|
1
|
Amini H, Namjoo AR, Narmi MT, Mardi N, Narimani S, Naturi O, Khosrowshahi ND, Rahbarghazi R, Saghebasl S, Hashemzadeh S, Nouri M. Exosome-bearing hydrogels and cardiac tissue regeneration. Biomater Res 2023; 27:99. [PMID: 37803483 PMCID: PMC10559618 DOI: 10.1186/s40824-023-00433-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 09/18/2023] [Indexed: 10/08/2023] Open
Abstract
BACKGROUND In recent years, cardiovascular disease in particular myocardial infarction (MI) has become the predominant cause of human disability and mortality in the clinical setting. The restricted capacity of adult cardiomyocytes to proliferate and restore the function of infarcted sites is a challenging issue after the occurrence of MI. The application of stem cells and byproducts such as exosomes (Exos) has paved the way for the alleviation of cardiac tissue injury along with conventional medications in clinics. However, the short lifespan and activation of alloreactive immune cells in response to Exos and stem cells are the main issues in patients with MI. Therefore, there is an urgent demand to develop therapeutic approaches with minimum invasion for the restoration of cardiac function. MAIN BODY Here, we focused on recent data associated with the application of Exo-loaded hydrogels in ischemic cardiac tissue. Whether and how the advances in tissue engineering modalities have increased the efficiency of whole-based and byproducts (Exos) therapies under ischemic conditions. The integration of nanotechnology and nanobiology for designing novel smart biomaterials with therapeutic outcomes was highlighted. CONCLUSION Hydrogels can provide suitable platforms for the transfer of Exos, small molecules, drugs, and other bioactive factors for direct injection into the damaged myocardium. Future studies should focus on the improvement of physicochemical properties of Exo-bearing hydrogel to translate for the standard treatment options.
Collapse
Affiliation(s)
- Hassan Amini
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of General and Vascular Surgery, Tabriz University of Medical Sciences, Tabriz, 51548/53431, Iran
| | - Atieh Rezaei Namjoo
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Taghavi Narmi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Narges Mardi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Samaneh Narimani
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ozra Naturi
- Department of Organic and Biochemistry, Faculty of Chemistry, University of Tabriz, Tabriz, Iran
| | - Nafiseh Didar Khosrowshahi
- Stem Cell and Tissue Engineering Research Laboratory, Sahand University of Technology, Tabriz, 51335-1996, Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, 51548/53431, Iran.
| | - Solmaz Saghebasl
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, 51548/53431, Iran.
| | - Shahriar Hashemzadeh
- Department of General and Vascular Surgery, Tabriz University of Medical Sciences, Tabriz, 51548/53431, Iran.
| | - Mohammad Nouri
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
2
|
Yang L, Hu R, Yuan C, Guan L, Mu Y. Screening of the best time window for MSC transplantation to treat acute myocardial infarction with SDF-1α antibody-loaded targeted ultrasonic microbubbles: An in vivo study in miniswine. Open Life Sci 2023; 18:20220620. [PMID: 37360786 PMCID: PMC10290280 DOI: 10.1515/biol-2022-0620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 04/04/2023] [Accepted: 04/27/2023] [Indexed: 06/28/2023] Open
Abstract
The present study aimed to screen the best time window for the transplantation of bone marrow mesenchymal stem cells (MSCs) after acute myocardial infarction (MI) through targeted ultrasound microbubbles loaded with SDF-1α antibody. Thirty-six MI miniswine were randomly divided into six experimental groups according to the duration after infarction (1 day, 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks after infarction). MSCs were labeled with BrdU and then injected through the coronary artery in the stem cell transplantation group to detect the number of transplanted MSCs at different time points after MI. Three miniswine were randomly selected as the control group (sham operation: open chest without ligation of the coronary artery). All SDF-1α groups and control groups were injected with a targeted microbubble ultrasound contrast agent. The values of the myocardial perfusion parameters (A, β, and A × β) were determined. A T, β T, and (A × β)T varied with time and peaked 1 week after MI (P < 0.05). The number of transplanted stem cells in the myocardium through coronary injection of MSCs at 1 week was the greatest and consistent with the changing tendency of A T, β T, and (A × β)T (r = 0.658, 0.778, 0.777, P < 0.05). β T(X), (A × β)T(X), and the number of transplanted stem cells was used to establish the regression equation as follows: Y = 36.11 + 17.601X; Y = 50.023 + 3.348X (R 2 = 0.605, 0.604, P < 0.05). The best time window for transplanting stem cells was 1 week after MI. The myocardial perfusion parameters of the SDF-1α targeted contrast agent can be used to predict the number of transplanted stem cells in the myocardial tissue.
Collapse
Affiliation(s)
- Lingjie Yang
- Department of Echocardiography, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Key Laboratory of Ultrasound Medicine, No. 137, Li Yu Shan South Road, Urmuqi830011, China
| | - Rong Hu
- Department of Echocardiography, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Key Laboratory of Ultrasound Medicine, No. 137, Li Yu Shan South Road, Urmuqi830011, China
| | - Chen Yuan
- Department of Echocardiography, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Key Laboratory of Ultrasound Medicine, No. 137, Li Yu Shan South Road, Urmuqi830011, China
| | - Lina Guan
- Department of Echocardiography, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Key Laboratory of Ultrasound Medicine, No. 137, Li Yu Shan South Road, Urmuqi830011, China
| | - Yuming Mu
- Department of Echocardiography, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Key Laboratory of Ultrasound Medicine, No. 137, Li Yu Shan South Road, Urmuqi830011, China
| |
Collapse
|
|
3
|
Lee CY, Lee S, Jeong S, Lee J, Seo HH, Shin S, Park JH, Song BW, Kim IK, Choi JW, Kim SW, Han G, Lim S, Hwang KC. Suppressing Pyroptosis Augments Post-Transplant Survival of Stem Cells and Cardiac Function Following Ischemic Injury. Int J Mol Sci 2021; 22:7946. [PMID: 34360711 PMCID: PMC8348609 DOI: 10.3390/ijms22157946] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/20/2021] [Accepted: 07/20/2021] [Indexed: 12/11/2022] Open
Abstract
The acute demise of stem cells following transplantation significantly compromises the efficacy of stem cell-based cell therapeutics for infarcted hearts. As the stem cells transplanted into the damaged heart are readily exposed to the hostile environment, it can be assumed that the acute death of the transplanted stem cells is also inflicted by the same environmental cues that caused massive death of the host cardiac cells. Pyroptosis, a highly inflammatory form of programmed cell death, has been added to the list of important cell death mechanisms in the damaged heart. However, unlike the well-established cell death mechanisms such as necrosis or apoptosis, the exact role and significance of pyroptosis in the acute death of transplanted stem cells have not been explored in depth. In the present study, we found that M1 macrophages mediate the pyroptosis in the ischemia/reperfusion (I/R) injured hearts and identified miRNA-762 as an important regulator of interleukin 1β production and subsequent pyroptosis. Delivery of exogenous miRNA-762 prior to transplantation significantly increased the post-transplant survival of stem cells and also significantly ameliorated cardiac fibrosis and heart functions following I/R injury. Our data strongly suggest that suppressing pyroptosis can be an effective adjuvant strategy to enhance the efficacy of stem cell-based therapeutics for diseased hearts.
