|
1
|
Hirai K, Sawada R, Hayashi T, Araki T, Nakagawa N, Kondo M, Yasuda K, Hirata T, Sato T, Nakatsuka Y, Yoshida M, Kasahara S, Baba K, Oh H. Eight-Year Outcomes of Cardiosphere-Derived Cells in Single Ventricle Congenital Heart Disease. J Am Heart Assoc 2024; 13:e038137. [PMID: 39526355 DOI: 10.1161/jaha.124.038137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 09/16/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Cardiosphere-derived cell (CDC) infusion was associated with better clinical outcomes at 2 years in patients with single ventricle heart disease. The current study investigates time-to-event outcomes at 8 years. METHODS AND RESULTS This cohort enrolled patients with single ventricles who underwent stage 2 or stage 3 palliation from January 2011 to January 2015 at 8 centers in Japan. The primary outcomes were time-dependent CDC treatment effects on death and late complications during 8 years of follow-up, assessed by restricted mean survival time. Among 93 patients enrolled (mean age, 2.3±1.3 years; 56% men), 40 received CDC infusion. Overall survival for CDC-treated versus control patients did not differ at 8 years (hazard ratio [HR], 0.60 [95% CI, 0.21-1.77]; P=0.35). Treatment effect had nonproportional hazards for death favoring CDCs at 4 years (restricted mean survival time difference +0.33 years [95% CI, 0.01-0.66]; P=0.043). In patients with heart failure with reduced ejection fraction, CDC treatment effect on survival was greater over 8 years (restricted mean survival time difference +1.58 years [95% CI, 0.05-3.12]; P=0.043). Compared with control participants, CDC-treated patients showed lower incidences of late failure (HR, 0.45 [95% CI, 0.21-0.93]; P=0.027) and adverse events (subdistribution HR, 0.50 [95% CI, 0.27-0.94]; P=0.036) at 8 years. CONCLUSIONS By 8 years, CDC infusion was associated with lower hazards of late failure and adverse events in single ventricle heart disease. CDC treatment effect on survival was notable by 4 years and showed a durable clinical benefit in patients with heart failure with reduced ejection fraction over 8 years. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01273857 and NCT01829750.
Collapse
Affiliation(s)
- Kenta Hirai
- Department of Pediatrics Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Okayama Japan
- Department of Regenerative Medicine, Center for Innovative Clinical Medicine Okayama University Hospital Okayama Japan
| | - Ryusuke Sawada
- Department of Pharmacology Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Okayama Japan
| | - Tomohiro Hayashi
- Department of Pediatrics Kurashiki Central Hospital Okayama Japan
| | - Toru Araki
- Department of Pediatrics National Hospital Organization Fukuyama Medical Center Hiroshima Japan
| | - Naomi Nakagawa
- Department of Pediatric Cardiology Hiroshima City Hiroshima Citizens Hospital Hiroshima Japan
| | - Maiko Kondo
- Department of Pediatrics Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Okayama Japan
- Department of Pediatrics Kochi Health Sciences Center Kochi Japan
| | - Kenji Yasuda
- Department of Pediatrics Shimane University Faculty of Medicine Izumo Shimane Japan
| | - Takuya Hirata
- Department of Pediatrics Kyoto University Graduate School of Medicine Kyoto Japan
| | - Tomoyuki Sato
- Department of Pediatrics Jichi Medical University Tochigi Japan
| | - Yuki Nakatsuka
- Department of Data Science, Center for Innovative Clinical Medicine Okayama University Hospital Okayama Japan
| | - Michihiro Yoshida
- Department of Data Science, Center for Innovative Clinical Medicine Okayama University Hospital Okayama Japan
| | - Shingo Kasahara
- Department of Cardiovascular Surgery Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Okayama Japan
| | - Kenji Baba
- Department of Pediatrics Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Okayama Japan
| | - Hidemasa Oh
- Department of Regenerative Medicine, Center for Innovative Clinical Medicine Okayama University Hospital Okayama Japan
| |
Collapse
|
|
2
|
Makkaoui N, Prasad V, Bagchi P, Carmona T, Li K, Latham OL, Zhang Y, Lee J, Furdui CM, Maxwell JT. Cell-based therapies reverse the heart failure-altered right ventricular proteome towards a pre-disease state. Stem Cell Res Ther 2024; 15:420. [PMID: 39533351 PMCID: PMC11559167 DOI: 10.1186/s13287-024-04009-3] [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: 07/19/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Congenital heart defects can lead to right ventricular (RV) pressure-overload and heart failure. Cell-based therapies, including mesenchymal stromal cells (MSCs) and c-kit positive cells (CPCs) have been studied clinically as options to restore heart function in disease states. Many studies have indicated these cells act through paracrine mechanisms to prevent apoptosis, promote cellular function, and regulate gene/protein expression. We aimed to determine the proteomic response of diseased hearts to cell therapy. METHODS We utilized a juvenile rat model of RV pressure overload created by banding the pulmonary artery (PAB). Two weeks post-banding, bone marrow-derived mesenchymal stromal cells (MSCs) and 3 populations of CPCs (nCPCs, cCPCs, ES-CPCs) were delivered to the RV free wall. RV function and cellular retention were measured for four weeks post-injection, at which point hearts were extracted and the RV was excised for liquid chromatography and tandem mass spectrometry. Resulting RV proteomes were compared and analyzed using systems biology and bioinformatics. RESULTS Proteomic profiling identified 1156 total proteins from the RV, of which 5.97% were significantly changed after PAB. This disease-altered proteome was responsive to cellular therapy, with 72% of the PAB-altered proteome being fully or partially reversed by MSC therapy. This was followed by nCPCs (54%), ES-CPCs (52%), and cCPCs (39%). Systems biology and bioinformatics analysis showed MSC, nCPC, or ES-CPC cell therapy is associated with a decrease in predicted adverse cardiac effects. We also observed an effect of cell therapy on the non-altered RV proteome, however, this was associated with minor predicted pathological endpoints. CONCLUSIONS Our data indicate MSCs, ES-CPCs, and nCPCs significantly reverse the PAB-altered proteome towards a pre-disease state in our animal model. These results indicate cell-based therapies show promise in improving RV function after pressure overload through partial restoration of the disease-altered cardiac proteome.
Collapse
Affiliation(s)
- Nour Makkaoui
- Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Children's Heart Research & Outcomes (HeRO) Center, Children's Healthcare of Atlanta & Emory University, Atlanta, GA, 30322, USA
| | - Vidhya Prasad
- Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Children's Heart Research & Outcomes (HeRO) Center, Children's Healthcare of Atlanta & Emory University, Atlanta, GA, 30322, USA
| | - Pritha Bagchi
- Emory Integrated Proteomics Core (EIPC), Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Tiffany Carmona
- Emory University College of Arts and Sciences, Atlanta, GA, 30322, USA
| | - Ke Li
- Emory University College of Arts and Sciences, Atlanta, GA, 30322, USA
| | - Olivia L Latham
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, 391 Technology Way, Winston-Salem, NC, 27101, USA
| | - Yuanyuan Zhang
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, 391 Technology Way, Winston-Salem, NC, 27101, USA
| | - Jingyun Lee
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Cristina M Furdui
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Joshua T Maxwell
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, 391 Technology Way, Winston-Salem, NC, 27101, USA.
- Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston-Salem, NC, USA.
| |
Collapse
|
|
3
|
Marbán E. Deconstructing Regenerative Medicine: From Mechanistic Studies of Cell Therapy to Novel Bioinspired RNA Drugs. Circ Res 2024; 135:877-885. [PMID: 39325847 PMCID: PMC11469554 DOI: 10.1161/circresaha.124.323058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/28/2024]
Abstract
All Food and Drug Administration-approved noncoding RNA (ncRNA) drugs (n≈20) target known disease-causing molecular pathways by mechanisms such as antisense. In a fortuitous evolution of work on regenerative medicine, my coworkers and I inverted the RNA drug discovery process: first we identified natural disease-modifying ncRNAs, then used them as templates for new synthetic RNA drugs. Mechanism was probed only after bioactivity had been demonstrated. The journey began with the development of cardiosphere-derived cells (CDCs) for cardiac regeneration. While testing CDCs in a first-in-human trial, we discovered they worked indirectly: ncRNAs within CDC-secreted extracellular vesicles mediate the therapeutic benefits. The vast majority of such ncRNAs are fragments of unknown function. We chose several abundant ncRNA species from CDC-secreted extracellular vesicles, synthesized and screened each of them in vitro and in vivo. Those with exceptional disease-modifying bioactivity inspired new chemical entities that conform to the structural conventions of the Food and Drug Administration-approved ncRNA armamentarium. This discovery arc-Cell-Derived RNA from Extracellular vesicles for bioinspired Drug develOpment, or CREDO-has yielded various promising lead compounds, each of which works via a unique, and often novel, mechanism. The process relies on emergent insights to shape therapeutic development. The initial focus of our inquiry-CDCs-are now themselves in phase 3 testing for Duchenne muscular dystrophy and its associated cardiomyopathy. But the intravenous delivery strategy and the repetitive dosing protocol for CDCs, which have proven key to clinical success, both arose from systematic mechanistic inquiry. Meanwhile, emergent insights have led to multiple cell-free therapeutic candidates: CDC-secreted extracellular vesicles are in preclinical development for ventricular arrhythmias, while the CREDO-conceived RNA drugs are in translation for diseases ranging from myocarditis to scleroderma.
Collapse
Affiliation(s)
- Eduardo Marbán
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| |
Collapse
|
|
4
|
Makkaoui N, Prasad V, Bagchi P, Carmona T, Li K, Latham O, Zhang Y, Lee J, Furdui C, Maxwell J. Cell-based therapies reverse the heart failure-altered right ventricular proteome. RESEARCH SQUARE 2024:rs.3.rs-4752035. [PMID: 39281857 PMCID: PMC11398576 DOI: 10.21203/rs.3.rs-4752035/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/18/2024]
Abstract
Background Congenital heart defects can lead to right ventricular (RV) pressure-overload and heart failure. Cell-based therapies, including mesenchymal stromal cells (MSCs) and c-kit positive cells (CPCs) have been studied clinically as options to restore heart function in disease states. Many studies have indicated these cells act through paracrine mechanisms to prevent apoptosis, promote cellular function, and regulate gene/protein expression. We aimed to determine the proteomic response of diseased hearts to cell therapy. Methods We utilized an animal model of RV pressure overload created by banding the pulmonary artery (PAB). Two weeks post-banding, bone marrow-derived mesenchymal stromal cells (MSCs) and 3 populations of CPCs (nCPCs, cCPCs, ES-CPCs) were delivered to the RV free wall. RV function and cellular retention were measured for four weeks post-injection, at which point hearts were extracted and the RV was excised for liquid chromatography and tandem mass spectrometry. Resulting RV proteomes were compared and analyzed using systems biology and bioinformatics. Results Proteomic profiling identified 1156 total proteins from the RV, of which 5.97% were significantly changed after PAB. This disease-altered proteome was responsive to cellular therapy, with 72% of the PAB-altered proteome being fully or partially reversed by MSC therapy. This was followed by nCPCs (54%), ES-CPCs (52%), and cCPCs (39%). Systems biology and bioinformatics analysis showed MSC, nCPC, or ES-CPC cell therapy is associated with a decrease in predicted adverse cardiac effects. We also observed an effect of cell therapy on the non-altered RV proteome, however, this was associated with minor predicted pathological endpoints. Conclusions Our data indicate MSCs, ES-CPCs, and nCPCs significantly reverse the PAB-altered proteome towards a pre-disease state. These results indicate cell-based therapies show promise in improving RV function after pressure overload through partial restoration of the disease-altered cardiac proteome.
Collapse
Affiliation(s)
| | | | | | | | - Ke Li
- Emory University Emory College of Arts and Sciences
| | | | | | | | | | | |
Collapse
|
|
5
|
Choubey U, Srinivas V, Trivedi YV, Garg N, Gupta V, Jain R. Regenerating the ailing heart: Stem cell therapies for hypoplastic left heart syndrome. Ann Pediatr Cardiol 2024; 17:124-131. [PMID: 39184114 PMCID: PMC11343389 DOI: 10.4103/apc.apc_24_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 04/14/2024] [Accepted: 04/14/2024] [Indexed: 08/27/2024] Open
Abstract
Hypoplastic left heart syndrome (HLHS) is a complex congenital heart defect (CHD) characterized by a spectrum of underdeveloped left-sided cardiac structures. It is a serious defect and warrants either 3-staged surgical palliation or a heart transplant. Despite numerous surgical advancements, long-term outcomes remain challenging and still have significant morbidity and mortality. There have been notable advancements in stem cell therapy for HLHS, including developments in diverse stem cell origins and methods of administration. Clinical trials have shown safety and potential benefits, including improved ventricular function, reduced heart failure, and fewer adverse events. Younger myocardium seems particularly receptive to stem cell signals, suggesting the importance of early intervention. This review explores the potential of emerging stem cell-based therapies as an adjunctive approach to improve the outcomes for HLHS patients.
