] [Citation(s) in RCA: 1126] [Impact Index Per Article: 86.6] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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18
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O'Gara PT, Kushner FG, Ascheim DD, Casey DE, Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2012; 61:e78-e140. [PMID: 23256914 DOI: 10.1016/j.jacc.2012.11.019] [Citation(s) in RCA: 2266] [Impact Index Per Article: 174.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Escobedo-Uribe CD, Monsiváis-Urenda AE, López-Quijano JM, Carrillo-Calvillo J, Leiva-Pons JL, Peña-Duque MA. [Cell therapy for ischemic heart disease]. ARCHIVOS DE CARDIOLOGIA DE MEXICO 2012; 82:218-29. [PMID: 23021359 DOI: 10.1016/j.acmx.2012.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2011] [Revised: 01/02/2012] [Accepted: 04/17/2012] [Indexed: 10/27/2022] Open
Abstract
Ischemic heart disease is the leading cause of death and heart failure worldwide. That is why it is important to develop new therapeutic modalities to decrease mortality and long-term complications in these patients. One of the main lines of research worldwide is myocardial regeneration, using progenitor cells in order to improve systolic and diastolic function in patients with ischemic heart disease, as well as to increase their survival. There have been carried out, with great enthusiasm worldwide, human and animal studies to define the usefulness of stem cells in the management of patients with ischemic heart disease. Today, regenerative therapy in ischemic heart disease is considered a novel therapeutic tool, with substantial theoretical benefits and few side effects. Here we present the scientific principles that support the use of this therapy, discuss the current clinical evidence available; and point out the controversial issues still not clarified on its use and usefulness in the short and long term.
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Possible clinical usefulness of embryonic stem cells. Rev Clin Esp 2012; 212:403-6. [PMID: 22765959 DOI: 10.1016/j.rce.2012.05.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2012] [Revised: 05/11/2012] [Accepted: 05/14/2012] [Indexed: 11/21/2022]
Abstract
Are embryonic stem cells being used for therapeutic purposes? The aim of this short report is to review to what extent are embryonic stem cells currently used for therapeutic purposes. To the best of our knowledge, only four clinical trials have been authorised so far to use human embryonic stem cells for therapeutic purposes; two of these are included in the ClinicalTrials.gov data base, and the other two, the study sponsored by Geron and the last one initiated by Advanced Cell Technology in the United Kingdom, are not. But, in addition, Geron withdrew the clinical trial which had been originally proposed by the company itself. This brief review focuses the debate on the use of embryonic stem cells in human cell therapy. To the best of our knowledge, only three trials are ongoing with therapeutic purposes thus far, with not all of them having begun to include patients, and of course without any of them yet having obtained evaluable clinical results.
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Folmes CDL, Nelson TJ, Dzeja PP, Terzic A. Energy metabolism plasticity enables stemness programs. Ann N Y Acad Sci 2012; 1254:82-89. [PMID: 22548573 DOI: 10.1111/j.1749-6632.2012.06487.x] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Engineering pluripotency through nuclear reprogramming and directing stem cells into defined lineages underscores cell fate plasticity. Acquisition of and departure from stemness are governed by genetic and epigenetic controllers, with modulation of energy metabolism and associated signaling increasingly implicated in cell identity determination. Transition from oxidative metabolism, typical of somatic tissues, into glycolysis is a prerequisite to fuel-proficient reprogramming, directing a differentiated cytotype back to the pluripotent state. The glycolytic metabotype supports the anabolic and catabolic requirements of pluripotent cell homeostasis. Conversely, redirection of pluripotency into defined lineages requires mitochondrial biogenesis and maturation of efficient oxidative energy generation and distribution networks to match demands. The vital function of bioenergetics in regulating stemness and lineage specification implicates a broader role for metabolic reprogramming in cell fate decisions and determinations of tissue regenerative potential.
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Affiliation(s)
- Clifford D L Folmes
- Center for Regenerative Medicine, Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA
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Ellison GM, Nadal-Ginard B, Torella D. Optimizing cardiac repair and regeneration through activation of the endogenous cardiac stem cell compartment. J Cardiovasc Transl Res 2012; 5:667-77. [PMID: 22688972 DOI: 10.1007/s12265-012-9384-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2012] [Accepted: 05/24/2012] [Indexed: 12/21/2022]
Abstract
Given the aging of the Western World and declining death rates due to acute coronary syndromes, the increasing trends in the magnitude and morbidity of heart failure (HF) are predicted to continue for the foreseeable future. It is imperative to develop effective therapies for the amelioration and prevention of HF. The search for the best cell type to be used in clinical protocols of cardiac regeneration is still on. That the adult mammalian heart harbors endogenous, multipotent cardiac stem/progenitor cells (eCSCs) and that cardiomyocytes are replaced throughout adulthood represent a paradigm shift in cardiovascular biology. The presence of eCSCs supports the view that the heart can repair itself if the eCSCs can be properly stimulated. Pending a better understanding of eCSC biology, it should be possible to replace autologous cell transplantation-based myocardial regeneration protocols with an "off-the-shelf," readily available, and effective regenerative/reparative therapy based on activation of the eCSCs in situ.