Collapse
Affiliation(s)
- Chang Youn Lee
- Department of Integrated Omics for Biomedical Sciences, Yonsei University, Seoul 03722, Korea; (C.Y.L.); (S.S.); (J.-H.P.); (G.H.)
| | - Seahyoung Lee
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si 25601, Korea; (S.L.); (S.J.); (B.-W.S.); (I.-K.K.); (J.-W.C.); (S.W.K.)
| | - Seongtae Jeong
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si 25601, Korea; (S.L.); (S.J.); (B.-W.S.); (I.-K.K.); (J.-W.C.); (S.W.K.)
| | - Jiyun Lee
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 03722, Korea; (J.L.); (H.-H.S.)
| | - Hyang-Hee Seo
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 03722, Korea; (J.L.); (H.-H.S.)
| | - Sunhye Shin
- Department of Integrated Omics for Biomedical Sciences, Yonsei University, Seoul 03722, Korea; (C.Y.L.); (S.S.); (J.-H.P.); (G.H.)
| | - Jun-Hee Park
- Department of Integrated Omics for Biomedical Sciences, Yonsei University, Seoul 03722, Korea; (C.Y.L.); (S.S.); (J.-H.P.); (G.H.)
| | - Byeong-Wook Song
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si 25601, Korea; (S.L.); (S.J.); (B.-W.S.); (I.-K.K.); (J.-W.C.); (S.W.K.)
| | - Il-Kwon Kim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si 25601, Korea; (S.L.); (S.J.); (B.-W.S.); (I.-K.K.); (J.-W.C.); (S.W.K.)
| | - Jung-Won Choi
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si 25601, Korea; (S.L.); (S.J.); (B.-W.S.); (I.-K.K.); (J.-W.C.); (S.W.K.)
| | - Sang Woo Kim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si 25601, Korea; (S.L.); (S.J.); (B.-W.S.); (I.-K.K.); (J.-W.C.); (S.W.K.)
| | - Gyoonhee Han
- Department of Integrated Omics for Biomedical Sciences, Yonsei University, Seoul 03722, Korea; (C.Y.L.); (S.S.); (J.-H.P.); (G.H.)
| | - Soyeon Lim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si 25601, Korea; (S.L.); (S.J.); (B.-W.S.); (I.-K.K.); (J.-W.C.); (S.W.K.)
| | - Ki-Chul Hwang
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si 25601, Korea; (S.L.); (S.J.); (B.-W.S.); (I.-K.K.); (J.-W.C.); (S.W.K.)
| |
Collapse
|
|
4
|
Carbone RG, Monselise A, Bottino G, Negrini S, Puppo F. Stem cells therapy in acute myocardial infarction: a new era? Clin Exp Med 2021; 21:231-237. [PMID: 33484381 PMCID: PMC8053645 DOI: 10.1007/s10238-021-00682-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 01/04/2021] [Indexed: 12/12/2022]
Abstract
Stem cells transplantation after acute myocardial infarction (AMI) has been claimed to restore cardiac function. However, this therapy is still restricted to experimental studies and clinical trials. Early un-blinded studies suggested a benefit from stem cell therapy following AMI. More recent blinded randomized trials have produced mixed results and, notably, the last largest pan-European clinical trial showed the inconclusive results. Furthermore, mechanisms of potential benefit remain uncertain. This review analytically evaluates 34 blinded and un-blinded clinical trials comprising 3142 patients and is aimed to: (1) identify the pros and cons of stem cell therapy up to a 6-month follow-up after AMI comparing benefit or no effectiveness reported in clinical trials; (2) provide useful information for planning future clinical programs of cardiac stem cell therapy.
Collapse
Affiliation(s)
- R G Carbone
- Department of Internal Medicine, University of Genoa, Genoa, Italy
| | | | - G Bottino
- Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - S Negrini
- Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - F Puppo
- Department of Internal Medicine, University of Genoa, Genoa, Italy.
| |
Collapse
|
|
5
|
Weber M, Fech A, Jäger L, Steinle H, Bühler L, Perl RM, Martirosian P, Mehling R, Sonanini D, Aicher WK, Nikolaou K, Schlensak C, Enderle MD, Wendel HP, Linzenbold W, Avci-Adali M. Hydrojet-based delivery of footprint-free iPSC-derived cardiomyocytes into porcine myocardium. Sci Rep 2020; 10:16787. [PMID: 33033281 PMCID: PMC7546722 DOI: 10.1038/s41598-020-73693-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 09/14/2020] [Indexed: 12/29/2022] Open
Abstract
The reprogramming of patient´s somatic cells into induced pluripotent stem cells (iPSCs) and the consecutive differentiation into cardiomyocytes enables new options for the treatment of infarcted myocardium. In this study, the applicability of a hydrojet-based method to deliver footprint-free iPSC-derived cardiomyocytes into the myocardium was analyzed. A new hydrojet system enabling a rapid and accurate change between high tissue penetration pressures and low cell injection pressures was developed. Iron oxide-coated microparticles were ex vivo injected into porcine hearts to establish the application parameters and the distribution was analyzed using magnetic resonance imaging. The influence of different hydrojet pressure settings on the viability of cardiomyocytes was analyzed. Subsequently, cardiomyocytes were delivered into the porcine myocardium and analyzed by an in vivo imaging system. The delivery of microparticles or cardiomyocytes into porcine myocardium resulted in a widespread three-dimensional distribution. In vitro, 7 days post-injection, only cardiomyocytes applied with a hydrojet pressure setting of E20 (79.57 ± 1.44%) showed a significantly reduced cell viability in comparison to the cells applied with 27G needle (98.35 ± 5.15%). Furthermore, significantly less undesired distribution of the cells via blood vessels was detected compared to 27G needle injection. This study demonstrated the applicability of the hydrojet-based method for the intramyocardial delivery of iPSC-derived cardiomyocytes. The efficient delivery of cardiomyocytes into infarcted myocardium could significantly improve the regeneration.
Collapse
Affiliation(s)
- Marbod Weber
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076, Tuebingen, Germany
| | - Andreas Fech
- Erbe Elektromedizin Tuebingen, Waldhoernlestr. 17, 72072, Tuebingen, Germany
| | - Luise Jäger
- Erbe Elektromedizin Tuebingen, Waldhoernlestr. 17, 72072, Tuebingen, Germany
| | - Heidrun Steinle
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076, Tuebingen, Germany
| | - Louisa Bühler
- Erbe Elektromedizin Tuebingen, Waldhoernlestr. 17, 72072, Tuebingen, Germany
| | - Regine Mariette Perl
- Diagnostic and Interventional Radiology, University Hospital Tuebingen, Hoppe-Seyler-Strasse 3, 72076, Tuebingen, Germany
| | - Petros Martirosian
- Diagnostic and Interventional Radiology, University Hospital Tuebingen, Hoppe-Seyler-Strasse 3, 72076, Tuebingen, Germany
| | - Roman Mehling
- Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University, Roentgenweg 13, 72076, Tuebingen, Germany
| | - Dominik Sonanini
- Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University, Roentgenweg 13, 72076, Tuebingen, Germany
| | - Wilhelm K Aicher
- Department of Urology, ZMF, University Hospital Tuebingen, Waldhoernlestr. 22, 72072, Tuebingen, Germany
| | - Konstantin Nikolaou
- Diagnostic and Interventional Radiology, University Hospital Tuebingen, Hoppe-Seyler-Strasse 3, 72076, Tuebingen, Germany
| | - Christian Schlensak
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076, Tuebingen, Germany
| | - Markus D Enderle
- Erbe Elektromedizin Tuebingen, Waldhoernlestr. 17, 72072, Tuebingen, Germany
| | - Hans Peter Wendel
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076, Tuebingen, Germany
| | - Walter Linzenbold
- Erbe Elektromedizin Tuebingen, Waldhoernlestr. 17, 72072, Tuebingen, Germany
| | - Meltem Avci-Adali
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076, Tuebingen, Germany.