Collapse
Affiliation(s)
- Udit Choubey
- Department of General Surgery, Shyam Shah Medical College, Rewa, Madhya Pradesh, India
| | - Varsha Srinivas
- Department of Internal Medicine, PES Institute of Medical Sciences and Research, Kuppam, Andhra Pradesh, India
| | - Yash Vardhan Trivedi
- Department of Internal Medicine, Jawaharlal Nehru Medical College, Ajmer, Rajasthan, India
| | - Nikita Garg
- Department of Pediatric College, Children’s Hospital of Michigan, Detroit, MI, USA
| | - Vasu Gupta
- Department of Internal Medicine, Cleveland Clinic Akron General, Akron, OH, USA
| | - Rohit Jain
- Penn State Milton S Hershey Medical Center, Hershey, PA, USA
| |
Collapse
|
|
6
|
Goto T, Ousaka D, Hirai K, Kotani Y, Kasahara S. Intravenous infusion of cardiac progenitor cells in animal models of single ventricular physiology. Eur J Cardiothorac Surg 2023; 64:ezad304. [PMID: 37824193 PMCID: PMC10576638 DOI: 10.1093/ejcts/ezad304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 08/17/2023] [Accepted: 10/11/2023] [Indexed: 10/13/2023] Open
Abstract
OBJECTIVES The goal of this study was to identify the practical applications of intravenous cell therapy for single-ventricle physiology (SVP) by establishing experimental SVP models. METHODS An SVP with a three-stage palliation was constructed in an acute swine model without cardiopulmonary bypass. A modified Blalock-Taussig (MBT) shunt was created using an aortopulmonary shunt with the superior and inferior venae cavae (SVC and IVC, respectively) connected to the left atrium (n = 10). A bidirectional cavopulmonary shunt (BCPS) was constructed using a graft between the IVC and the left atrium with an SVC cavopulmonary connection (n = 10). The SVC and the IVC were connected to the pulmonary artery to establish a total cavopulmonary connection (TCPC, n = 10). The survival times of half of the animal models were studied. The other half and the biventricular sham control (n = 5) were injected intravenously with cardiosphere-derived cells (CDCs), and the cardiac retention of CDCs was assessed after 2 h. RESULTS All SVP models died within 20 h. Perioperative mortality was higher in the BCPS group because of lower oxygen saturation (P < 0.001). Cardiac retention of intravenously delivered CDCs, as detected by magnetic resonance imaging and histologic analysis, was significantly higher in the modified Blalock-Taussig and BCPS groups than in the TCPC group (P < 0.01). CONCLUSIONS Without the total right heart exclusion, stage-specific SVP models can be functionally constructed in pigs with stable outcomes. Intravenous CDC injections may be applicable in patients with SVP before TCPC completion, given that the initial lung trafficking is efficiently bypassed and sufficient systemic blood flow is supplied from the single ventricle.
Collapse
Affiliation(s)
- Takuya Goto
- Department of Cardiovascular Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences and Okayama University Hospital, Okayama, Japan
| | - Daiki Ousaka
- Department of Cardiovascular Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences and Okayama University Hospital, Okayama, Japan
| | - Kenta Hirai
- Department of Cardiovascular Pediatrics, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences and Okayama University Hospital, Okayama, Japan
| | - Yasuhiro Kotani
- Department of Cardiovascular Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences and Okayama University Hospital, Okayama, Japan
| | - Shingo Kasahara
- Department of Cardiovascular Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences and Okayama University Hospital, Okayama, Japan
| |
Collapse
|
|
7
|
Williams K, Khan A, Lee YS, Hare JM. Cell-based therapy to boost right ventricular function and cardiovascular performance in hypoplastic left heart syndrome: Current approaches and future directions. Semin Perinatol 2023; 47:151725. [PMID: 37031035 PMCID: PMC10193409 DOI: 10.1016/j.semperi.2023.151725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/10/2023]
Abstract
Congenital heart disease remains one of the most frequently diagnosed congenital diseases of the newborn, with hypoplastic left heart syndrome (HLHS) being considered one of the most severe. This univentricular defect was uniformly fatal until the introduction, 40 years ago, of a complex surgical palliation consisting of multiple staged procedures spanning the first 4 years of the child's life. While survival has improved substantially, particularly in experienced centers, ventricular failure requiring heart transplant and a number of associated morbidities remain ongoing clinical challenges for these patients. Cell-based therapies aimed at boosting ventricular performance are under clinical evaluation as a novel intervention to decrease morbidity associated with surgical palliation. In this review, we will examine the current burden of HLHS and current modalities for treatment, discuss various cells therapies as an intervention while delineating challenges and future directions for this therapy for HLHS and other congenital heart diseases.
Collapse
Affiliation(s)
- Kevin Williams
- Department of Pediatrics, University of Miami Miller School of Medicine. Miami FL, USA; Batchelor Children's Research Institute University of Miami Miller School of Medicine. Miami FL, USA
| | - Aisha Khan
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami FL, USA
| | - Yee-Shuan Lee
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami FL, USA
| | - Joshua M Hare
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami FL, USA; Division of Cardiology, Department of Medicine, University of Miami Miller School of Medicine. Miami FL, USA.
| |
Collapse
|
|
8
|
Damianos A, Sammour I. Barriers in translating stem cell therapies for neonatal diseases. Semin Perinatol 2023; 47:151731. [PMID: 36990922 DOI: 10.1016/j.semperi.2023.151731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
Abstract
Over the last 20 years, stem cells of varying origin and their associated secretome have been investigated as a therapeutic option for a myriad of neonatal models of disease, with very promising results. Despite the devastating nature of some of these disorders, translation of the preclinical evidence to the bedside has been slow. In this review, we explore the existing clinical evidence for stem cell therapies in neonates, highlight the barriers faced by researchers and suggest potential solutions to move the field forward.
Collapse
Affiliation(s)
- Andreas Damianos
- Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, Ohio
| | - Ibrahim Sammour
- Riley Hospital for Children, Indiana University, Indianapolis, USA.
| |
Collapse
|
|
9
|
Kaushal S, Hare JM, Hoffman JR, Boyd RM, Ramdas KN, Pietris N, Kutty S, Tweddell JS, Husain SA, Menon SC, Lambert LM, Danford DA, Kligerman SJ, Hibino N, Korutla L, Vallabhajosyula P, Campbell MJ, Khan A, Naioti E, Yousefi K, Mehranfard D, McClain-Moss L, Oliva AA, Davis ME. Intramyocardial cell-based therapy with Lomecel-B during bidirectional cavopulmonary anastomosis for hypoplastic left heart syndrome: the ELPIS phase I trial. EUROPEAN HEART JOURNAL OPEN 2023; 3:oead002. [PMID: 36950450 PMCID: PMC10026620 DOI: 10.1093/ehjopen/oead002] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 12/19/2022] [Accepted: 01/06/2023] [Indexed: 01/13/2023]
Abstract
Aims Hypoplastic left heart syndrome (HLHS) survival relies on surgical reconstruction of the right ventricle (RV) to provide systemic circulation. This substantially increases the RV load, wall stress, maladaptive remodelling, and dysfunction, which in turn increases the risk of death or transplantation. Methods and results We conducted a phase 1 open-label multicentre trial to assess the safety and feasibility of Lomecel-B as an adjunct to second-stage HLHS surgical palliation. Lomecel-B, an investigational cell therapy consisting of allogeneic medicinal signalling cells (MSCs), was delivered via intramyocardial injections. The primary endpoint was safety, and measures of RV function for potential efficacy were obtained. Ten patients were treated. None experienced major adverse cardiac events. All were alive and transplant-free at 1-year post-treatment, and experienced growth comparable to healthy historical data. Cardiac magnetic resonance imaging (CMR) suggested improved tricuspid regurgitant fraction (TR RF) via qualitative rater assessment, and via significant quantitative improvements from baseline at 6 and 12 months post-treatment (P < 0.05). Global longitudinal strain (GLS) and RV ejection fraction (EF) showed no declines. To understand potential mechanisms of action, circulating exosomes from intramyocardially transplanted MSCs were examined. Computational modelling identified 54 MSC-specific exosome ribonucleic acids (RNAs) corresponding to changes in TR RF, including miR-215-3p, miR-374b-3p, and RNAs related to cell metabolism and MAPK signalling. Conclusion Intramyocardially delivered Lomecel-B appears safe in HLHS patients and may favourably affect RV performance. Circulating exosomes of transplanted MSC-specific provide novel insight into bioactivity. Conduct of a controlled phase trial is warranted and is underway.Trial registration number NCT03525418.
Collapse
Affiliation(s)
- Sunjay Kaushal
- The Heart Center, Division of Cardiovascular-Thoracic Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, 225 E. Chicago Avenue, Chicago, IL 60611, USA
| | - Joshua M Hare
- Longeveron Inc, 1951 NW 7th Avenue, Suite 520, Miami, FL 33136, USA
- Department of Medicine and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, 1501 NW 10th Avenue, Miami, FL 33136, USA
| | - Jessica R Hoffman
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University School of Medicine, 313 Ferst Drive, Atlanta, GA 30332, USA
| | - Riley M Boyd
- The Heart Center, Division of Cardiovascular-Thoracic Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, 225 E. Chicago Avenue, Chicago, IL 60611, USA
| | - Kevin N Ramdas
- Longeveron Inc, 1951 NW 7th Avenue, Suite 520, Miami, FL 33136, USA
| | - Nicholas Pietris
- Division of Pediatric Cardiology, Department of Pediatrics, University of Maryland School of Medicine, 110 S. Paca Street, Baltimore, MD 21201, USA
| | - Shelby Kutty
- Helen B. Taussig Heart Center, The Johns Hopkins Hospital and Johns Hopkins University, 1800 Orleans St., Baltimore, MD 21287, USA
| | - James S Tweddell
- Heart Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
| | - S Adil Husain
- Division of Pediatric Cardiothoracic Surgery, University of Utah/Primary Children's Medical Center, 295 Chipeta Way, Salt Lake City, Utah 84108, USA
| | - Shaji C Menon
- Department of Radiology, University of Utah/Primary Children's Medical Center, 295 Chipeta Way, Salt Lake City, UT 84108, USA
| | - Linda M Lambert
- Division of Pediatric Cardiology, University of Utah/Primary Children's Medical Center, 295 Chipeta Way, Salt Lake City, UT 84108, USA
| | - David A Danford
- Division of Cardiology, Children's Hospital & Medical Center, Nebraska Medicine, Department of Pediatrics, University of Nebraska, 983332 Nebraska Medical Center, Omaha, NE 68198, USA
| | - Seth J Kligerman
- Department of Radiology, University of California San Diego, 200 W. Arbor Drive, San Diego, CA 92103, USA
| | - Narutoshi Hibino
- Department of Surgery, The University of Chicago Medical Center, 5841 S. Maryland Avenue, Chicago, IL 60637, USA
| | - Laxminarayana Korutla
- Department of Surgery (Cardiac), Yale School of Medicine, Yale University, 789 Howard Avenue, New Haven, CT 06510, USA
| | - Prashanth Vallabhajosyula
- Department of Surgery (Cardiac), Yale School of Medicine, Yale University, 789 Howard Avenue, New Haven, CT 06510, USA
| | - Michael J Campbell
- Department of Pediatrics, Duke University School of Medicine, 2301 Erwin Road, Durham, NC 27705, USA
| | - Aisha Khan
- Department of Medicine and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, 1501 NW 10th Avenue, Miami, FL 33136, USA
| | - Eric Naioti
- Longeveron Inc, 1951 NW 7th Avenue, Suite 520, Miami, FL 33136, USA
| | - Keyvan Yousefi
- Longeveron Inc, 1951 NW 7th Avenue, Suite 520, Miami, FL 33136, USA
| | | | | | - Anthony A Oliva
- Longeveron Inc, 1951 NW 7th Avenue, Suite 520, Miami, FL 33136, USA
| | - Michael E Davis
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University School of Medicine, 313 Ferst Drive, Atlanta, GA 30332, USA
| |
Collapse
|
|
10
|
Julian K, Garg N, Hibino N, Jain R. Stem Cells and Congenital Heart Disease: The Future Potential Clinical Therapy Beyond Current Treatment. Curr Cardiol Rev 2023; 19:e310522205424. [PMID: 35642109 PMCID: PMC10201894 DOI: 10.2174/1573403x18666220531093326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/12/2022] [Accepted: 04/15/2022] [Indexed: 11/22/2022] Open
Abstract
Congenital heart disease (CHD) is the most common congenital anomaly in newborns. Current treatment for cyanotic CHD largely relies on the surgical intervention; however, significant morbidity and mortality for patients with CHD remain. Recent research to explore new avenues of treating CHD includes the utility of stem cells within the field. Stem cells have since been used to both model and potentially treat CHD. Most clinical applications to date have focused on hypoplastic left heart syndrome. Here, we examine the current role of stem cells in CHD and discuss future applications within the field.