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Affiliation(s)
- Georgina M Ellison
- Stem Cell & Regenerative Biology Unit (BioStem), RISES, Liverpool John Moores University, Byrom Street, Liverpool, UK.
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Ellison GM, Torella D, Dellegrottaglie S, Perez-Martinez C, Perez de Prado A, Vicinanza C, Purushothaman S, Galuppo V, Iaconetti C, Waring CD, Smith A, Torella M, Cuellas Ramon C, Gonzalo-Orden JM, Agosti V, Indolfi C, Galiñanes M, Fernandez-Vazquez F, Nadal-Ginard B. Endogenous cardiac stem cell activation by insulin-like growth factor-1/hepatocyte growth factor intracoronary injection fosters survival and regeneration of the infarcted pig heart. J Am Coll Cardiol 2011; 58:977-86. [PMID: 21723061 DOI: 10.1016/j.jacc.2011.05.013] [Citation(s) in RCA: 182] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2011] [Revised: 05/20/2011] [Accepted: 05/24/2011] [Indexed: 11/20/2022]
Abstract
OBJECTIVES The purpose of this study was to test the ability of insulin-like growth factor (IGF)-1/hepatocyte growth factor (HGF) to activate resident endogenous porcine cardiac stem/progenitor cells (epCSCs) and to promote myocardial repair through a clinically applicable intracoronary injection protocol in a pig model of myocardial infarction (MI) relevant to human disease. BACKGROUND In rodents, cardiac stem/progenitor cell (CSC) transplantation as well as in situ activation through intramyocardial injection of specific growth factors has been shown to result in myocardial regeneration after acute myocardial infarction (AMI). METHODS Acute MI was induced in pigs by a 60-min percutaneous transluminal coronary angiography left anterior descending artery occlusion. The IGF-1 and HGF were co-administered through the infarct-related artery in a single dose (ranging from 0.5 to 2 μg HGF and 2 to 8 μg IGF-1) 30 min after coronary reperfusion. Pigs were sacrificed 21 days later for dose-response relationship evaluation by immunohistopathology or 2 months later for cardiac function evaluation by cardiac magnetic resonance imaging. RESULTS The IGF-1/HGF activated c-kit positive-CD45 negative epCSCs and increased their myogenic differentiation in vitro. The IGF-1/HGF, in a dose-dependent manner, improved cardiomyocyte survival, and reduced fibrosis and cardiomyocyte reactive hypertrophy. It significantly increased c-kit positive-CD45 negative epCSC number and fostered the generation of new myocardium (myocytes and microvasculature) in infarcted and peri-infarct/border regions at 21 and 60 days after AMI. The IGF-1/HGF reduced infarct size and improved left ventricular function at 2 months after AMI. CONCLUSIONS In an animal model of AMI relevant to the human disease, intracoronary administration of IGF-1/HGF is a practical and effective strategy to reduce pathological cardiac remodeling, induce myocardial regeneration, and improve ventricular function.
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Affiliation(s)
- Georgina M Ellison
- The Stem Cell and Regenerative Biology Unit (BioStem), RISES, Liverpool John Moores University, Liverpool, UK
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Terzic A, Folmes CD, Martinez-Fernandez A, Behfar A. Regenerative medicine: on the vanguard of health care. Mayo Clin Proc 2011; 86:600-2. [PMID: 21719616 PMCID: PMC3127554 DOI: 10.4065/mcp.2011.0325] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Terzic A, Waldman SA. Translational medicine: path to personalized and public health. Biomark Med 2011; 4:787-90. [PMID: 21133696 DOI: 10.2217/bmm.10.101] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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Nuclear reprogramming strategy modulates differentiation potential of induced pluripotent stem cells. J Cardiovasc Transl Res 2011; 4:131-7. [PMID: 21207217 PMCID: PMC3047690 DOI: 10.1007/s12265-010-9250-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2010] [Accepted: 11/17/2010] [Indexed: 01/23/2023]
Abstract
Bioengineered by ectopic expression of stemness factors, induced pluripotent stem (iPS) cells demonstrate embryonic stem cell-like properties and offer a unique platform for derivation of autologous pluripotent cells from somatic tissue sources. In the process of nuclear reprogramming, somatic tissues are converted to a pluripotent ground state, thus unlocking an unlimited potential to expand progenitor pools. Molecular dissection of nuclear reprogramming suggests that a residual memory derived from the original parental source, along with the remnants of the reprogramming process itself, leads to a biased potential of the bioengineered progeny to differentiate into target tissues such as cardiac cytotypes. In this way, iPS cells that fulfill pluripotency criteria may display heterogeneous profiles for lineage specification. Small molecule-based strategies have been identified that modulate the epigenetic state of reprogrammed cells and are optimized to erase the residual memory and homogenize the differentiation potential of iPS cells derived from distinct backgrounds. Here, we describe the salient components of the reprogramming process and their effect on the downstream differentiation capacity of the iPS populations in the context of cardiovascular regenerative applications.