| |
Collapse
|
|
6
|
Chan JL, Miller JG, Zhou Y, Robey PG, Stroncek DF, Arai AE, Sachdev V, Horvath KA. Intramyocardial Bone Marrow Stem Cells in Patients Undergoing Cardiac Surgical Revascularization. Ann Thorac Surg 2020; 109:1142-1149. [PMID: 31526779 PMCID: PMC8045460 DOI: 10.1016/j.athoracsur.2019.07.093] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 07/04/2019] [Accepted: 07/29/2019] [Indexed: 01/14/2023]
Abstract
BACKGROUND Bone marrow stromal or stem cells (BMSCs) remain a promising potential therapy for ischemic cardiomyopathy. The primary objective of this study was to evaluate the safety and feasibility of direct intramyocardial injection of autologous BMSCs in patients undergoing transmyocardial revascularization (TMR) or coronary artery bypass graft surgery (CABG). METHODS A phase I trial was conducted on adult patients who had ischemic heart disease with depressed left ventricular ejection fraction and who were scheduled to undergo TMR or CABG. Autologous BMSCs were expanded for 3 weeks before the scheduled surgery. After completion of surgical revascularization, BMSCs were directly injected into ischemic myocardium. Safety and feasibility of therapy were assessed. Cardiac functional status and changes in quality of life were evaluated at 1 year. RESULTS A total of 14 patients underwent simultaneous BMSC and surgical revascularization therapy (TMR+BMSCs = 10; CABG+BMSCs = 4). BMSCs were successfully expanded, and no significant complications occurred as a result of the procedure. Regional contractility in the cell-treated areas demonstrated improvement at 12 months compared with baseline (TMR+BMSCs Δ strain: -4.6% ± 2.1%; P = .02; CABG+MSCs Δ strain: -4.2% ± 6.0%; P = .30). Quality of life was enhanced, with substantial reduction in angina scores at 1 year after treatment (TMR+BMSCs: 1.3 ± 1.2; CABG+MSCs: 1.0 ± 1.4). CONCLUSIONS In this phase I trial, direct intramyocardial injection of autologous BMSCs in conjunction with TMR or CABG was technically feasible and could be performed safely. Preliminary results demonstrate improved cardiac function and quality of life in patients at 1 year after treatment.
Collapse
Affiliation(s)
- Joshua L Chan
- Cardiothoracic Surgery Research Program, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Justin G Miller
- Cardiothoracic Surgery Research Program, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Yifu Zhou
- Cardiothoracic Surgery Research Program, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Pamela G Robey
- NIH Bone Marrow Stromal Cell Transplantation Center, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
| | - David F Stroncek
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Andrew E Arai
- Advanced Cardiovascular Imaging Group, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Vandana Sachdev
- Echocardiography Laboratory, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Keith A Horvath
- Cardiothoracic Surgery Research Program, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
| |
Collapse
|
|
7
|
Mesenchymal Stem Cells from Human Exfoliated Deciduous Teeth and the Orbicularis Oris Muscle: How Do They Behave When Exposed to a Proinflammatory Stimulus? Stem Cells Int 2020; 2020:3670412. [PMID: 32184831 PMCID: PMC7060870 DOI: 10.1155/2020/3670412] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 01/04/2020] [Accepted: 02/01/2020] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have been studied as a promising type of stem cell for use in cell therapies because of their ability to regulate the immune response. Although they are classically isolated from the bone marrow, many studies have sought to isolate MSCs from noninvasive sources. The objective of this study was to evaluate how MSCs isolated from the dental pulp of human exfoliated deciduous teeth (SHED) and fragments of the orbicularis oris muscle (OOMDSCs) behave when treated with an inflammatory IFN-γ stimulus, specifically regarding their proliferative, osteogenic, and immunomodulatory potentials. The results demonstrated that the proliferation of SHED and OOMDSCs was inhibited by the addition of IFN-γ to their culture medium and that treatment with IFN-γ at higher concentrations resulted in a greater inhibition of the proliferation of these cells than treatment with IFN-γ at lower concentrations. SHED and OOMDSCs maintained their osteogenic differentiation potential after stimulation with IFN-γ. Additionally, SHED and OOMDSCs have been shown to have low immunogenicity because they lack expression of HLA-DR and costimulatory molecules such as CD40, CD80, and CD86 before and after IFN-γ treatment. Last, SHED and OOMDSCs expressed the immunoregulatory molecule HLA-G, and the expression of this antigen increased after IFN-γ treatment. In particular, an increase in intracellular HLA-G expression was observed. The results obtained suggest that SHED and OOMDSCs lack immunogenicity and have immunomodulatory properties that are enhanced when they undergo inflammatory stimulation with IFN-γ, which opens new perspectives for the therapeutic use of these cells.
Collapse
|
|
8
|
Pooria A, Pourya A, Gheini A. Animal- and human-based evidence for the protective effects of stem cell therapy against cardiovascular disorders. J Cell Physiol 2019; 234:14927-14940. [PMID: 30811030 DOI: 10.1002/jcp.28330] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 12/06/2018] [Accepted: 01/22/2019] [Indexed: 01/24/2023]
Abstract
The increasing rate of mortality and morbidity because of cardiac diseases has called for efficient therapeutic needs. With the advancement in cell-based therapies, stem cells are abundantly studied in this area. Nearly, all sources of stem cells are experimented to treat cardiac injuries. Tissue engineering has also backed this technique by providing an advantageous platform to improve stem cell therapy. After in vitro studies, primary treatment-based research studies comprise small and large animal studies. Furthermore, these studies are implemented in human models in the form of clinical trials. Purpose of this review is to highlight the animal- and human-based studies, exploiting various stem cell sources, to treat cardiovascular disorders.
Collapse
Affiliation(s)
- Ali Pooria
- Department of Cardiology, Lorestan University of Medical Sciences, Khoramabad, Iran
| | - Afsoun Pourya
- Student of Research committee, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Gheini
- Department of Cardiology, Lorestan University of Medical Sciences, Khoramabad, Iran
| |
Collapse
|
|
9
|
Liu Y, Niu R, Li W, Lin J, Stamm C, Steinhoff G, Ma N. Therapeutic potential of menstrual blood-derived endometrial stem cells in cardiac diseases. Cell Mol Life Sci 2019; 76:1681-1695. [PMID: 30721319 PMCID: PMC11105669 DOI: 10.1007/s00018-019-03019-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 12/13/2018] [Accepted: 01/15/2019] [Indexed: 12/21/2022]
Abstract
Despite significant developments in medical and surgical strategies, cardiac diseases remain the leading causes of morbidity and mortality worldwide. Numerous studies involving preclinical and clinical trials have confirmed that stem cell transplantation can help improve cardiac function and regenerate damaged cardiac tissue, and stem cells isolated from bone marrow, heart tissue, adipose tissue and umbilical cord are the primary candidates for transplantation. During the past decade, menstrual blood-derived endometrial stem cells (MenSCs) have gradually become a promising alternative for stem cell-based therapy due to their comprehensive advantages, which include their ability to be periodically and non-invasively collected, their abundant source material, their ability to be regularly donated, their superior proliferative capacity and their ability to be used for autologous transplantation. MenSCs have shown positive therapeutic potential for the treatment of various diseases. Therefore, aside from a brief introduction of the biological characteristics of MenSCs, this review focuses on the progress being made in evaluating the functional improvement of damaged cardiac tissue after MenSC transplantation through preclinical and clinical studies. Based on published reports, we conclude that the paracrine effect, transdifferentiation and immunomodulation by MenSC promote both regeneration of damaged myocardium and improvement of cardiac function.