Collapse
Affiliation(s)
| | - Nikita Garg
- Department of Pediatrics, Southern Illinois University, Carbondale, Illinois, USA
| | - Narutoshi Hibino
- Department of Cardiothoracic Surgery, University of Chicago, Hershey, Pennsylvania, USA
| | - Rohit Jain
- Penn State College of Medicine, Hershey, Pennsylvania, USA
| |
Collapse
|
|
11
|
Wald R, Mertens L. Hypoplastic Left Heart Syndrome Across the Lifespan: Clinical Considerations for Care of the Fetus, Child, and Adult. Can J Cardiol 2022; 38:930-945. [PMID: 35568266 DOI: 10.1016/j.cjca.2022.04.028] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 04/22/2022] [Accepted: 04/24/2022] [Indexed: 12/14/2022] Open
Abstract
Hypoplastic left heart syndrome (HLHS) is the most common anatomic lesion in children born with single ventricle physiology and is characterized by the presence of a dominant right ventricle and a hypoplastic left ventricle along with small left-sided heart structures. Diagnostic subgroups of HLHS reflect the extent of inflow and outflow obstruction at the aortic and mitral valves, specifically stenosis or atresia. If left unpalliated, HLHS is a uniformly fatal lesion in infancy. Following introduction of the Norwood operation, early survival has steadily improved over the past four decades, mirroring advances in operative and peri-operative management as well as reflecting refinements in patient surveillance and interstage clinical care. Notably, survival following staged palliation has increased from 0% to a 5-year survival of 60-65% for children in some centres. Despite the prevalence of HLHS in childhood with relatively favourable surgical outcomes in contemporary series, this cohort is only now reaching early adult life and longer-term outcomes have yet to be elucidated. In this article we focus on contemporary clinical management strategies for patients with HLHS across the lifespan, from fetal to adult life. Nomenclature and diagnostic considerations are discussed and current literature pertaining to putative genetic etiologies is reviewed. The spectrum of fetal and pediatric interventional strategies, both percutaneous and surgical, are described. Clinical, patient-reported and neurodevelopmental outcomes of HLHS are delineated. Finally, note is made of current areas of clinical uncertainty and suggested directions for future research are highlighted.
Collapse
Affiliation(s)
- Rachel Wald
- Labatt Family Heart Centre, Division of Cardiology, Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; Peter Munk Cardiac Centre, Division of Cardiology, University Health Network, Department of Medicine,University of Toronto, Toronto, Ontario, Canada
| | - Luc Mertens
- Labatt Family Heart Centre, Division of Cardiology, Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; Peter Munk Cardiac Centre, Division of Cardiology, University Health Network, Department of Medicine,University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
12
|
Kelly JM, Anderson C, Breuer CK. The Potential Role of Regenerative Medicine on the Future Management of Hypoplastic Left Heart Syndrome. J Cardiovasc Dev Dis 2022; 9:jcdd9040107. [PMID: 35448083 PMCID: PMC9030758 DOI: 10.3390/jcdd9040107] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/21/2022] [Accepted: 03/25/2022] [Indexed: 01/27/2023] Open
Abstract
The development and translation of regenerative medicine approaches for the treatment of hypoplastic left heart syndrome (HLHS) provides a promising alternative to the current standard of care. We review the strategies that have been pursued to date and those that hold the greatest promise in moving forward. Significant challenges remain. Continued scientific advances and technological breakthroughs will be required if we are to translate this technology to the clinic and move from palliative to curative treatment.
Collapse
Affiliation(s)
- John M. Kelly
- Center for Regenerative Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
- The Heart Center, Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Cole Anderson
- Biomedical Engineering Graduate Program, The Ohio State University, Columbus, OH 43210, USA;
| | - Christopher K. Breuer
- Center for Regenerative Medicine, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
- Department of Surgery, Nationwide Children’s Hospital, Columbus, OH 43205, USA
- Correspondence: ; Tel.: +1-614-722-2000
| |
Collapse
|
|
13
|
Mehanna RA, Essawy MM, Barkat MA, Awaad AK, Thabet EH, Hamed HA, Elkafrawy H, Khalil NA, Sallam A, Kholief MA, Ibrahim SS, Mourad GM. Cardiac stem cells: Current knowledge and future prospects. World J Stem Cells 2022; 14:1-40. [PMID: 35126826 PMCID: PMC8788183 DOI: 10.4252/wjsc.v14.i1.1] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 07/02/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
Regenerative medicine is the field concerned with the repair and restoration of the integrity of damaged human tissues as well as whole organs. Since the inception of the field several decades ago, regenerative medicine therapies, namely stem cells, have received significant attention in preclinical studies and clinical trials. Apart from their known potential for differentiation into the various body cells, stem cells enhance the organ's intrinsic regenerative capacity by altering its environment, whether by exogenous injection or introducing their products that modulate endogenous stem cell function and fate for the sake of regeneration. Recently, research in cardiology has highlighted the evidence for the existence of cardiac stem and progenitor cells (CSCs/CPCs). The global burden of cardiovascular diseases' morbidity and mortality has demanded an in-depth understanding of the biology of CSCs/CPCs aiming at improving the outcome for an innovative therapeutic strategy. This review will discuss the nature of each of the CSCs/CPCs, their environment, their interplay with other cells, and their metabolism. In addition, important issues are tackled concerning the potency of CSCs/CPCs in relation to their secretome for mediating the ability to influence other cells. Moreover, the review will throw the light on the clinical trials and the preclinical studies using CSCs/CPCs and combined therapy for cardiac regeneration. Finally, the novel role of nanotechnology in cardiac regeneration will be explored.
Collapse
Affiliation(s)
- Radwa A Mehanna
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa M Essawy
- Oral Pathology Department, Faculty of Dentistry/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Mona A Barkat
- Human Anatomy and Embryology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ashraf K Awaad
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Eman H Thabet
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Heba A Hamed
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Hagar Elkafrawy
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Nehal A Khalil
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Abeer Sallam
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa A Kholief
- Forensic Medicine and Clinical toxicology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Samar S Ibrahim
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ghada M Mourad
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt.
| |
Collapse
|
|
14
|
Mehanna RA, Essawy MM, Barkat MA, Awaad AK, Thabet EH, Hamed HA, Elkafrawy H, Khalil NA, Sallam A, Kholief MA, Ibrahim SS, Mourad GM. Cardiac stem cells: Current knowledge and future prospects. World J Stem Cells 2022. [PMID: 35126826 DOI: 10.4252/wjsc.v14.i1.1]] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Regenerative medicine is the field concerned with the repair and restoration of the integrity of damaged human tissues as well as whole organs. Since the inception of the field several decades ago, regenerative medicine therapies, namely stem cells, have received significant attention in preclinical studies and clinical trials. Apart from their known potential for differentiation into the various body cells, stem cells enhance the organ's intrinsic regenerative capacity by altering its environment, whether by exogenous injection or introducing their products that modulate endogenous stem cell function and fate for the sake of regeneration. Recently, research in cardiology has highlighted the evidence for the existence of cardiac stem and progenitor cells (CSCs/CPCs). The global burden of cardiovascular diseases' morbidity and mortality has demanded an in-depth understanding of the biology of CSCs/CPCs aiming at improving the outcome for an innovative therapeutic strategy. This review will discuss the nature of each of the CSCs/CPCs, their environment, their interplay with other cells, and their metabolism. In addition, important issues are tackled concerning the potency of CSCs/CPCs in relation to their secretome for mediating the ability to influence other cells. Moreover, the review will throw the light on the clinical trials and the preclinical studies using CSCs/CPCs and combined therapy for cardiac regeneration. Finally, the novel role of nanotechnology in cardiac regeneration will be explored.
Collapse
Affiliation(s)
- Radwa A Mehanna
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa M Essawy
- Oral Pathology Department, Faculty of Dentistry/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Mona A Barkat
- Human Anatomy and Embryology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ashraf K Awaad
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Eman H Thabet
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Heba A Hamed
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Hagar Elkafrawy
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Nehal A Khalil
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Abeer Sallam
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa A Kholief
- Forensic Medicine and Clinical toxicology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Samar S Ibrahim
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ghada M Mourad
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt.
| |
Collapse
|
|
15
|
Zhao D, Liu Y, Xu Z, Shen H, Chen S, Zhang S, Li Y, Zhang H, Zou C, Ma X. Integrative Bioinformatics Analysis Revealed Mitochondrial Defects Underlying Hypoplastic Left Heart Syndrome. Int J Gen Med 2021; 14:9747-9760. [PMID: 34934349 PMCID: PMC8684406 DOI: 10.2147/ijgm.s345921] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 12/02/2021] [Indexed: 12/15/2022] Open
Abstract
Background Hypoplastic left heart syndrome (HLHS) is one of the most complex congenital cardiac malformations, and the molecular mechanism of heart failure (HF) in HLHS is still elusive. Methods Integrative bioinformatics analysis was performed to unravel the underlying genes and mechanisms involved in HF in HLHS. Microarray dataset GSE23959 was screened out for the differentially expressed genes (DEGs), after which the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were carried out using the Metascape. The protein-protein interaction (PPI) network was generated, and the modules and hub genes were identified with the Cytoscape-plugin. And the integrated network of transcription factor (TF)-DEGs and miRNA-DEGs was constructed, respectively. Results A total of 210 DEGs were identified, including 135 up-regulated and 75 down-regulated genes. The functional enrichment analysis of DEGs pointed towards the mitochondrial-related biological processes, cellular components, molecular functions and signaling pathways. A PPI network was constructed including 155 nodes as well as 363 edges. And 15 hub genes, such as NDUFB6, UQCRQ, SDHD, ATP5H, were identified based on three topological analysis methods and mitochondrial components and functions were the most relevant. Furthermore, by integrating network interaction construction, 23 TFs (NFKB1, RELA, HIF1A, VHL, GATA1, PPAR-γ, etc.) as well as several miRNAs (hsa-miR-155-5p, hsa-miR-191-5p, hsa-mir-124-3p, hsa-miR-1-3p, etc.) were detected and indicated the possible involvement of NF-κB signaling pathways in mitochondrial dysfunction in HLHS. Conclusion The present study applied the integrative bioinformatics analysis and revealed the mitochondrial-related key genes, regulatory pathways, TFs and miRNAs underlying the HF in HLHS, which improved the understanding of disease mechanisms and the development of novel therapeutic targets.
Collapse
Affiliation(s)
- Diming Zhao
- Department of Cardiovascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Yilin Liu
- Department of Ophthalmology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Zhenqiang Xu
- Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China.,Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, People's Republic of China
| | - Hechen Shen
- Department of Cardiovascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Shanghao Chen
- Department of Cardiovascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Shijie Zhang
- Department of Cardiovascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Yi Li
- Department of Cardiovascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Haizhou Zhang
- Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China.,Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, People's Republic of China
| | - Chengwei Zou
- Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China.,Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, People's Republic of China
| | - Xiaochun Ma
- Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China.,Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, People's Republic of China
| |
Collapse
|
|
16
|
O'Leary PW, Qureshi MY, Cetta F, Nelson TJ, Holst KA, Dearani JA. Cone Reconstruction for Ebstein Anomaly: Ventricular Remodeling and Preliminary Impact of Stem Cell Therapy. Mayo Clin Proc 2021; 96:3053-3061. [PMID: 34479739 DOI: 10.1016/j.mayocp.2021.02.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 02/02/2021] [Indexed: 11/17/2022]
Abstract
OBJECTIVE To define the impact of tricuspid valve cone reconstruction (CR) on ventricular performance in Ebstein anomaly, both independently and after stem cell therapy. PATIENTS AND METHODS The control group included 257 patients who had CR between June 2007 and December 2019. Ten subjects of a phase I stem cell therapy trial (May 2017 - March 2019) were compared with the controls to assess the echocardiographic impact on ventricular remodeling. RESULTS After CR, right ventricular (RV) size decreased and left ventricular (LV) volume increased in all patients. Apical and biplane RV fractional area change (FAC) initially decreased, but rebounded by 6 months postoperation. Short-axis FAC increased early and was maintained at 6 months post-CR in the control group. At 6 months post-CR, cell therapy patients showed a significantly larger increase in short-axis FAC (24.4% vs 29.9%, P=.003). In addition, whereas LV ejection fraction (EF) was unchanged at 6 months post-CR in controls, cell therapy patients showed a significant increase in EF relative to baseline and to controls (55.6% vs 65.0%, P=.007). CONCLUSION Cone reconstruction reduces tricuspid regurgitation and RV size, but is also associated with increased RV FAC and LV volume. Furthermore, injection of bone marrow-derived stem cells augmented the increase in RV FAC and was associated with improved LV EF at 6 months post-CR. This is evidence of a favorable interventricular interaction. These findings provide motivation for continued investigation into the potential benefits of stem cell therapy in Ebstein anomaly and other congenital cardiac malformations. TRIAL REGISTRATION clinicaltrials.gov identifier: NCT02914171.