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Bardelli S, Astori G, Sürder D, Tallone T, Terzic A, Soldati G, Moccetti T. Stem cell update: highlights from the 2010 Lugano Stem Cell Meeting. J Cardiovasc Transl Res 2010; 4:192-9. [PMID: 21052883 DOI: 10.1007/s12265-010-9232-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Accepted: 10/19/2010] [Indexed: 01/08/2023]
Abstract
The 2010 edition of the Lugano Stem Cell Meeting, under the auspices of the Swiss center of excellence in cardiovascular diseases "Cardiocentro Ticino" and the Swiss Stem Cell Foundation, offered an update on clinical, translational, and biotechnological advances in regenerative science and medicine pertinent to cardiovascular applications. Highlights from the international forum ranged from innate mechanisms of heart repair, safety, and efficacy of ongoing and completed clinical trials, novel generations of stem cell biologics, bioengineered platforms, and regulatory processes. In the emerging era of regenerative medicine, accelerating the critical path from discovery to product development will require integrated multidisciplinary teams to ensure timely translation of new knowledge into validated algorithms for practice adoption.
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Abstract
Nuclear reprogramming of somatic cells with ectopic stemness factors to bioengineer pluripotent autologous stem cells signals a new era in regenerative medicine. The study of developmental biology has provided a roadmap for cardiac differentiation from embryonic tissue formation to adult heart muscle rejuvenation. Understanding the molecular mechanisms of stem-cell-derived cardiogenesis enables the reproducible generation, isolation, and monitoring of progenitors that have the capacity to recapitulate embryogenesis and differentiate into mature cardiac tissue. With the advent of induced pluripotent stem (iPS) cell technology, patient-specific stem cells provide a reference point to systematically decipher cardiogenic differentiation through discrete stages of development. Interrogation of iPS cells and their progeny from selected cohorts of patients is an innovative approach towards uncovering the molecular mechanisms of disease. Thus, the principles of cardiogenesis can now be applied to regenerative medicine in order to optimize personalized therapeutics, diagnostics, and discovery-based science for the development of novel clinical applications.
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Chiriac A, Terzic A, Park S, Ikeda Y, Faustino R, Nelson TJ. SDF-1-enhanced cardiogenesis requires CXCR4 induction in pluripotent stem cells. J Cardiovasc Transl Res 2010; 3:674-82. [PMID: 20842469 DOI: 10.1007/s12265-010-9219-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2010] [Accepted: 08/19/2010] [Indexed: 12/11/2022]
Abstract
Transformation of pluripotent stem cells into cardiac tissue is the hallmark of cardiogenesis, yet pro-cardiogenic signals remain partially understood. Preceding cardiogenic induction, a surge in CXCR4 chemokine receptor expression in the early stages of stem cell lineage specification coincides with the acquisition of pre-cardiac profiles. Accordingly, CXCR4 selection, in conjunction with mesoderm-specific VEGF type II receptor FLK-1 co-expression, segregates cardiogenic populations. To assess the functionality of the CXCR4 biomarker, targeted activation and disruption were here exploited in the context of embryonic stem cell-derived cardiogenesis. Implicated as a cardiogenic hub through unbiased bioinformatics analysis, induction of the CXCR4/SDF-1 receptor-ligand axis triggered enhanced beating activity in stem cell progeny. Gene expression knockdown of CXCR4 disrupted spontaneous embryoid body differentiation and blunted the expression of cardiogenic markers MEF2C, Nkx2.5, MLC2a, MLC2v, and cardiac-MHC. Exogenous SDF-1 treatment failed to rescue cardiogenic-deficient phenotype, demonstrating a requirement for CXCR4 expression in mediating SDF-1 effects. Thus, a pro-cardiogenic signaling role for the CXCR4/SDF1 axis is herein revealed within pluripotent stem cell progenitors, exposing a functional target to promote lineage-specific differentiation.
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Affiliation(s)
- Anca Chiriac
- Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Department of Medical Genetics, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
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