Collapse
Affiliation(s)
- Yanli Liu
- Stem Cell and Biotherapy Technology Research Center, College of Life Science and Technology, Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, 453003, People's Republic of China
- Institute of Chemistry and Biochemistry, Free University Berlin, 14195, Berlin, Germany
| | - Rongcheng Niu
- Stem Cell and Biotherapy Technology Research Center, College of Life Science and Technology, Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, 453003, People's Republic of China
| | - Wenzhong Li
- Institute of Chemistry and Biochemistry, Free University Berlin, 14195, Berlin, Germany.
| | - Juntang Lin
- Stem Cell and Biotherapy Technology Research Center, College of Life Science and Technology, Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, 453003, People's Republic of China.
| | - Christof Stamm
- Deutsches Herzzentrum Berlin (DHZB), Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health, Berlin, Germany
| | - Gustav Steinhoff
- Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Rostock, 18055, Rostock, Germany
| | - Nan Ma
- Institute of Chemistry and Biochemistry, Free University Berlin, 14195, Berlin, Germany
- Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy, University Rostock, 18055, Rostock, Germany
- Institute of Biomaterial Science and Berlin-Brandenburg Center for Regenerative Therapies, Helmholtz-Zentrum Geesthacht, 14513, Teltow, Germany
| |
Collapse
|
|
10
|
Oliveira ALDA, Scheffer JP, Markoski M, Koche A, Balbinot A, Antunes F, Kalil R. Vascular endothelial growth factor association with angiopoietin 1 promotes improvement in ventricular function after ischemic cardiomyopathy induced in mini pigs. Acta Cir Bras 2018; 33:386-395. [PMID: 29768541 DOI: 10.1590/s0102-865020180040000010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Accepted: 03/23/2018] [Indexed: 01/14/2023] Open
Abstract
PURPOSE To investigate the safety and clinical, hemodynamic and tissue improvement ability in mini pigs undergoing cell and gene therapy for the treatment of acute myocardial infarction. METHODS Thirty-two mini pigs Br1 lineage, 12 months old, undergoing induction of acute myocardial infarction by occlusion of the diagonal branch of the paraconal coronary. They were divided into 4 groups: one control group and 3 treatment groups (cell therapy and gene cell therapy). Echocardiography reviews were performed on three occasions and histopathological analysis was performed after 4 weeks. Analysis of variance (ANOVA), Tukey and Wilcoxon tests, were performed. RESULTS Association of vascular endothelial growth factor (VEGF) with angiopoietin1 (Ang1) presented satisfactory results in the improvement of ventricular function following ischemic cardiomyopathy in mini pigs when compared to the results of the other treated groups. CONCLUSION The therapy with VEGF and the combination of VEGF with Ang1, promoted recovered function of the myocardium, characterized by reduced akinetic area and induction of neovascularization.
Collapse
Affiliation(s)
- André Lacerda de Abreu Oliveira
- PhD, Associate Professor, Laboratory of Animal Health, Center for Agricultural Sciences and Technologies, Animal Experimentation Unit, Universidade Estadual do Norte Fluminense Darcy Ribeiro (UENF), Campos dos Goytacazes-RJ, Brazil. Technical procedures, critical revision, final approval the manuscript
| | - Jussara Peters Scheffer
- Fellow PhD degree, Laboratory of Animal Health, Center for Agricultural Sciences and Technologies, Animal Experimentation Unit, UENF Darcy Ribeiro, Campos dos Goytacazes-RJ, Brazil. Conception and design of the study, technical procedures, acquisition and analysis of data, manuscript preparation
| | - Melissa Markoski
- PhD, Associate Professor, Institute of Cardiology of Rio Grande do Sul, University Foundation of Cardiology, Porto Alegre-RS, Brazil. Critical revision, final approval the manuscript
| | - Andreia Koche
- PhD, Associate Professor, Institute of Cardiology of Rio Grande do Sul, University Foundation of Cardiology, Porto Alegre-RS, Brazil. Technical procedures
| | - Alexsandra Balbinot
- PhD, Associate Professor, Institute of Cardiology of Rio Grande do Sul, University Foundation of Cardiology, Porto Alegre-RS, Brazil. Technical procedures
| | - Fernanda Antunes
- PhD, Associate Professor, Laboratory of Animal Health, Center for Agricultural Sciences and Technologies, Animal Experimentation Unit, UENF Darcy Ribeiro, Campos dos Goytacazes-RJ, Brazil. Technical procedures
| | - Renato Kalil
- PhD, Associate Professor, Institute of Cardiology of Rio Grande do Sul, University Foundation of Cardiology, Porto Alegre-RS, Brazil. Critical revision, final approval the manuscript
| |
Collapse
|
|
11
|
Huang R, Lv H, Yao K, Ge L, Ye Z, Ding H, Zhang Y, Lu H, Huang Z, Zhang S, Zou Y, Ge J. Effects of different doses of granulocyte colony-stimulating factor mobilization therapy on ischemic cardiomyopathy. Sci Rep 2018; 8:5922. [PMID: 29651017 PMCID: PMC5897440 DOI: 10.1038/s41598-018-24020-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Accepted: 03/21/2018] [Indexed: 01/14/2023] Open
Abstract
G-CSF mobilization might be beneficial to ICM, but the relationship between effect/safety and the dosage of G-CSF remains unclear. In this study, 24 pigs were used to build ICM models and were randomized into four groups. Four weeks later, different dosages of G-CSF were given daily by subcutaneous injection for 5 days. Another 4 weeks later, all the animals were sacrificed. Electrocardiography, coronary arteriography, left ventriculography, transthoracic echocardiography, cardiac MRI, and SPECT, histopathologic analysis, and immunohistochemistry techniques were used to evaluate left ventricular function and myocardial infarct size. Four weeks after G-CSF treatment, pigs in middle-dose G-CSF group exhibited obvious improvements of left ventricular remodeling and function. Moderate G-CSF mobilization ameliorated the regional contractility of ICM, preserved myocardial viability, and reduced myocardial infarct size. More neovascularization and fewer apoptotic myocardial cells were observed in the ischemic region of the heart in middle-dose group. Expression of vWF, VEGF and MCP-1 were up-regulated, and Akt1 was activated in high- and middle-dose groups. Moreover, CRP, TNF-α and S-100 were elevated after high-dose G-CSF mobilization. Middle-dose G-CSF mobilization therapy is an effective and safe treatment for ICM, and probably acts via a mechanism involving promoting neovascularization, inhibiting cardiac fibrosis and anti-apoptosis.
Collapse
Affiliation(s)
- Rongchong Huang
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, 222 Zhongshan Road, Dalian, 116011, China
| | - Haichen Lv
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, 222 Zhongshan Road, Dalian, 116011, China
| | - Kang Yao
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Lei Ge
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Zhishuai Ye
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, 222 Zhongshan Road, Dalian, 116011, China
| | - Huaiyu Ding
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, 222 Zhongshan Road, Dalian, 116011, China
| | - Yiqi Zhang
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Hao Lu
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Zheyong Huang
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Shuning Zhang
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China
| | - Yunzeng Zou
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China.,Institutes of Biomedical Science, Fudan University, 138 Dong'an Road, Shanghai, 200032, China
| | - Junbo Ge
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China. .,Institutes of Biomedical Science, Fudan University, 138 Dong'an Road, Shanghai, 200032, China.
| |
Collapse
|
|
12
|
Dorobantu M, Popa-Fotea NM, Popa M, Rusu I, Micheu MM. Pursuing meaningful end-points for stem cell therapy assessment in ischemic cardiac disease. World J Stem Cells 2017; 9:203-218. [PMID: 29321822 PMCID: PMC5746641 DOI: 10.4252/wjsc.v9.i12.203] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 11/08/2017] [Accepted: 11/27/2017] [Indexed: 02/06/2023] Open
Abstract
Despite optimal interventional and medical therapy, ischemic heart disease is still an important cause of morbidity and mortality worldwide. Although not included in standard of care rehabilitation, stem cell therapy (SCT) could be a solution for prompting cardiac regeneration. Multiple studies have been published from the beginning of SCT until now, but overall no unanimous conclusion could be drawn in part due to the lack of appropriate end-points. In order to appreciate the impact of SCT, multiple markers from different categories should be considered: Structural, biological, functional, physiological, but also major adverse cardiac events or quality of life. Imaging end-points are among the most used - especially left ventricle ejection fraction (LVEF) measured through different methods. Other imaging parameters are infarct size, myocardial viability and perfusion. The impact of SCT on all of the aforementioned end-points is controversial and debatable. 2D-echocardiography is widely exploited, but new approaches such as tissue Doppler, strain/strain rate or 3D-echocardiography are more accurate, especially since the latter one is comparable with the MRI gold standard estimation of LVEF. Apart from the objective parameters, there are also patient-centered evaluations to reveal the benefits of SCT, such as quality of life and performance status, the most valuable from the patient point of view. Emerging parameters investigating molecular pathways such as non-coding RNAs or inflammation cytokines have a high potential as prognostic factors. Due to the disadvantages of current techniques, new imaging methods with labelled cells tracked along their lifetime seem promising, but until now only pre-clinical trials have been conducted in humans. Overall, SCT is characterized by high heterogeneity not only in preparation, administration and type of cells, but also in quantification of therapy effects.