Collapse
Affiliation(s)
- Patrick W O'Leary
- Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN; Wanek Family Program for Hypoplastic Left Heart Syndrome, Mayo Clinic, Rochester, MN.
| | - M Yasir Qureshi
- Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN; Wanek Family Program for Hypoplastic Left Heart Syndrome, Mayo Clinic, Rochester, MN
| | - Frank Cetta
- Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN; Wanek Family Program for Hypoplastic Left Heart Syndrome, Mayo Clinic, Rochester, MN
| | - Timothy J Nelson
- Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN; Wanek Family Program for Hypoplastic Left Heart Syndrome, Mayo Clinic, Rochester, MN
| | - Kimberly A Holst
- Wanek Family Program for Hypoplastic Left Heart Syndrome, Mayo Clinic, Rochester, MN; Department of Cardiovascular Surgery, Mayo Clinic, Rochester, MN
| | - Joseph A Dearani
- Wanek Family Program for Hypoplastic Left Heart Syndrome, Mayo Clinic, Rochester, MN; Department of Cardiovascular Surgery, Mayo Clinic, Rochester, MN
| | | |
Collapse
|
|
17
|
Hypoplastic left heart syndrome (HLHS): molecular pathogenesis and emerging drug targets for cardiac repair and regeneration. Expert Opin Ther Targets 2021; 25:621-632. [PMID: 34488532 DOI: 10.1080/14728222.2021.1978069] [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] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Hypoplastic left heart syndrome (HLHS) is a severe developmental defect characterized by the underdevelopment of the left ventricle along with aortic and valvular defects. Multiple palliative surgeries are required for survival. Emerging studies have identified potential mechanisms for the disease onset, including genetic and hemodynamic causes. Genetic variants associated with HLHS include transcription factors, chromatin remodelers, structural proteins, and signaling proteins necessary for normal heart development. Nonetheless, current therapies are being tested clinically and have shown promising results at improving cardiac function in patients who have undergone palliative surgeries. AREAS COVERED We searched PubMed and clinicaltrials.gov to review most of the mechanistic research and clinical trials involving HLHS. This review discusses the anatomy and pathology of HLHS hearts. We highlight some of the identified genetic variants that underly the molecular pathogenesis of HLHS. Additionally, we discuss some of the emerging therapies and their limitations for HLHS. EXPERT OPINION While HLHS etiology is largely obscure, palliative therapies remain the most viable option for the patients. It is necessary to generate animal and stem cell models to understand the underlying genetic causes directly leading to HLHS and facilitate the use of gene-based therapies to improve cardiac development and regeneration.
Collapse
|
|
18
|
Bittle GJ, Morales D, Pietris N, Parchment N, Parsell D, Peck K, Deatrick KB, Rodriguez-Borlado L, Smith RR, Marbán L, Kaushal S. Exosomes isolated from human cardiosphere–derived cells attenuate pressure overload–induced right ventricular dysfunction. J Thorac Cardiovasc Surg 2021; 162:975-986.e6. [DOI: 10.1016/j.jtcvs.2020.06.154] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 06/10/2020] [Accepted: 06/27/2020] [Indexed: 01/27/2023]
|
|
19
|
Vaka R, Davis DR. State-of-play for cellular therapies in cardiac repair and regeneration. Stem Cells 2021; 39:1579-1588. [PMID: 34448513 PMCID: PMC9290630 DOI: 10.1002/stem.3446] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/10/2021] [Indexed: 12/24/2022]
Abstract
Cardiovascular disease is the primary cause of death around the world. For almost two decades, cell therapy has been proposed as a solution for heart disease. In this article, we report on the “state‐of‐play” of cellular therapies for cardiac repair and regeneration. We outline the progression of new ideas from the preclinical literature to ongoing clinical trials. Recent data supporting the mechanics and mechanisms of myogenic and paracrine therapies are evaluated in the context of long‐term cardiac engraftment. This discussion informs on promising new approaches to indicate future avenues for the field.
Collapse
Affiliation(s)
- Ramana Vaka
- Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Canada
| | - Darryl R Davis
- Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Canada
| |
Collapse
|
|
20
|
Abstract
Cardiovascular diseases top the list of fatal illnesses worldwide. Cardiac tissues is known to be one of te least proliferative in the human body, with very limited regenraive capacity. Stem cell therapy has shown great potential for treatment of cardiovascular diseases in the experimental setting, but success in human trials has been limited. Applications of stem cell therapy for cardiovascular regeneration necessitate understamding of the complex and unique structure of the heart unit, and the embryologic development of the heart muscles and vessels. This chapter aims to provide an insight into cardiac progenitor cells and their potential applications in regenerative medicine. It also provides an overview of the embryological development of cardiac tissue, and the major findings on the development of cardiac stem cells, their characterization, and differentiation, and their regenerative potential. It concludes with clinical applications in treating cardiac disease using different approaches, and concludes with areas for future research.
Collapse
|
|
21
|
Hirai K, Ousaka D, Fukushima Y, Kondo M, Eitoku T, Shigemitsu Y, Hara M, Baba K, Iwasaki T, Kasahara S, Ohtsuki S, Oh H. Cardiosphere-derived exosomal microRNAs for myocardial repair in pediatric dilated cardiomyopathy. Sci Transl Med 2021; 12:12/573/eabb3336. [PMID: 33298561 DOI: 10.1126/scitranslmed.abb3336] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 10/15/2020] [Indexed: 12/31/2022]
Abstract
Although cardiosphere-derived cells (CDCs) improve cardiac function and outcomes in patients with single ventricle physiology, little is known about their safety and therapeutic benefit in children with dilated cardiomyopathy (DCM). We aimed to determine the safety and efficacy of CDCs in a porcine model of DCM and translate the preclinical results into this patient population. A swine model of DCM using intracoronary injection of microspheres created cardiac dysfunction. Forty pigs were randomized as preclinical validation of the delivery method and CDC doses, and CDC-secreted exosome (CDCex)-mediated cardiac repair was analyzed. A phase 1 safety cohort enrolled five pediatric patients with DCM and reduced ejection fraction to receive CDC infusion. The primary endpoint was to assess safety, and the secondary outcome measure was change in cardiac function. Improved cardiac function and reduced myocardial fibrosis were noted in animals treated with CDCs compared with placebo. These functional benefits were mediated via CDCex that were highly enriched with proangiogenic and cardioprotective microRNAs (miRNAs), whereas isolated CDCex did not recapitulate these reparative effects. One-year follow-up of safety lead-in stage was completed with favorable profile and preliminary efficacy outcomes. Increased CDCex-derived miR-146a-5p expression was associated with the reduction in myocardial fibrosis via suppression of proinflammatory cytokines and transcripts. Collectively, intracoronary CDC administration is safe and improves cardiac function through CDCex in a porcine model of DCM. The safety lead-in results in patients provide a translational framework for further studies of randomized trials and CDCex-derived miRNAs as potential paracrine mediators underlying this therapeutic strategy.
Collapse
Affiliation(s)
- Kenta Hirai
- Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Daiki Ousaka
- Department of Cardiovascular Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Yosuke Fukushima
- Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Maiko Kondo
- Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Takahiro Eitoku
- Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Yusuke Shigemitsu
- Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Mayuko Hara
- Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Kenji Baba
- Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Tatsuo Iwasaki
- Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Shingo Kasahara
- Department of Cardiovascular Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Shinichi Ohtsuki
- Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Hidemasa Oh
- Department of Regenerative Medicine, Center for Innovative Clinical Medicine, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
| |
Collapse
|
|
22
|
Allogeneic Mesenchymal Stromal Cell Injection to Alleviate Ischemic Heart Failure Following Arterial Switch Operation. JACC Case Rep 2021; 3:724-727. [PMID: 34041498 PMCID: PMC8134060 DOI: 10.1016/j.jaccas.2021.02.039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 02/15/2021] [Indexed: 01/22/2023]
Abstract
Cell therapy is a promising tool to prevent and treat heart failure in congenital heart disease. We report the first case of intramyocardial injection of allogeneic mesenchymal stromal cells as rescue therapy in a neonate with ischemic heart failure following arterial switch procedure for isolated transposition of the great arteries. (Level of Difficulty: Advanced.)
Collapse
|
|
23
|
Povsic TJ, Gersh BJ. Stem Cells in Cardiovascular Diseases: 30,000-Foot View. Cells 2021; 10:cells10030600. [PMID: 33803227 PMCID: PMC8001267 DOI: 10.3390/cells10030600] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/01/2021] [Accepted: 03/03/2021] [Indexed: 12/15/2022] Open
Abstract
Stem cell and regenerative approaches that might rejuvenate the heart have immense intuitive appeal for the public and scientific communities. Hopes were fueled by initial findings from preclinical models that suggested that easily obtained bone marrow cells might have significant reparative capabilities; however, after initial encouraging pre-clinical and early clinical findings, the realities of clinical development have placed a damper on the field. Clinical trials were often designed to detect exceptionally large treatment effects with modest patient numbers with subsequent disappointing results. First generation approaches were likely overly simplistic and relied on a relatively primitive understanding of regenerative mechanisms and capabilities. Nonetheless, the field continues to move forward and novel cell derivatives, platforms, and cell/device combinations, coupled with a better understanding of the mechanisms that lead to regenerative capabilities in more primitive models and modifications in clinical trial design suggest a brighter future.
Collapse
Affiliation(s)
- Thomas J. Povsic
- Department of Medicine, and Duke Clinical Research Institute, Duke University, Durham, NC 27705, USA
- Correspondence:
| | - Bernard J. Gersh
- Department of Cardiovascular Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA;
| |
Collapse
|
|
24
|
Andriolo G, Provasi E, Brambilla A, Lo Cicero V, Soncin S, Barile L, Turchetto L, Radrizzani M. GMP-Grade Methods for Cardiac Progenitor Cells: Cell Bank Production and Quality Control. Methods Mol Biol 2021; 2286:131-166. [PMID: 33381854 DOI: 10.1007/7651_2020_286] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Cardiac explant-derived cells (cEDC), also referred as cardiac progenitors cells (CPC) (Barile et al., Cardiovasc Res 103(4):530-541, 2014; Barile et al., Cardiovasc Res 114(7):992-1005, 2018), represent promising candidates for the development of cell-based therapies, a novel and interesting treatment for cardioprotective strategy in heart failure (Kreke et al., Expert Rev Cardiovasc Ther 10(9):1185-1194, 2012). CPC have been tested in a preclinical setting for direct cell transplantation and tissue engineering or as a source for production of extracellular vesicles (EV) (Oh et al., J Cardiol 68(5):361-367, 2016; Barile et al., Eur Heart J 38(18):1372-1379, 2017; Rosen et al., J Am Coll Cardiol 64(9):922-937, 2014). CPC cultured as cardiospheres derived cells went through favorable Phase 1 and 2 studies demonstrating safety and possible efficacy (Makkar et al., Lancet 379(9819):895-904, 2012; Ishigami et al., Circ Res 120(7):1162-1173, 2017; Ishigami et al., Circ Res 116 (4):653-664, 2015; Tarui et al., J Thorac Cardiovasc Surg 150(5):1198-1207, 1208 e1191-1192, 2015). In this context and in view of clinical applications, cells have to be prepared and released according to Good Manufacturing Practices (GMP) (EudraLex-volume 4-good manufacturing practice (GMP) guidelines-Part I-basic requirements for medicinal products. http://ec.europa.eu/health/documents/eudralex/vol-4 ; EudraLex-volume 4-good manufacturing practice (GMP) guidelines-Part IV-guidelines on good manufacturing practices specific to advanced therapy medicinal products. http://ec.europa.eu/health/documents/eudralex/vol-4 ). This chapter describes GMP-grade methods for production and testing of a CPC Master Cell Bank (MCB), consisting of frozen aliquots of cells that may be used either as a therapeutic product or as source for the manufacturing of Exo for clinical trials.The MCB production method has been designed to isolate and expand CPC from human cardiac tissue in xeno-free conditions (Andriolo et al., Front Physiol 9:1169, 2018). The quality control (QC) methods have been implemented to assess the safety (sterility, endotoxin, mycoplasma, cell senescence, tumorigenicity) and identity/potency/purity (cell count and viability, RT-PCR, immunophenotype) of the cells (Andriolo et al., Front Physiol 9:1169, 2018).