Collapse
Affiliation(s)
- Maria Dorobantu
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Bucharest 014461, Romania
| | | | - Mihaela Popa
- Carol Davila, University of Medicine, "Carol Davila" University of Medicine and Pharmacy Bucharest, Bucharest 020022, Romania
| | - Iulia Rusu
- Carol Davila, University of Medicine, "Carol Davila" University of Medicine and Pharmacy Bucharest, Bucharest 020022, Romania
| | - Miruna Mihaela Micheu
- Department of Cardiology, Clinical Emergency Hospital of Bucharest, Bucharest 014461, Romania.
| |
Collapse
|
|
13
|
Chaudhuri R, Ramachandran M, Moharil P, Harumalani M, Jaiswal AK. Biomaterials and cells for cardiac tissue engineering: Current choices. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2017. [DOI: 10.1016/j.msec.2017.05.121] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
|
|
14
|
Qureshi MY, Cabalka AK, Khan SP, Hagler DJ, Haile DT, Cannon BC, Olson TM, Cantero-Peral S, Dietz AB, Radel DJ, Taggart NW, Kelle AM, Rodriguez V, Dearani JA, O'Leary PW. Cell-Based Therapy for Myocardial Dysfunction After Fontan Operation in Hypoplastic Left Heart Syndrome. Mayo Clin Proc Innov Qual Outcomes 2017; 1:185-191. [PMID: 30225415 PMCID: PMC6134900 DOI: 10.1016/j.mayocpiqo.2017.07.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Myocardial dysfunction after Fontan palliation for univentricular congenital heart disease is a challenging clinical problem. The medical treatment has a limited impact, with cardiac transplant being the ultimate management step. Cell-based therapies are evolving as a new treatment for heart failure. Phase 1 clinical trials using regenerative therapeutic strategies in congenital heart disease are ongoing. We report the first case of autologous bone marrow-derived mononuclear cell administration for ventricular dysfunction, 23 years after Fontan operation in a patient with hypoplastic left heart syndrome. The cells were delivered into the coronary circulation by cardiac catheterization. Ventricular size decreased and several parameters reflecting ventricular function improved, with maximum change noted 3 months after cell delivery. Such regenerative therapeutic options may help in delaying and preventing cardiac transplant.
Collapse
Affiliation(s)
| | | | - Shakila P Khan
- Division of Pediatric Hematology and Oncology, Mayo Clinic, Rochester, MN
| | - Donald J Hagler
- Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN
| | - Dawit T Haile
- Division of Pediatric Anesthesia, Mayo Clinic, Rochester, MN
| | - Bryan C Cannon
- Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN
| | - Timothy M Olson
- Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN
| | | | - Allan B Dietz
- Division of Transfusion Medicine, Mayo Clinic, Rochester, MN
| | - Darcie J Radel
- Division of Transfusion Medicine, Mayo Clinic, Rochester, MN
| | | | - Angela M Kelle
- Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN
| | - Vilmarie Rodriguez
- Division of Pediatric Hematology and Oncology, Mayo Clinic, Rochester, MN
| | | | | | | |
Collapse
|
|
15
|
Ramos GA, Hare JM. Cardiac Cell-Based Therapy: Cell Types and Mechanisms of Actions. Cell Transplant 2017; 16:951-61. [DOI: 10.3727/096368907783338208] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Over the past decade, the concept that the heart could undergo cardiac regeneration has rapidly evolved. Studies have indicated that numerous sites in the body harbor stem or progenitor cells, prompting clinical trials of these potential therapeutic cell-based approaches. Most notable are the series of trials utilizing either skeletal myoblasts or autologous whole bone marrow. More recently the quest has focused on specific bone marrow constituents, most notably the mesenchymal stem cell, which has several unique advantages including immunoprivilege, immunosuppression, and the ability to home to areas of tissue injury. Most recently, cells have been identified within the heart itself that are capable of self-replication and differentiation. The discovery of cardiac stem cells offers not only a potential therapeutic approach but also provides a plausible target for endogenous activation as a therapeutic strategy. Together the new insights obtained from studies of cell-based cardiac therapy have ushered in new biological paradigms and enormous potential for novel therapeutic strategies for cardiac disease.
Collapse
Affiliation(s)
- Geraldo A. Ramos
- The Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Joshua M. Hare
- The Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, USA
| |
Collapse
|
|
16
|
DaCosta JC, Portuguez MW, Marinowic DR, Schilling LP, Torres CM, DaCosta DI, Carrion MJM, Raupp EF, Machado DC, Soder RB, Lardi SL, Garicochea B. Safety and seizure control in patients with mesial temporal lobe epilepsy treated with regional superselective intra‐arterial injection of autologous bone marrow mononuclear cells. J Tissue Eng Regen Med 2017; 12:e648-e656. [DOI: 10.1002/term.2334] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2015] [Revised: 07/29/2016] [Accepted: 09/26/2016] [Indexed: 01/13/2023]
Affiliation(s)
- Jaderson C. DaCosta
- Brain Institute of Rio Grande do Sul (BraIns)Pontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
- Biomedical Research InstitutePontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
- Postgraduate Program in Medicine and Health SciencesPontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
- School of MedicinePontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
- São Lucas HospitalPontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
| | - Mirna W. Portuguez
- Brain Institute of Rio Grande do Sul (BraIns)Pontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
- Biomedical Research InstitutePontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
- Postgraduate Program in Medicine and Health SciencesPontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
- School of MedicinePontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
- São Lucas HospitalPontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
| | - Daniel R. Marinowic
- Brain Institute of Rio Grande do Sul (BraIns)Pontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
- Biomedical Research InstitutePontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
| | - Lucas P. Schilling
- Brain Institute of Rio Grande do Sul (BraIns)Pontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
- Postgraduate Program in Medicine and Health SciencesPontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
- São Lucas HospitalPontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
| | - Carolina M. Torres
- São Lucas HospitalPontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
| | - Danielle I. DaCosta
- Brain Institute of Rio Grande do Sul (BraIns)Pontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
- Postgraduate Program in Medicine and Health SciencesPontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
- São Lucas HospitalPontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
| | - Maria Júlia M. Carrion
- Postgraduate Program in Medicine and Health SciencesPontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
| | | | - Denise C. Machado
- Biomedical Research InstitutePontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
- Postgraduate Program in Medicine and Health SciencesPontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
- School of MedicinePontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
| | - Ricardo B. Soder
- Brain Institute of Rio Grande do Sul (BraIns)Pontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
- School of MedicinePontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
| | - Silvia L. Lardi
- School of MedicinePontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
| | - Bernardo Garicochea
- Postgraduate Program in Medicine and Health SciencesPontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
- School of MedicinePontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
- São Lucas HospitalPontifical Catholic University of Rio Grande do Sul Porto Alegre RS Brazil
- Teaching and Research Oncology CenterHospital Sírio Libanes São Paulo SP Brazil
| |
Collapse
|
|
17
|
Bejar MT, Hernández-Vera R, Vilahur G, Badimon L. Bone Marrow Cell Transplant From Donors With Cardiovascular Risk Factors Increases the Pro-atherosclerotic Phenotype in the Recipients. Am J Transplant 2016; 16:3392-3403. [PMID: 27421708 DOI: 10.1111/ajt.13962] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Revised: 06/17/2016] [Accepted: 07/10/2016] [Indexed: 01/25/2023]
Abstract
Improvement of long-term survival after hematopoietic stem cell transplantation has revealed that these patients have an increased appearance of de novo cardiovascular risk factors. Even though in these clinical studies no relation to transplant-related factors has been found, no attention has been paid to the influence of cardiovascular risk factors affecting the bone marrow donors on the cardiovascular risk of the recipients. Thus, the aim of this study was to analyze, using an animal model, whether transplantation of bone marrow from donors with cardiovascular risk factors increases cardiovascular risk in healthy recipients. Results from transplantation experiments have shown that bone marrow from donors with cardiovascular risk factors induced pro-atherogenic modifications in the cholesterol profile of healthy recipients, increasing the low-density lipoprotein cholesterol fraction in comparison to those transplanted with control bone marrow. Moreover, bone marrow from donors with cardiovascular risk factors induced significant alterations in liver pro-inflammatory state and lipid metabolism-related gene expression that could contribute to alter cholesterol homeostasis. Altogether, these results suggest that cardiovascular risk factors in the donor confer a cardiometabolic alteration to their bone marrow cells that is transferred to noncardiovascular disease transplant recipients, affecting their liver function and increasing their cardiovascular risk.