Collapse
Affiliation(s)
- Gabriella Andriolo
- Lugano Cell Factory, Fondazione Cardiocentro Ticino, Lugano, Switzerland
| | - Elena Provasi
- Lugano Cell Factory, Fondazione Cardiocentro Ticino, Lugano, Switzerland
| | - Andrea Brambilla
- Lugano Cell Factory, Fondazione Cardiocentro Ticino, Lugano, Switzerland
| | - Viviana Lo Cicero
- Lugano Cell Factory, Fondazione Cardiocentro Ticino, Lugano, Switzerland
| | - Sabrina Soncin
- Lugano Cell Factory, Fondazione Cardiocentro Ticino, Lugano, Switzerland
| | - Lucio Barile
- Laboratory for Cardiovascular Theranostics, Fondazione Cardiocentro Ticino, Lugano, Switzerland
| | - Lucia Turchetto
- Lugano Cell Factory, Fondazione Cardiocentro Ticino, Lugano, Switzerland
| | - Marina Radrizzani
- Lugano Cell Factory, Fondazione Cardiocentro Ticino, Lugano, Switzerland.
| |
Collapse
|
|
25
|
Abdullah M, Kegel S, Gunasekaran M, Saha P, Fu X, Mishra R, Sharma S, Sunjay Kaushal. Stem Cell Therapy in Single-Ventricle Physiology: Recent Progress and Future Directions. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2021; 24:67-76. [PMID: 34116785 DOI: 10.1053/j.pcsu.2021.03.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 02/08/2021] [Accepted: 03/09/2021] [Indexed: 12/29/2022]
Abstract
Current surgical and medical treatment options for single ventricle physiology conditions remain palliative. On the long term, despite treatment, the systemic ventricle has a significant risk of developing failure. There are unmet needs to develop novel treatment modalities to help ameliorate the ventricular dysfunction. Advances in the field of stem cell therapy have been promising for the treatment of heart failure. Numerous stem cell populations have been identified. Preclinical studies in small and large animal models provide evidence for effectiveness of this treatment modality and reveal several mechanisms of action by which stem cells exert their effect. Many clinical trials have been designed to further investigate the therapeutic potential that stem cell therapy may hold for pediatric populations with single ventricle physiology. In this review, we discuss the stem cell types used in these populations, some preclinical studies, and the clinical trials of stem cell therapy in single ventricle patients.
Collapse
Affiliation(s)
| | - Samantha Kegel
- University of Maryland School of Medicine, Baltimore, Maryland
| | - Muthukumar Gunasekaran
- Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Feinburg School of Medicine, Chicago, Illinois
| | - Progyaparamita Saha
- Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Feinburg School of Medicine, Chicago, Illinois
| | - Xuebin Fu
- Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Feinburg School of Medicine, Chicago, Illinois
| | - Rachana Mishra
- Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Feinburg School of Medicine, Chicago, Illinois
| | - Sudhish Sharma
- Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Feinburg School of Medicine, Chicago, Illinois
| | - Sunjay Kaushal
- Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Feinburg School of Medicine, Chicago, Illinois.
| |
Collapse
|
|
26
|
Vekstein AM, Turek JW, Andersen ND. Commentary: Cardiosphere-derived exosomes for single-ventricle heart disease: Are some of the parts greater than the whole? J Thorac Cardiovasc Surg 2020; 162:990-991. [PMID: 33246569 DOI: 10.1016/j.jtcvs.2020.08.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 08/11/2020] [Accepted: 08/12/2020] [Indexed: 11/16/2022]
Affiliation(s)
- Andrew M Vekstein
- Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Duke University Medical Center, Durham, NC
| | - Joseph W Turek
- Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Duke University Medical Center, Durham, NC
| | - Nicholas D Andersen
- Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Duke University Medical Center, Durham, NC.
| |
Collapse
|
|
27
|
Haller C, Friedberg MK, Laflamme MA. The role of regenerative therapy in the treatment of right ventricular failure: a literature review. Stem Cell Res Ther 2020; 11:502. [PMID: 33239066 PMCID: PMC7687832 DOI: 10.1186/s13287-020-02022-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 11/09/2020] [Indexed: 01/13/2023] Open
Abstract
Right ventricular (RV) failure is a commonly encountered problem in patients with congenital heart disease but can also be a consequence of left ventricular disease, primary pulmonary hypertension, or RV-specific cardiomyopathies. Improved survival of the aforementioned pathologies has led to increasing numbers of patients suffering from RV dysfunction, making it a key contributor to morbidity and mortality in this population. Currently available therapies for heart failure were developed for the left ventricle (LV), and there is clear evidence that LV-specific strategies are insufficient or inadequate for the RV. New therapeutic strategies are needed to address this growing clinical problem, and stem cells show significant promise. However, to properly evaluate the prospects of a potential stem cell-based therapy for RV failure, one needs to understand the unique pathophysiology of RV dysfunction and carefully consider available data from animal models and human clinical trials. In this review, we provide a comprehensive overview of the molecular mechanisms involved in RV failure such as hypertrophy, fibrosis, inflammation, changes in energy metabolism, calcium handling, decreasing RV contractility, and apoptosis. We also summarize the available preclinical and clinical experience with RV-specific stem cell therapies, covering the broad spectrum of stem cell sources used to date. We describe two different scientific rationales for stem cell transplantation, one of which seeks to add contractile units to the failing myocardium, while the other aims to augment endogenous repair mechanisms and/or attenuate harmful remodeling. We emphasize the limitations and challenges of regenerative strategies, but also highlight the characteristics of the failing RV myocardium that make it a promising target for stem cell therapy.
Collapse
Affiliation(s)
- Christoph Haller
- Division of Cardiovascular Surgery, The Labatt Family Heart Centre, The Hospital for Sick Children, Toronto, Canada.,Department of Surgery, University of Toronto, Toronto, Canada.,McEwen Stem Cell Institute, Peter Munk Cardiac Centre, University Health Network, Toronto, Canada
| | - Mark K Friedberg
- Division of Cardiology, The Labatt Family Heart Centre, The Hospital for Sick Children, Toronto, Canada.,Department of Pediatrics, University of Toronto, Toronto, Canada.,Department of Physiology, University of Toronto, Toronto, Canada
| | - Michael A Laflamme
- McEwen Stem Cell Institute, Peter Munk Cardiac Centre, University Health Network, Toronto, Canada. .,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada. .,McEwen Stem Cell Institute, Toronto Medical Discovery Tower, 101 College Street, Toronto, Ontario, M5G 1L7, Canada.
| |
Collapse
|
|
28
|
Ishigami S, Sano T, Krishnapura S, Ito T, Sano S. An overview of stem cell therapy for paediatric heart failure. Eur J Cardiothorac Surg 2020; 58:881-887. [PMID: 32588055 DOI: 10.1093/ejcts/ezaa155] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 04/02/2020] [Accepted: 04/06/2020] [Indexed: 11/13/2022] Open
Abstract
Significant achievements in paediatric cardiology, surgical treatment and intensive care of congenital heart disease have drastically changed clinical outcomes for paediatric patients. Nevertheless, late-onset heart failure in children after staged surgeries still remains a serious concern in the medical community. Heart transplantation is an option for treatment; however, the shortage of available organs is a persistent problem in many developed countries. In order to resolve these issues, advanced technologies, such as innovative mechanical circulatory support devices and regenerative therapies, are strongly desired. Accumulated evidence regarding cell-based cardiac regenerative therapies has suggested their safety and efficacy in treating adult heart failure. Given that young children seem to have a higher regenerative capacity than adults, stem cell-based therapies appear a promising treatment option for paediatric heart failure as well. Based on the findings from past trials and studies, we present the potential of various different types of stem cells, ranging from bone marrow mononuclear cells to cardiosphere-derived stem cells for use in paediatric cell-based therapies. Here, we assess both the current challenges associated with cell-based therapies and novel strategies that may be implemented in the future to advance stem cell therapy in the paediatric population.
Collapse
Affiliation(s)
- Shuta Ishigami
- Department of Pediatric Cardiothoracic Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Toshikazu Sano
- Department of Pediatric Cardiothoracic Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Sunaya Krishnapura
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
| | - Tatsuo Ito
- Department of Hygiene, Kawasaki Medical University, Kurashiki, Japan
| | - Shunji Sano
- Department of Pediatric Cardiothoracic Surgery, University of California, San Francisco, San Francisco, CA, USA
| |
Collapse
|
|
29
|
Martinez J, Zoretic S, Moreira A, Moreira A. Safety and efficacy of cell therapies in pediatric heart disease: a systematic review and meta-analysis. Stem Cell Res Ther 2020; 11:272. [PMID: 32641168 PMCID: PMC7341627 DOI: 10.1186/s13287-020-01764-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 06/04/2020] [Accepted: 06/08/2020] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND Adult clinical trials have reported safety and the therapeutic potential of stem cells for cardiac disease. These observations have now translated to the pediatric arena. We conducted a meta-analysis to assess safety and efficacy of cell-based therapies in animal and human studies of pediatric heart disease. METHODS AND RESULTS A literature search was conducted to examine the effects of cell-based therapies on: (i) safety and (ii) cardiac function. In total, 18 pre-clinical and 13 human studies were included. Pre-clinical: right ventricular dysfunction was the most common animal model (80%). Cardiac-derived (28%) and umbilical cord blood (24%) cells were delivered intravenously (36%) or intramyocardially (35%). Mortality was similar between cell-based and control groups (OR 0.94; 95% CI 0.05, 17.41). Cell-based treatments preserved ejection fraction by 6.9% (p < 0.01), while intramyocardial at a dose of 1-10 M cells/kg optimized ejection fraction. Clinical: single ventricle physiology was the most common cardiac disease (n = 9). Cardiac tissue was a frequent cell source, dosed from 3.0 × 105 to 2.4 × 107 cells/kg. A decrease in adverse events occurred in the cell-based cohort (OR 0.17, p < 0.01). Administration of cell-based therapies improved ejection fraction (MD 4.84; 95% CI 1.62, 8.07; p < 0.01). CONCLUSIONS In this meta-analysis, cell-based therapies were safe and improved specific measures of cardiac function. Implications from this review may provide methodologic recommendations (source, dose, route, timing) for future clinical trials. Of note, many of the results described in this study pattern those seen in adult stem cell reviews and meta-analyses.
Collapse
Affiliation(s)
- John Martinez
- Department of Pediatrics, University of Texas Health San Antonio, San Antonio, TX, 77229, USA
| | - Sarah Zoretic
- Department of Pediatrics, University of Texas Health San Antonio, San Antonio, TX, 77229, USA
| | - Axel Moreira
- Department of Pediatrics, University of Texas Health San Antonio, San Antonio, TX, 77229, USA
- Department of Pediatrics, Texas Children's Hospital, Houston, TX, 77030, USA
| | - Alvaro Moreira
- Department of Pediatrics, University of Texas Health San Antonio, San Antonio, TX, 77229, USA.
- Department of Pediatrics, UT Health San Antonio, 7703 Floyd Curl Drive, MC 7812, San Antonio, TX, 78229, USA.
| |
Collapse
|
|
30
|
Rafatian G, Kamkar M, Parent S, Michie C, Risha Y, Molgat ASD, Seymour R, Suuronen EJ, Davis DR. Mybl2 rejuvenates heart explant-derived cells from aged donors after myocardial infarction. Aging Cell 2020; 19:e13174. [PMID: 32558221 PMCID: PMC7433005 DOI: 10.1111/acel.13174] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 04/30/2020] [Accepted: 05/21/2020] [Indexed: 12/22/2022] Open
Abstract
While cell therapy is emerging as a promising option for patients with ischemic cardiomyopathy (ICM), the influence of advanced donor age and a history of ischemic injury on the reparative performance of these cells are not well defined. As such, intrinsic changes that result from advanced donor age and ischemia are explored in hopes of identifying a molecular candidate capable of restoring the lost reparative potency of heart explant‐derived cells (EDCs) used in cell therapy. EDCs were cultured from myocardial biopsies obtained from young or old mice 4 weeks after randomization to experimental myocardial infarction or no intervention. Advanced donor age reduces cell yield while increasing cell senescence and the secretion of senescence‐associated cytokines. A history of ischemic injury magnifies these effects as cells are more senescent and have lower antioxidant reserves. Consistent with these effects, intramyocardial injection of EDCs from aged ischemic donors provided less cell‐mediated cardiac repair. A transcriptome comparison of ICM EDCs shows aging modifies many of the pathways responsible for effective cell cycle control and DNA damage/repair. Over‐expression of the barely explored antisenescent transcription factor, Mybl2, in EDCs from aged ICM donors reduces cell senescence while conferring salutary effects on antioxidant activity and paracrine production. In vivo, we observed an increase in cell retention and vasculogenesis after treatment with Mybl2‐over‐expressing EDCs which improved heart function in infarcted recipient hearts. In conclusion, Mybl2 over‐expression rejuvenates senescent EDCs sourced from aged ICM donors to confer cell‐mediated effects comparable to cells from young nonischemic donors.