Collapse
Affiliation(s)
- M T Bejar
- Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau (UAB) and IIB-Santpau, Barcelona, Spain
| | - R Hernández-Vera
- Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau (UAB) and IIB-Santpau, Barcelona, Spain
| | - G Vilahur
- Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau (UAB) and IIB-Santpau, Barcelona, Spain
| | - L Badimon
- Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau (UAB) and IIB-Santpau, Barcelona, Spain.,Cardiovascular Research Chair, UAB, Barcelona, Spain
| |
Collapse
|
|
18
|
Choudhury T, Mozid A, Hamshere S, Yeo C, Pellaton C, Arnous S, Saunders N, Brookman P, Jain A, Locca D, Archbold A, Knight C, Wragg A, Davies C, Mills P, Parmar M, Rothman M, Choudry F, Jones DA, Agrawal S, Martin J, Mathur A. An exploratory randomized control study of combination cytokine and adult autologous bone marrow progenitor cell administration in patients with ischaemic cardiomyopathy: the REGENERATE-IHD clinical trial. Eur J Heart Fail 2016; 19:138-147. [PMID: 27790824 PMCID: PMC5248636 DOI: 10.1002/ejhf.676] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Revised: 07/21/2016] [Accepted: 07/22/2016] [Indexed: 12/28/2022] Open
Abstract
Aims The effect of combined cytokine and cell therapy in ischaemic cardiomyopathy is unknown. Meta‐analyses suggest improved cardiac function with cell therapy. The optimal cell delivery route remains unclear. We investigated whether granulocyte colony‐stimulating factor (G‐CSF) alone or in combination with intracoronary (i.c.) or intramyocardial (i.m.) injection of autologous bone marrow‐derived cells (BMCs) improves cardiac function. Methods and results Ninety patients with symptomatic ischaemic cardiomyopathy and no further treatment options were enrolled in the randomized, placebo‐controlled, single‐centre REGENERATE‐IHD study. Randomization was to one of three arms: peripheral, i.c., or i.m. In each arm, patients were randomized to active treatment or placebo. All patients, apart from the peripheral placebo group (saline only) received G‐CSF for 5 days. The i.c. and i.m. arms received either BMCs or serum (placebo). The primary endpoint was change in LVEF at 1 year assessed by cardiac magnetic resonance imaging/computed tomography. The i.m. BMC group showed a significant improvement in LVEF of 4.99% (95% confidence interval 0.33–9.6%; P = 0.038) at 1 year. This group also showed a reduction in NYHA class at 1 year and NT‐proBNP at 6 months. No other group showed a significant change in LVEF. This finding is supported by post‐hoc between‐group comparisons. Conclusion We have shown that G‐CSF combined with autologous i.m. BMCs has a beneficial effect on cardiac function and symptoms. However, this result should be considered preliminary in support of a clinical benefit of i.m. stem cell infusion in ‘no option’ patients and needs further exploration in a larger study.
Collapse
Affiliation(s)
- Tawfiq Choudhury
- Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK
| | - Abdul Mozid
- Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK
| | - Steve Hamshere
- Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK
| | - Chia Yeo
- Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK
| | - Cyril Pellaton
- Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK
| | - Samer Arnous
- Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK
| | - Natalie Saunders
- Stem Cell Laboratory, Barts Health NHS Trust and Blizard Institute, Queen Mary University of London, London, UK
| | - Pat Brookman
- Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK
| | - Ajay Jain
- Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK
| | - Didier Locca
- Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK
| | - Andrew Archbold
- Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK
| | - Charles Knight
- Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK
| | - Andrew Wragg
- Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK
| | - Ceri Davies
- Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK
| | - Peter Mills
- Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK
| | | | - Martin Rothman
- Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK
| | - Fizzah Choudry
- Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK
| | - Daniel A Jones
- Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK
| | - Samir Agrawal
- Stem Cell Laboratory, Barts Health NHS Trust and Blizard Institute, Queen Mary University of London, London, UK
| | - John Martin
- British Heart Foundation Laboratories, Department of Medicine, University College London, London, UK
| | - Anthony Mathur
- Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK
| |
Collapse
|
|
19
|
Nelson TJ, Cantero Peral S. Stem Cell Therapy and Congenital Heart Disease. J Cardiovasc Dev Dis 2016; 3:jcdd3030024. [PMID: 29367570 PMCID: PMC5715673 DOI: 10.3390/jcdd3030024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 06/07/2016] [Accepted: 06/28/2016] [Indexed: 12/18/2022] Open
Abstract
For more than a decade, stem cell therapy has been the focus of intensive efforts for the treatment of adult heart disease, and now has promise for treating the pediatric population. On the basis of encouraging results in the adult field, the application of stem cell-based strategies in children with congenital heart disease (CHD) opens a new therapy paradigm. To date, the safety and efficacy of stem cell-based products to promote cardiac repair and recovery in dilated cardiomyopathy and structural heart disease in infants have been primarily demonstrated in scattered clinical case reports, and supported by a few relevant pre-clinical models. Recently the TICAP trial has shown the safety and feasibility of intracoronary infusion of autologous cardiosphere-derived cells in children with hypoplastic left heart syndrome. A focus on preemptive cardiac regeneration in the pediatric setting may offer new insights as to the timing of surgery, location of cell-based delivery, and type of cell-based regeneration that could further inform acquired cardiac disease applications. Here, we review the current knowledge on the field of stem cell therapy and tissue engineering in children with CHD, and discuss the gaps and future perspectives on cell-based strategies to treat patients with CHD.
Collapse
Affiliation(s)
- Timothy J Nelson
- Division of General Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
- Transplant Center, Mayo Clinic, Rochester, MN 55905, USA.