Collapse
Affiliation(s)
- Ghazaleh Rafatian
- Department of Cellular and Molecular MedicineUniversity of Ottawa Ottawa ON Canada
- Division of CardiologyUniversity of Ottawa Heart Institute Ottawa ON Canada
| | - Maryam Kamkar
- Division of CardiologyUniversity of Ottawa Heart Institute Ottawa ON Canada
| | - Sandrine Parent
- Department of Cellular and Molecular MedicineUniversity of Ottawa Ottawa ON Canada
- Division of CardiologyUniversity of Ottawa Heart Institute Ottawa ON Canada
| | - Connor Michie
- Department of Cellular and Molecular MedicineUniversity of Ottawa Ottawa ON Canada
- Division of CardiologyUniversity of Ottawa Heart Institute Ottawa ON Canada
| | - Yousef Risha
- Division of CardiologyUniversity of Ottawa Heart Institute Ottawa ON Canada
| | - André S. D. Molgat
- Division of CardiologyUniversity of Ottawa Heart Institute Ottawa ON Canada
| | - Richard Seymour
- Division of CardiologyUniversity of Ottawa Heart Institute Ottawa ON Canada
| | - Erik J. Suuronen
- Department of Cellular and Molecular MedicineUniversity of Ottawa Ottawa ON Canada
- Division of Cardiac SurgeryUniversity of Ottawa Heart Institute Ottawa ON Canada
| | - Darryl R. Davis
- Department of Cellular and Molecular MedicineUniversity of Ottawa Ottawa ON Canada
- Division of CardiologyUniversity of Ottawa Heart Institute Ottawa ON Canada
| |
Collapse
|
|
31
|
Dergilev KV, Vasilets ID, Tsokolaeva ZI, Zubkova ES, Parfenova EV. [Perspectives of cell therapy for myocardial infarction and heart failure based on cardiosphere cells]. TERAPEVT ARKH 2020; 92:111-120. [PMID: 32598708 DOI: 10.26442/00403660.2020.04.000634] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Indexed: 12/13/2022]
Abstract
Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. In recent years, researchers are attracted to the use of cell therapy based on stem cell and progenitor cells, which has been a promising strategy for cardiac repair after injury. However, conducted research using intracoronary or intramyocardial transplantation of various types of stem/progenitor cells as a cell suspension showed modest efficiency. This is due to the low degree of integration and cell survival after transplantation. To overcome these limitations, the concept of the use of multicellular spheroids modeling the natural microenvironment of cells has been proposed, which allows maintaining their viability and therapeutic properties. It is of great interest to use so-called cardial spheroids (cardiospheres) spontaneously forming three-dimensional structures under low-adhesive conditions, consisting of a heterogeneous population of myocardial progenitor cells and extracellular matrix proteins. This review presents data on methods for creating cardiospheres, directed regulation of their properties and reparative potential, as well as the results of preclinical and clinical studies on their use for the treatment of heart diseases.
Collapse
Affiliation(s)
| | | | - Z I Tsokolaeva
- National Medical Research Center for Cardiology.,Negovsky Scientific Research Institute of General Reanimatology of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology
| | - E S Zubkova
- National Medical Research Center for Cardiology
| | - E V Parfenova
- National Medical Research Center for Cardiology.,Lomonosov Moscow State University
| |
Collapse
|
|
32
|
Liufu R, Shi G, He X, Lv J, Liu W, Zhu F, Wen C, Zhu Z, Chen H. The therapeutic impact of human neonatal BMSC in a right ventricular pressure overload model in mice. Stem Cell Res Ther 2020; 11:96. [PMID: 32122393 PMCID: PMC7052971 DOI: 10.1186/s13287-020-01593-y] [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: 08/17/2019] [Revised: 01/07/2020] [Accepted: 02/10/2020] [Indexed: 12/12/2022] Open
Abstract
Objective To determine the impact of donor age on the therapeutic effect of bone marrow-derived mesenchymal stem cells (BMSCs) in treating adverse remodeling as the result of right ventricle (RV) pressure overload. Methods BMSCs were isolated from neonatal (< 1 month), infant (1 month to 1 year), and young children (1 year to 5 years) and were compared in their migration potential, surface marker expression, VEGF secretion, and matrix metalloprotein (MMP) 9 expression. Four-week-old male C57 mice underwent pulmonary artery banding and randomized to treatment and untreated control groups. During the surgery, BMSCs were administered to the mice by intramyocardial injection into the RV free wall. Four weeks later, RV function and tissue were analyzed by echocardiography, histology, and quantitative real-time polymerase chain reaction. Results Human neonatal BMSCs demonstrated the greatest migration capacity and secretion of vascular endothelial growth factor but no difference in expression of surface markers. Neonate BMSCs administration resulted in increasing expression of VEGF, a significant reduction in RV wall thickness, and internal diameter in mice after PA banding. These beneficial effects were probably associated with paracrine secretion as no cardiomyocyte transdifferentiation was observed. Conclusions Human BMSCs from different age groups have different characteristics, and the youngest BMSCs may favorably impact the application of stem cell-based therapy to alleviate adverse RV remodeling induced by pressure overload.
Collapse
Affiliation(s)
- Rong Liufu
- Cardiovascular Intensive Care Unit, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Guocheng Shi
- Department of Cardiothoracic Surgery, Congenital Heart Center, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Dongfang Road No. 1678, Shanghai, China
| | - Xiaomin He
- Department of Cardiothoracic Surgery, Congenital Heart Center, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Dongfang Road No. 1678, Shanghai, China
| | - Jingjing Lv
- Department of Cardiothoracic Surgery, Congenital Heart Center, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Dongfang Road No. 1678, Shanghai, China
| | - Wei Liu
- Department of Cardiothoracic Surgery, Congenital Heart Center, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Dongfang Road No. 1678, Shanghai, China
| | - Fang Zhu
- Department of Cardiothoracic Surgery, Congenital Heart Center, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Dongfang Road No. 1678, Shanghai, China
| | - Chen Wen
- Department of Cardiothoracic Surgery, Congenital Heart Center, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Dongfang Road No. 1678, Shanghai, China
| | - Zhongqun Zhu
- Department of Cardiothoracic Surgery, Congenital Heart Center, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Dongfang Road No. 1678, Shanghai, China.
| | - Huiwen Chen
- Department of Cardiothoracic Surgery, Congenital Heart Center, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Dongfang Road No. 1678, Shanghai, China.
| |
Collapse
|
|
33
|
Toubat O, Kumar SR. Molecular Approaches in Single Ventricle Management. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2020; 23:77-85. [PMID: 32354551 PMCID: PMC9232387 DOI: 10.1053/j.pcsu.2020.03.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 03/05/2020] [Indexed: 04/21/2023]
Abstract
Advances in medical and surgical management have significantly improved early outcomes in single ventricle congenital heart disease over the last 2 decades. Despite these advances, long-term outcomes remain suboptimal and therapeutic options to address systemic ventricular and/or Fontan failure are limited even in the modern era. Intricate molecular biologic techniques have shed light into the mechanisms of development of single ventricle disease. Efforts are underway to leverage this knowledge to improve clinical diagnosis, therapy, and prognostication. Cell-based therapies aimed at inducing cardiomyocyte proliferation and preventing delayed cardiac dysfunction have already entered the clinical realm. Several more novel biological therapies are expected to become available for patients with single ventricle disease in the near future. These scientific advancements provide us hope and reaffirm our faith that molecular medicine will usher in the next generation of therapies for single ventricle management.
Collapse
Affiliation(s)
- Omar Toubat
- Division of Cardiac Surgery, Department of Surgery, University of Southern California, Los Angeles, California
| | - S Ram Kumar
- Division of Cardiac Surgery, Department of Surgery, University of Southern California, Los Angeles, California; Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; Heart Institute, Children's Hospital, Los Angeles, Los Angeles, California.
| |
Collapse
|
|
34
|
Nitkin CR, Rajasingh J, Pisano C, Besner GE, Thébaud B, Sampath V. Stem cell therapy for preventing neonatal diseases in the 21st century: Current understanding and challenges. Pediatr Res 2020; 87:265-276. [PMID: 31086355 PMCID: PMC6854309 DOI: 10.1038/s41390-019-0425-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 04/24/2019] [Indexed: 02/06/2023]
Abstract
Diseases of the preterm newborn such as bronchopulmonary dysplasia, necrotizing enterocolitis, cerebral palsy, and hypoxic-ischemic encephalopathy continue to be major causes of infant mortality and long-term morbidity. Effective therapies for the prevention or treatment for these conditions are still lacking as recent clinical trials have shown modest or no benefit. Stem cell therapy is rapidly emerging as a novel therapeutic tool for several neonatal diseases with encouraging pre-clinical results that hold promise for clinical translation. However, there are a number of unanswered questions and facets to the development of stem cell therapy as a clinical intervention. There is much work to be done to fully elucidate the mechanisms by which stem cell therapy is effective (e.g., anti-inflammatory versus pro-angiogenic), identifying important paracrine mediators, and determining the timing and type of therapy (e.g., cellular versus secretomes), as well as patient characteristics that are ideal. Importantly, the interaction between stem cell therapy and current, standard-of-care interventions is nearly completely unknown. In this review, we will focus predominantly on the use of mesenchymal stromal cells for neonatal diseases, highlighting the promises and challenges in clinical translation towards preventing neonatal diseases in the 21st century.
Collapse
Affiliation(s)
- Christopher R Nitkin
- Division of Neonatology, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, MO, USA
| | - Johnson Rajasingh
- Department of Cardiovascular Medicine, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, MO, USA
| | - Courtney Pisano
- Department of Pediatric Surgery, Center for Perinatal Research, Nationwide Children's Hospital, Columbus, OH, USA
| | - Gail E Besner
- Department of Pediatric Surgery, Center for Perinatal Research, Nationwide Children's Hospital, Columbus, OH, USA
| | - Bernard Thébaud
- Division of Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario (CHEO) and CHEO Research Institute, Ottawa, ON, Canada
- Ottawa Hospital Research Institute, Regenerative Medicine Program, Ottawa, ON, Canada
| | - Venkatesh Sampath
- Division of Neonatology, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, MO, USA.
| |
Collapse
|
|
35
|
Ferrari MR, Di Maria MV, Jacot JG. Review on Mechanical Support and Cell-Based Therapies for the Prevention and Recovery of the Failed Fontan-Kreutzer Circulation. Front Pediatr 2020; 8:627660. [PMID: 33575233 PMCID: PMC7870783 DOI: 10.3389/fped.2020.627660] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 12/31/2020] [Indexed: 12/13/2022] Open
Abstract
Though the current staged surgical strategy for palliation of single ventricle heart disease, culminating in a Fontan circulation, has increased short-term survival, mounting evidence has shown that the single ventricle, especially a morphologic right ventricle (RV), is inadequate for long-term circulatory support. In addition to high rates of ventricular failure, high central venous pressures (CVP) lead to liver fibrosis or cirrhosis, lymphatic dysfunction, kidney failure, and other comorbidities. In this review, we discuss the complications seen with Fontan physiology, including causes of ventricular and multi-organ failure. We then evaluate the clinical use, results, and limitations of long-term mechanical assist devices intended to reduce RV work and high CVP, as well as biological therapies for failed Fontan circulations. Finally, we discuss experimental tissue engineering solutions designed to prevent Fontan circulation failure and evaluate knowledge gaps and needed technology development to realize a more robust single ventricle therapy.
Collapse
Affiliation(s)
- Margaret R Ferrari
- Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Michael V Di Maria
- Division of Cardiology, Heart Institute, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Jeffrey G Jacot
- Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.,Department of Pediatrics, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| |
Collapse
|
|
36
|
Mohamed IA, El-Badri N, Zaher A. Wnt Signaling: The double-edged sword diminishing the potential of stem cell therapy in congenital heart disease. Life Sci 2019; 239:116937. [PMID: 31629761 DOI: 10.1016/j.lfs.2019.116937] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 09/26/2019] [Accepted: 10/04/2019] [Indexed: 12/26/2022]
Abstract
Stem cell therapy using bone marrow derived or mesenchymal stem cells has become a popular option for cardiovascular disease treatment, however the administration of embryonic stem cells has been mostly experimental. Remarkably, most of these ongoing clinical trials involve adult patients, but little is known regarding the safety and efficacy of stem cell therapy in newborns and children battling congenital heart diseases. Furthermore, cell delivery methods involve the administration of stem cells without pre-differentiation, and without consideration for the consequent process of cardiac development. Interestingly, in-vitro studies have demonstrated that the differentiation of embryonic stem cells into cardiomyocytes imitates the stages of cardiogenesis. Wnt signaling plays a profound role during the earliest stages of cardiogenesis and cardiac differentiation. In fact inappropriate Wnt signaling is associated with numerous cardiac disorders especially congenital heart disease. Furthermore, cell-extracellular matrix interactions were shown to be critical for stem cell differentiation and adequate cardiogenesis. Since extracellular matrix molecules are fundamental for maintenance and repair during heart disease and congenital heart disease, they may offer a novel approach for therapy. Herein we aim to review the critical role of Wnt signaling, as well as the profound importance of cell extracellular matrix interaction, during cardiogenesis. Both of these processes are crucial for precise stem cell differentiation into cardiomyocytes and developing efficacious regenerative therapy for congenital heart disease.
Collapse
Affiliation(s)
- Iman A Mohamed
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, 12588, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, 12588, Egypt
| | - Amr Zaher
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, 12588, Egypt; National Heart Institute, Giza, Egypt.
| |
Collapse
|
|
37
|
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.
Collapse
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.)
| |
Collapse
|
|
38
|
Brown MA, Rajamarthandan S, Francis B, O'Leary-Kelly MK, Sinha P. Update on stem cell technologies in congenital heart disease. J Card Surg 2019; 35:174-179. [PMID: 31705822 DOI: 10.1111/jocs.14312] [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: 11/28/2022]
Abstract
BACKGROUND Congenital heart disease (CHD) continues to be among the most common birth defects, affecting an estimated 40 000 births annually in the United States. The most common complication of CHD is heart failure. With improved medical management and surgical outcomes, survival for complex congenital heart defects has dramatically improved, but consequentially there are more adults with CHD than children with CHD. Due to longer-term sequelae of CHD, surgical and medical treatment previously thought to be curative is now realized at best to be palliative, and there is a considerable burden of CHD-related heart failure. Stem cell therapy as an adjunct to current surgical and medical strategies is being explored in an effort to ameliorate CHD-related heart failure. This review aims to explore the current literature with regard to stem cell therapy for CHD as well as ongoing trials. METHODS A MEDLINE (Ovid), MEDLINE (Pubmed), and clinicaltrials.gov search were performed using the medical subject headings congenital heart defects combined with hematopoietic stem cells, stem cell transplantation, mesenchymal stem cells (MSC), cell- or tissue-based therapy, or MSC transplantation. Articles must have been published after 2010. RESULTS Twenty three articles and 9 ongoing trials met all inclusion criteria. CONCLUSIONS Areas of interest include myocardiocyte regeneration, tissue graft development to minimize reoperations, and methods of stem cell delivery. While several small trials are showing promise, it is too soon to make definitive statements about the future of stem cell therapies in this field.
Collapse
Affiliation(s)
- Matthew A Brown
- School of Medicine, Georgetown University, Washington, District of Columbia
| | | | - Berline Francis
- School of Medicine, Georgetown University, Washington, District of Columbia
| | | | - Pranava Sinha
- Department of Cardiac Surgery, Children's National Medical Center, Washington, District of Columbia
| |
Collapse
|
|
39
|
Mount S, Kanda P, Parent S, Khan S, Michie C, Davila L, Chan V, Davies RA, Haddad H, Courtman D, Stewart DJ, Davis DR. Physiologic expansion of human heart-derived cells enhances therapeutic repair of injured myocardium. Stem Cell Res Ther 2019; 10:316. [PMID: 31685023 PMCID: PMC6829847 DOI: 10.1186/s13287-019-1418-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 09/03/2019] [Accepted: 09/13/2019] [Indexed: 01/08/2023] Open
Abstract
Background Serum-free xenogen-free defined media and continuous controlled physiological cell culture conditions have been developed for stem cell therapeutics, but the effect of these conditions on the relative potency of the cell product is unknown. As such, we conducted a head-to-head comparison of cell culture conditions on human heart explant-derived cells using established in vitro measures of cell potency and in vivo functional repair. Methods Heart explant-derived cells cultured from human atrial or ventricular biopsies within a serum-free xenogen-free media and a continuous physiological culture environment were compared to cells cultured under traditional (high serum) cell culture conditions in a standard clean room facility. Results Transitioning from traditional high serum cell culture conditions to serum-free xenogen-free conditions had no effect on cell culture yields but provided a smaller, more homogenous, cell product with only minor antigenic changes. Culture within continuous physiologic conditions markedly boosted cell proliferation while increasing the expression of stem cell-related antigens and ability of cells to stimulate angiogenesis. Intramyocardial injection of physiologic cultured cells into immunodeficient mice 1 week after coronary ligation translated into improved cardiac function and reduced scar burden which was attributable to increased production of pro-healing cytokines, extracellular vesicles, and microRNAs. Conclusions Continuous physiological cell culture increased cell growth, paracrine output, and treatment outcomes to provide the greatest functional benefit after experimental myocardial infarction.
Collapse
Affiliation(s)
- Seth Mount
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, University of Ottawa, H3214 40 Ruskin Ave, Ottawa, ON, K1Y4W7, Canada
| | - Pushpinder Kanda
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, University of Ottawa, H3214 40 Ruskin Ave, Ottawa, ON, K1Y4W7, Canada
| | - Sandrine Parent
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, University of Ottawa, H3214 40 Ruskin Ave, Ottawa, ON, K1Y4W7, Canada
| | - Saad Khan
- Ottawa Hospital Research Institute, Division of Regenerative Medicine, Department of Medicine, University of Ottawa, Ottawa, K1H8L6, Canada
| | - Connor Michie
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, University of Ottawa, H3214 40 Ruskin Ave, Ottawa, ON, K1Y4W7, Canada
| | - Liliana Davila
- Ottawa Hospital Research Institute, Division of Regenerative Medicine, Department of Medicine, University of Ottawa, Ottawa, K1H8L6, Canada
| | - Vincent Chan
- University of Ottawa Heart Institute, Division of Cardiac Surgery, Department of Medicine, University of Ottawa, Ottawa, K1Y4W7, Canada
| | - Ross A Davies
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, University of Ottawa, H3214 40 Ruskin Ave, Ottawa, ON, K1Y4W7, Canada
| | | | - David Courtman
- Ottawa Hospital Research Institute, Division of Regenerative Medicine, Department of Medicine, University of Ottawa, Ottawa, K1H8L6, Canada
| | - Duncan J Stewart
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, University of Ottawa, H3214 40 Ruskin Ave, Ottawa, ON, K1Y4W7, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, K1H8M5, Canada.,Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, K1H8L6, Canada
| | - Darryl R Davis
- University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, University of Ottawa, H3214 40 Ruskin Ave, Ottawa, ON, K1Y4W7, Canada. .,Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, K1H8L6, Canada.
| |
Collapse
|
|
40
|
Desai M, Sinha L, Yerebakan C. Commentary: Myocardial regeneration with stem cells-Hope was never the problem! J Thorac Cardiovasc Surg 2019; 158:1624-1625. [PMID: 31590959 DOI: 10.1016/j.jtcvs.2019.07.071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 07/20/2019] [Accepted: 07/25/2019] [Indexed: 11/19/2022]
Affiliation(s)
- Manan Desai
- Department of Cardiovascular Surgery, Children's National Heart Institute, The George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Lok Sinha
- Department of Cardiovascular Surgery, Children's National Heart Institute, The George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Can Yerebakan
- Department of Cardiovascular Surgery, Children's National Heart Institute, The George Washington University School of Medicine and Health Sciences, Washington, DC.
| |
Collapse
|
|
41
|
Exosomes in ischemic heart disease: novel carriers for bioinformation. Biomed Pharmacother 2019; 120:109451. [PMID: 31586900 DOI: 10.1016/j.biopha.2019.109451] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 08/25/2019] [Accepted: 09/09/2019] [Indexed: 12/31/2022] Open
Abstract
The occurrence of ischemic heart disease(IHD) is a multi-step chain process from potential risk factors to overt clinical diseases. Vascular cells, blood cells, cardiomyocytes and stem cells are all involved in the pathophysiological links via continual and polynary crosstalk. Exosomes,as powerful vectors for intercellular communication,have been a hotspot for basic and clinical research. Plenty of evidence has shown that exosomes largely participate in the evolution of IHD, including endothelial dysfunction, lipid deposition, atheromatous plaque formation and rupture, myocardial ischemia-reperfusion(I/R) injury,and heart failure (HF), while the rules for detailed communication in the different stages of this continuous disease are still poorly understood. This review will systematically describe characteristics of exosomal crosstalk between different cells in the diverse periods, and also cast light on the potential and challenges for exosome application as therapeutic targets, hoping to offer supporting background for the following research.
Collapse
|
|
42
|
Bittle GJ, Morales D, Deatrick KB, Parchment N, Saha P, Mishra R, Sharma S, Pietris N, Vasilenko A, Bor C, Ambastha C, Gunasekaran M, Li D, Kaushal S. Stem Cell Therapy for Hypoplastic Left Heart Syndrome: Mechanism, Clinical Application, and Future Directions. Circ Res 2019; 123:288-300. [PMID: 29976693 DOI: 10.1161/circresaha.117.311206] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hypoplastic left heart syndrome is a type of congenital heart disease characterized by underdevelopment of the left ventricle, outflow tract, and aorta. The condition is fatal if aggressive palliative operations are not undertaken, but even after the complete 3-staged surgical palliation, there is significant morbidity because of progressive and ultimately intractable right ventricular failure. For this reason, there is interest in developing novel therapies for the management of right ventricular dysfunction in patients with hypoplastic left heart syndrome. Stem cell therapy may represent one such innovative approach. The field has identified numerous stem cell populations from different tissues (cardiac or bone marrow or umbilical cord blood), different age groups (adult versus neonate-derived), and different donors (autologous versus allogeneic), with preclinical and clinical experience demonstrating the potential utility of each cell type. Preclinical trials in small and large animal models have elucidated several mechanisms by which stem cells affect the injured myocardium. Our current understanding of stem cell activity is undergoing a shift from a paradigm based on cellular engraftment and differentiation to one recognizing a primarily paracrine effect. Recent studies have comprehensively evaluated the individual components of the stem cells' secretomes, shedding new light on the intracellular and extracellular pathways at the center of their therapeutic effects. This research has laid the groundwork for clinical application, and there are now several trials of stem cell therapies in pediatric populations that will provide important insights into the value of this therapeutic strategy in the management of hypoplastic left heart syndrome and other forms of congenital heart disease. This article reviews the many stem cell types applied to congenital heart disease, their preclinical investigation and the mechanisms by which they might affect right ventricular dysfunction in patients with hypoplastic left heart syndrome, and finally, the completed and ongoing clinical trials of stem cell therapy in patients with congenital heart disease.
Collapse
Affiliation(s)
- Gregory J Bittle
- From the Division of Cardiac Surgery (G.J.B., D.M., K.B.D., N. Parchment, P.S., R.M., S.S., A.V., C.B., C.A., M.G., D.L., S.K.)
| | - David Morales
- From the Division of Cardiac Surgery (G.J.B., D.M., K.B.D., N. Parchment, P.S., R.M., S.S., A.V., C.B., C.A., M.G., D.L., S.K.)
| | - Kristopher B Deatrick
- From the Division of Cardiac Surgery (G.J.B., D.M., K.B.D., N. Parchment, P.S., R.M., S.S., A.V., C.B., C.A., M.G., D.L., S.K.)
| | - Nathaniel Parchment
- From the Division of Cardiac Surgery (G.J.B., D.M., K.B.D., N. Parchment, P.S., R.M., S.S., A.V., C.B., C.A., M.G., D.L., S.K.)
| | - Progyaparamita Saha
- From the Division of Cardiac Surgery (G.J.B., D.M., K.B.D., N. Parchment, P.S., R.M., S.S., A.V., C.B., C.A., M.G., D.L., S.K.)
| | - Rachana Mishra
- From the Division of Cardiac Surgery (G.J.B., D.M., K.B.D., N. Parchment, P.S., R.M., S.S., A.V., C.B., C.A., M.G., D.L., S.K.)
| | - Sudhish Sharma
- From the Division of Cardiac Surgery (G.J.B., D.M., K.B.D., N. Parchment, P.S., R.M., S.S., A.V., C.B., C.A., M.G., D.L., S.K.)
| | - Nicholas Pietris
- Division of Cardiology (N. Pietris), University of Maryland School of Medicine, Baltimore
| | - Alexander Vasilenko
- From the Division of Cardiac Surgery (G.J.B., D.M., K.B.D., N. Parchment, P.S., R.M., S.S., A.V., C.B., C.A., M.G., D.L., S.K.)
| | - Casey Bor
- From the Division of Cardiac Surgery (G.J.B., D.M., K.B.D., N. Parchment, P.S., R.M., S.S., A.V., C.B., C.A., M.G., D.L., S.K.)
| | - Chetan Ambastha
- From the Division of Cardiac Surgery (G.J.B., D.M., K.B.D., N. Parchment, P.S., R.M., S.S., A.V., C.B., C.A., M.G., D.L., S.K.)