- Center for Regenerative Medicine, Mayo Clinic, Rochester, MN 55905, USA.
| | - Susana Cantero Peral
- Division of General Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
- Center for Regenerative Medicine, Mayo Clinic, Rochester, MN 55905, USA.
| |
Collapse
|
|
20
|
YUAN YE, ZHANG YINGYING, ZHANG XIAOXU, YU YANAN, LI BING, WANG PENGQIAN, LI HAIXIA, ZHAO YIJUN, SHEN CHUNTI, WANG ZHONG. Deciphering the genetic and modular connections between coronary heart disease, idiopathic pulmonary arterial hypertension and pulmonary heart disease. Mol Med Rep 2016; 14:661-70. [PMID: 27221156 PMCID: PMC4918609 DOI: 10.3892/mmr.2016.5298] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Accepted: 04/26/2016] [Indexed: 01/13/2023] Open
Abstract
Coronary heart disease (CHD), idiopathic pulmonary arterial hypertension (IPAH) and pulmonary heart disease (PHD) are circulatory system diseases that may simultaneously emerge in a patient and they are often treated together in clinical practice. However, the molecular mechanisms connecting these three diseases remain unclear. In order to determine the multidimensional characteristic correlations between these three diseases based on genomic networks to aid in medical decision-making, genes from the Online Mendelian Inheritance in Man database were obtained, and applied network construction and modularized analysis were conducted. Functional enrichment analysis was conducted to explore the associations between overlapping genes, modules and pathways. A total of 29 overlapping genes and 3 common modules were identifed for the 3 diseases. Glycosphingolipid biosynthesis and the arachidonic acid metabolism are common pathways, and the biosynthetic process is suggested to be the major function involved in the three diseases. The current study reported, to the best of our knowledge for the first time, the role of glycosphingolipid biosynthesis in IPAH and PHD. The present study provided an improved understanding of the pathological mechanisms underlying CHD, IPAH and PHD. The overlapping genes, modules and pathways suggest novel areas for further research, and drug targets. The observations of the current study additionally suggest that drug indications can be broadened because of the presence of common targets.
Collapse
Affiliation(s)
- YE YUAN
- Department of Respiration, Changzhou Hospital of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Changzhou, Jiangsu 213003, P.R. China
| | - YINGYING ZHANG
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, P.R. China
| | - XIAOXU ZHANG
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, P.R. China
| | - YANAN YU
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, P.R. China
| | - BING LI
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, P.R. China
| | - PENGQIAN WANG
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, P.R. China
| | - HAIXIA LI
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, P.R. China
| | - YIJUN ZHAO
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, P.R. China
| | - CHUNTI SHEN
- Department of Respiration, Changzhou Hospital of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Changzhou, Jiangsu 213003, P.R. China
| | - ZHONG WANG
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, P.R. China
| |
Collapse
|
|
21
|
Vento A, Hämmäinen P, Pätilä T, Kankuri E, Harjula A. Somatic Stem Cell Transplantation for the Failing Heart. Scand J Surg 2016; 96:131-9. [PMID: 17679355 DOI: 10.1177/145749690709600208] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- A Vento
- Cell Therapy Research Consortium, Helsinki University Central Hospital, 3rd Department of Surgery, Meilahti Hospital, Helsinki, Finland
| | | | | | | | | |
Collapse
|
|
22
|
Cai M, Shen R, Song L, Lu M, Wang J, Zhao S, Tang Y, Meng X, Li Z, He ZX. Bone Marrow Mesenchymal Stem Cells (BM-MSCs) Improve Heart Function in Swine Myocardial Infarction Model through Paracrine Effects. Sci Rep 2016; 6:28250. [PMID: 27321050 PMCID: PMC4913323 DOI: 10.1038/srep28250] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 06/01/2016] [Indexed: 12/14/2022] Open
Abstract
Stem cells are promising for the treatment of myocardial infarction (MI) and large animal models should be used to better understand the full spectrum of stem cell actions and preclinical evidences. In this study, bone marrow mesenchymal stem cells (BM-MSCs) were transplanted into swine heart ischemia model. To detect glucose metabolism in global left ventricular myocardium and regional myocardium, combined with assessment of cardiac function, positron emission tomography-computer tomography (PET-CT) and magnetic resonance imaging (MRI) were performed. To study the changes of glucose transporters and glucose metabolism-related enzymes and the signal transduction pathway, RT-PCR, Western-blot, and immunohistochemistry were carried out. Myocardium metabolic evaluation by PET-CT showed that mean signal intensity (MSI) increased in these segments at week 4 compared with that at week 1 after BM-MSCs transplantation. Moreover, MRI demonstrated significant function enhancement in BM-MSCs group. The gene expressions of glucose transporters (GLUT1, GLUT4), glucose metabolism-related enzymes phosphofructokinase (PFK), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH)) and 70-kDa ribosomal protein S6 kinase (p70s6k) in BM-MSCs injected areas were up-regulated at week 4 after BM-MSCs transplantation and this was confirmed by Western-blot and immunohistochemistry. In conclusions, BM-MSCs transplantation could improve cardiac function in swine MI model by activation of mTOR signal transduction pathway.
Collapse
Affiliation(s)
- Min Cai
- Department of Nuclear Medicine, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center of Cardiovascular Disease, Peking Union Medical College &Chinese Academy of Medical Sciences, Beijing, China.,Department of Radiology, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center of Cardiovascular Disease, Peking Union Medical College &Chinese Academy of Medical Sciences, Beijing, China
| | - Rui Shen
- Department of Nuclear Medicine, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center of Cardiovascular Disease, Peking Union Medical College &Chinese Academy of Medical Sciences, Beijing, China
| | - Lei Song
- Department of Nuclear Medicine, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center of Cardiovascular Disease, Peking Union Medical College &Chinese Academy of Medical Sciences, Beijing, China
| | - Minjie Lu
- Department of Radiology, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center of Cardiovascular Disease, Peking Union Medical College &Chinese Academy of Medical Sciences, Beijing, China
| | - Jianguang Wang
- Department of Nuclear Medicine, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center of Cardiovascular Disease, Peking Union Medical College &Chinese Academy of Medical Sciences, Beijing, China
| | - Shihua Zhao
- Department of Nuclear Medicine, Shanxi Provincial People's Hospital, Taiyuan, China
| | - Yue Tang
- Department of Nuclear Medicine, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center of Cardiovascular Disease, Peking Union Medical College &Chinese Academy of Medical Sciences, Beijing, China
| | - Xianmin Meng
- Department of Nuclear Medicine, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center of Cardiovascular Disease, Peking Union Medical College &Chinese Academy of Medical Sciences, Beijing, China
| | - Zongjin Li
- Department of Pathophysiology, Nankai University School of Medicine, Tianjin, China
| | - Zuo-Xiang He
- Department of Nuclear Medicine, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center of Cardiovascular Disease, Peking Union Medical College &Chinese Academy of Medical Sciences, Beijing, China
| |
Collapse
|
|
23
|
Xu X, Li H. Integrated microRNA‑gene analysis of coronary artery disease based on miRNA and gene expression profiles. Mol Med Rep 2016; 13:3063-73. [PMID: 26936111 PMCID: PMC4805068 DOI: 10.3892/mmr.2016.4936] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 01/12/2016] [Indexed: 12/14/2022] Open
Abstract
The present study aimed to investigate the key genes and microRNAs (miRNA/miRs) associated with coronary artery disease (CAD) progression. The gene expression profile of GSE20680 and GSE12288, and the miRNA expression profile of GSE28858 were downloaded from the gene expression omnibus database. The differentially expressed genes (DEGs) in GSE20680 and GSE12288, and the differentially expressed miRNAs in GSE28858 were screened using the limma package in R software. Common DEGs between GSE20680 and GSE12288 were selected. Functions and pathways of DEGs and miRNAs were enriched using the DAVID tool from the GO and KEGG databases. The regulatory network of miRNA and selected CAD-associated DEGs was constructed. A total of 270 DEGs (167 upregulated and 103 downregulated) based on the GSE20680 dataset, and 2,268 DEGs (534 upregulated and 1,734 downregulated) based on the GSE12288 dataset, were screened. For the differentially expressed miRNAs, 214 were identified (102 upregulated and 112 downregulated) in CAD samples and were screened. Interferon regulatory factor 2 (IRF2) and cell death-inducing DFFA-like effector b (CIDEB), which are regulated by signal transducer and activator of transcription 3 and myc-associated factor X, were identified as common DEGs for CAD. miR-455-5p, miR-455-3p and miR-1257, which are involved in the major histocompatibility complex (MHC)protein assembly pathway and peptide antigen assembly with MHC class I protein complex pathway, may regulate various miRNAs and target genes, including pro-opiomelancortin (POMC), toll-like receptor 4 (TLR4), interleukin 10 (IL10), activating transcription factor 6 (ATF6) and calreticulin (CALR). The current study identified IRF2 and CIDEB as crucial genes, and miRNA-455-5p, miRNA-455-3p and miR-1257 along with their target genes POMC, TLR4 and CALR, as miRNAs involved in CAD progression. Thus, the present study may provide a basis for future research into the progression mechanism of CAD.