| | - Muthukumar Gunasekaran
- From the Division of Cardiac Surgery (G.J.B., D.M., K.B.D., N. Parchment, P.S., R.M., S.S., A.V., C.B., C.A., M.G., D.L., S.K.)
| | - Deqiang Li
- From the Division of Cardiac Surgery (G.J.B., D.M., K.B.D., N. Parchment, P.S., R.M., S.S., A.V., C.B., C.A., M.G., D.L., S.K.)
| | - Sunjay Kaushal
- From the Division of Cardiac Surgery (G.J.B., D.M., K.B.D., N. Parchment, P.S., R.M., S.S., A.V., C.B., C.A., M.G., D.L., S.K.)
| |
Collapse
|
|
43
|
Ibrahim A, Grigorian-Shamagian L, Rogers RG, Marbán E. Letter by Ibrahim et al Regarding Article, "Lack of Cardiac Improvement After Cardiosphere-Derived Cell Transplantation in Aging Mouse Hearts". Circ Res 2019; 123:e65-e66. [PMID: 30566047 DOI: 10.1161/circresaha.118.314147] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Ahmed Ibrahim
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | | | - Russell G Rogers
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Eduardo Marbán
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| |
Collapse
|
|
44
|
Villanueva M, Michie C, Parent S, Kanaan GN, Rafatian G, Kanda P, Ye B, Liang W, Harper ME, Davis DR. Glyoxalase 1 Prevents Chronic Hyperglycemia Induced Heart-Explant Derived Cell Dysfunction. Theranostics 2019; 9:5720-5730. [PMID: 31534514 PMCID: PMC6735395 DOI: 10.7150/thno.36639] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 07/06/2019] [Indexed: 12/20/2022] Open
Abstract
Decades of work have shown that diabetes increases the risk of heart disease and worsens clinical outcomes after myocardial infarction. Because diabetes is an absolute contraindication to heart transplant, cell therapy is increasingly being explored as a means of improving heart function for these patients with very few other options. Given that hyperglycemia promotes the generation of toxic metabolites, the influence of the key detoxification enzyme glyoxalase 1 (Glo1) on chronic hyperglycemia induced heart explant-derived cell (EDC) dysfunction was investigated. Methods: EDCs were cultured from wild type C57Bl/6 or Glo1 over-expressing transgenic mice 2 months after treatment with the pancreatic beta cell toxin streptozotocin or vehicle. The effects of Glo1 overexpression was evaluated using in vitro and in vivo models of myocardial ischemia. Results: Chronic hyperglycemia reduced overall culture yields and increased the reactive dicarbonyl cell burden within EDCs. These intrinsic cell changes reduced the angiogenic potential and production of pro-healing exosomes while promoting senescence and slowing proliferation. Compared to intra-myocardial injection of normoglycemic cells, chronic hyperglycemia attenuated cell-mediated improvements in myocardial function and reduced the ability of transplanted cells to promote new blood vessel and cardiomyocyte growth. In contrast, Glo1 overexpression decreased oxidative damage while restoring both cell culture yields and EDC-mediated repair of ischemic myocardium. The latter was associated with enhanced production of pro-healing extracellular vesicles by Glo1 cells without altering the pro-healing microRNA cargo within. Conclusions: Chronic hyperglycemia decreases the regenerative performance of EDCs. Overexpression of Glo1 reduces dicarbonyl stress and prevents chronic hyperglycemia-induced dysfunction by rejuvenating the production of pro-healing extracellular vesicles.
Collapse
|
|
45
|
Graupner O, Enzensberger C, Axt-Fliedner R. New Aspects in the Diagnosis and Therapy of Fetal Hypoplastic Left Heart Syndrome. Geburtshilfe Frauenheilkd 2019; 79:863-872. [PMID: 31423021 PMCID: PMC6690741 DOI: 10.1055/a-0828-7968] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 12/29/2018] [Accepted: 12/30/2018] [Indexed: 12/26/2022] Open
Abstract
Fetal hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease with a lethal prognosis without postnatal therapeutic intervention or surgery. The aim of this article is to give a brief overview of new findings in the field of prenatal diagnosis and the therapy of HLHS. As cardiac output in HLHS children depends on the right ventricle (RV), prenatal assessment of fetal RV function is of interest to predict poor functional RV status before the RV becomes the systemic ventricle. Prenatal cardiac interventions such as fetal aortic valvuloplasty and non-invasive procedures such as maternal hyperoxygenation seem to be promising treatment options but will need to be evaluated with regard to long-term outcomes. Novel approaches such as stem cell therapy or neuroprotection provide important clues about the complexity of the disease. New aspects in diagnostics and therapy of HLHS show the potential of a targeted prenatal treatment planning. This could be used to optimize parental counseling as well as pre- and postnatal management of affected children.
Collapse
Affiliation(s)
- Oliver Graupner
- Department of Obstetrics and Gynecology, University Hospital rechts der Isar, Technical University of Munich, Munich, Germany
| | - Christian Enzensberger
- Department of Obstetrics and Gynecology, Division of Prenatal Medicine, University Hospital UKGM, Justus-Liebig University, Giessen, Germany
| | - Roland Axt-Fliedner
- Department of Obstetrics and Gynecology, Division of Prenatal Medicine, University Hospital UKGM, Justus-Liebig University, Giessen, Germany
| |
Collapse
|
|
46
|
Commentary: Stem cell therapy for single-ventricle congenital heart disease: Exciting, but a long way to go. J Thorac Cardiovasc Surg 2019; 158:851-852. [PMID: 31277816 DOI: 10.1016/j.jtcvs.2019.05.041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 05/15/2019] [Indexed: 11/22/2022]
|
|
47
|
Sano S, Ishigami S, Sano T. New era of heart failure therapy in pediatrics: Cardiac stem cell therapy on the start line. J Thorac Cardiovasc Surg 2019; 158:845-849. [PMID: 31248633 DOI: 10.1016/j.jtcvs.2019.05.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 05/14/2019] [Accepted: 05/15/2019] [Indexed: 12/24/2022]
Affiliation(s)
- Shunji Sano
- Department of Pediatric Cardiothoracic Surgery, University of California, San Francisco, San Francisco, Calif.
| | - Shuta Ishigami
- Department of Pediatric Cardiothoracic Surgery, University of California, San Francisco, San Francisco, Calif
| | - Toshikazu Sano
- Department of Pediatric Cardiothoracic Surgery, University of California, San Francisco, San Francisco, Calif
| |
Collapse
|
|
48
|
Shoja-Taheri F, George A, Agarwal U, Platt MO, Gibson G, Davis ME. Using Statistical Modeling to Understand and Predict Pediatric Stem Cell Function. CIRCULATION. GENOMIC AND PRECISION MEDICINE 2019; 12:e002403. [PMID: 31100989 PMCID: PMC6581595 DOI: 10.1161/circgen.118.002403] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 05/17/2019] [Indexed: 12/31/2022]
Abstract
BACKGROUND Congenital heart defects are a leading cause of morbidity and mortality in children, and despite advanced surgical treatments, many patients progress to heart failure. Currently, transplantation is the only effective cure and is limited by donor availability and organ rejection. Recently, cell therapy has emerged as a novel method for treating pediatric heart failure with several ongoing clinical trials. However, efficacy of stem cell therapy is variable, and choosing stem cells with the highest reparative effects has been a challenge. METHODS We previously demonstrated the age-dependent reparative effects of human c-kit+ progenitor cells (hCPCs) in a rat model of juvenile heart failure. Using a small subset of patient samples, computational modeling analysis showed that regression models could be made linking sequencing data to phenotypic outcomes. In the current study, we used a similar quantitative model to determine whether predictions can be made in a larger population of patients and validated the model using neonatal hCPCs. We performed RNA sequencing from c-kit+ progenitor cells isolated from 32 patients, including 8 neonatal samples. We tested 2 functional parameters of our model, cellular proliferation and chemotactic potential of conditioned media. RESULTS Interestingly, the observed proliferation and migration responses in each of the selected neonatal hCPC lines matched their predicted counterparts. We then performed canonical pathway analysis to determine potential mechanistic signals that regulated hCPC performance and identified several immune response genes that correlated with performance. ELISA analysis confirmed the presence of selected cytokines in good performing hCPCs and provided many more signals to further validate. CONCLUSIONS These data show that cell behavior may be predicted using large datasets like RNA sequencing and that we may be able to identify patients whose c-kit+ progenitor cells exceed or underperform expectations. With systems biology approaches, interventions can be tailored to improve cell therapy or mimic the qualities of reparative cells.
Collapse
Affiliation(s)
- Farnaz Shoja-Taheri
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA
| | - Alex George
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA
| | - Udit Agarwal
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Manu O. Platt
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA
| | - Greg Gibson
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA
| | - Michael E. Davis
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA
- Children’s Heart Research and Outcomes (HeRO) Center, Emory University & Children’s Healthcare of Atlanta, Atlanta, GA
| |
Collapse
|
|
49
|
Michel-Behnke I, Pavo I, Recla S, Khalil M, Jux C, Schranz D. Regenerative therapies in young hearts with structural or congenital heart disease. Transl Pediatr 2019; 8:140-150. [PMID: 31161081 PMCID: PMC6514281 DOI: 10.21037/tp.2019.03.01] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Pediatric heart failure (HF) is rare. The prognosis is generally poor. HF is most frequently related to cardiomyopathy or congenital heart disease (CHD). Associated phenotypes are HF with preserved (HFpEF) or reduced ejection fraction (HFrEF); both in children with biventricular or univentricular circulation. Cardiac growth, differentiation, proliferation and consecutively regenerative and repair mechanisms are inversely related to the patient's age; edaphic and circulating cardiac progenitor cells as well; in sum, there are enormous endogenous potentials repairing a diseased heart in particular in young children. Efforts supporting pediatric cardiac regeneration are clearly justified; cell-based therapies have been addressed in small series of children with end-stage HF of either the left or right ventricle, more recently in randomized clinical trials. Different cell populations like autologous bone marrow mononuclear cells, progenitor cells or cardiac derived cells have been injected into coronaries or directly into the myocardium. Beneficial at least transient improvement of cardiac function was observed in patients with dilative cardiomyopathy and CHD, mainly hypoplastic left heart syndrome (HLHS). Cellular repopulation and possibly more crucial, paracrine effects contributed in slowing down progression of pediatric end-stage HF. Our review summarizes the current knowledge in different scenarios of HF by cell-based cardiac therapies in critically ill children. Based on the actual clinical experience future work to distinguish responders from non-responders among other refinements will lead to individualized precision treatment of HF in children, what means a lot to a child on a long list waiting for heart transplantation (HTX).
Collapse
Affiliation(s)
- Ina Michel-Behnke
- University Hospital for Children and Adolescent Medicine, Division of Pediatric Cardiology, Pediatric Heart Center, Medical University Vienna, Vienna, Austria
| | - Imre Pavo
- University Hospital for Children and Adolescent Medicine, Division of Pediatric Cardiology, Pediatric Heart Center, Medical University Vienna, Vienna, Austria
| | - Sabine Recla
- Pediatric Heart Center, Justus-Liebig University, Giessen, Germany
| | - Markus Khalil
- Pediatric Heart Center, Justus-Liebig University, Giessen, Germany
| | - Christian Jux
- Pediatric Heart Center, Justus-Liebig University, Giessen, Germany
| | - Dietmar Schranz
- Pediatric Heart Center, Justus-Liebig University, Giessen, Germany
| |
Collapse
|
|
50
|
Rafatian G, Davis DR. Concise Review: Heart-Derived Cell Therapy 2.0: Paracrine Strategies to Increase Therapeutic Repair of Injured Myocardium. Stem Cells 2018; 36:1794-1803. [PMID: 30171743 DOI: 10.1002/stem.2910] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2018] [Revised: 08/13/2018] [Accepted: 08/20/2018] [Indexed: 01/09/2023]
Abstract
Despite progress in cardiovascular medicine, the incidence of heart failure is rising and represents a growing challenge. To address this, ex vivo proliferated heart-derived cell products have emerged as a promising investigational cell-treatment option. Despite being originally proposed as a straightforward myocyte replacement strategy, emerging evidence has shown that cell-mediated gains in cardiac function are leveraged on paracrine stimulation of endogenous repair and tissue salvage. In this concise review, we focus on the paracrine repertoire of heart-derived cells and outline strategies used to boost cell potency by targeting cytokines, metabolic preconditioning and supportive biomaterials. Mechanistic insights from these studies will shape future efforts to use defined factors and/or synthetic cell approaches to help the millions of patients worldwide suffering from heart failure. Stem Cells 2018;36:1794-10.
Collapse
Affiliation(s)
- Ghazaleh Rafatian
- Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
| | - Darryl R Davis
- Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
| |
Collapse
|