Collapse
Affiliation(s)
- Xiangdong Xu
- Vasculocardiology Department, Jiading Central Hospital, Shanghai 201800, P.R China
| | - Hongsong Li
- Vasculocardiology Department, Jiading Central Hospital, Shanghai 201800, P.R China
| |
Collapse
|
|
24
|
Affiliation(s)
| | | | - Doris A Taylor
- Department of Regenerative Medicine Research, Texas Heart Institute, Houston, TX
| | | |
Collapse
|
|
25
|
Alrefai MT, Murali D, Paul A, Ridwan KM, Connell JM, Shum-Tim D. Cardiac tissue engineering and regeneration using cell-based therapy. STEM CELLS AND CLONING-ADVANCES AND APPLICATIONS 2015; 8:81-101. [PMID: 25999743 PMCID: PMC4437607 DOI: 10.2147/sccaa.s54204] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Stem cell therapy and tissue engineering represent a forefront of current research in the treatment of heart disease. With these technologies, advancements are being made into therapies for acute ischemic myocardial injury and chronic, otherwise nonreversible, myocardial failure. The current clinical management of cardiac ischemia deals with reestablishing perfusion to the heart but not dealing with the irreversible damage caused by the occlusion or stenosis of the supplying vessels. The applications of these new technologies are not yet fully established as part of the management of cardiac diseases but will become so in the near future. The discussion presented here reviews some of the pioneering works at this new frontier. Key results of allogeneic and autologous stem cell trials are presented, including the use of embryonic, bone marrow-derived, adipose-derived, and resident cardiac stem cells.
Collapse
Affiliation(s)
- Mohammad T Alrefai
- Division of Cardiac Surgery, McGill University Health Center, Montreal, QC, Canada ; Division of Surgical Research, McGill University Health Center, Montreal, QC, Canada ; King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia
| | - Divya Murali
- Department of Chemical and Petroleum Engineering, School of Engineering, University of Kansas, Lawrence, KS, USA
| | - Arghya Paul
- Department of Chemical and Petroleum Engineering, School of Engineering, University of Kansas, Lawrence, KS, USA
| | - Khalid M Ridwan
- Division of Cardiac Surgery, McGill University Health Center, Montreal, QC, Canada ; Division of Surgical Research, McGill University Health Center, Montreal, QC, Canada
| | - John M Connell
- Division of Cardiac Surgery, McGill University Health Center, Montreal, QC, Canada ; Division of Surgical Research, McGill University Health Center, Montreal, QC, Canada
| | - Dominique Shum-Tim
- Division of Cardiac Surgery, McGill University Health Center, Montreal, QC, Canada ; Division of Surgical Research, McGill University Health Center, Montreal, QC, Canada
| |
Collapse
|
|
26
|
Liebson PR. Stem-cell angiogenesis and regeneration of the heart: review of a saga of 2 decades. Clin Cardiol 2015; 38:309-16. [PMID: 25955103 DOI: 10.1002/clc.22381] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Revised: 11/26/2014] [Accepted: 12/01/2014] [Indexed: 12/20/2022] Open
Abstract
Advances in the novel approach to control ischemic heart disease and heart failure using stem cells or progenitor cells from bone marrow, mesenchyme, or myocardial tissue itself have demonstrated efficacy for increasing left ventricular function, decreasing infarct scar tissue, improving exercise tolerance and heart failure symptoms, and, in some studies, decreasing mortality and reducing rehospitalization for intractable angina or subsequent myocardial infarction. The most common techniques utilize injections of cells into the coronary vasculature or directly into specific areas of vulnerable myocardium. Although few adverse effects have been noted in clinical trials of these procedures, further clinical trials over the next decade should provide further advances in interventional techniques, ancillary supporting technologies to enhance cell regeneration, and applications in ischemic heart disease, cardiomyopathies, and cardiac genetic disorders.
Collapse
Affiliation(s)
- Philip R Liebson
- Department of Preventive Medicine, Rush University Medical Center, Chicago, Illinois
| |
Collapse
|
|
27
|
Lerman DA, Alotti N, Ume KL, Péault B. Cardiac Repair and Regeneration: The Value of Cell Therapies. Eur Cardiol 2015; 11:43-48. [PMID: 27499812 DOI: 10.15420/ecr.2016:8:1] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Ischaemic heart disease is the predominant contributor to cardiovascular morbidity and mortality; one million myocardial Infarctions occur per year in the USA, while more than five million patients suffer from chronic heart failure. Recently, heart failure has been singled out as an epidemic and is a staggering clinical and public health problem associated with significant mortality, morbidity and healthcare expenditures, particularly among those aged ≥65 years. Death rates have improved dramatically over the last four decades, but new approaches are nevertheless urgently needed for those patients who go on to develop ventricular dysfunction and chronic heart failure. Over the past decade, stem cell transplantation has emerged as a promising therapeutic strategy for acute or chronic ischaemic cardiomyopathy. Multiple candidate cell types have been used in preclinical animal models and in humans to repair or regenerate the injured heart, either directly or indirectly (through paracrine effects), including: embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), neonatal cardiomyocytes, skeletal myoblasts (SKMs), endothelial progenitor cells, bone marrow mononuclear cells (BMMNCs), mesenchymal stem cells (MSCs) and, most recently, cardiac stem cells (CSCs). Although no consensus has emerged yet, the ideal cell type for the treatment of heart disease should: (a) improve heart function; (b) create healthy and functional cardiac muscle and vasculature, integrated into the host tissue; (c) be amenable to delivery by minimally invasive clinical methods; (d) be available 'off the shelf' as a standardised reagent; (e) be tolerated by the immune system; (f) be safe oncologically, i.e. not create tumours; and (g) circumvent societal ethical concerns. At present, it is not clear whether such a 'perfect' stem cell exists; what is apparent, however, is that some cell types are more promising than others. In this brief review, we provide ongoing data on agreement and controversy arising from clinical trials and touch upon the future directions of cell therapy for heart disease.
Collapse
Affiliation(s)
- Daniel Alejandro Lerman
- Department of Cardiothoracic Surgery, Royal Infirmary Hospital of Edinburgh (NHS Lothian), University of Edinburgh, Scotland, UK; MRC Centre for Regenerative Medicine and College of Medicine and Veterinary, University of Edinburgh, Scotland, UK
| | | | | | - Bruno Péault
- MRC Centre for Regenerative Medicine and College of Medicine and Veterinary, University of Edinburgh, Scotland, UK; David Geffen School of Medicine at UCLA, Orthopaedic Hospital Research Centre, University of California at Los Angeles, USA
| |
Collapse
|
|
28
|
Fisher SA, Doree C, Mathur A, Martin-Rendon E. Meta-Analysis of Cell Therapy Trials for Patients With Heart Failure. Circ Res 2015; 116:1361-77. [DOI: 10.1161/circresaha.116.304386] [Citation(s) in RCA: 181] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2014] [Accepted: 01/20/2015] [Indexed: 02/06/2023]
Affiliation(s)
- Sheila A Fisher
- From the Systematic Review Group, R&D Department, NHS Blood and Transplant, Oxford, UK (S.A.F., C.D.); Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, UK (S.A.F., C.D., E.M.-R.); Department of Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK (A.M.); and Stem Cell Research Laboratory, R&D Department, NHS Blood and Transplant, Oxford, UK (E.M.-R.)
| | - Carolyn Doree
- From the Systematic Review Group, R&D Department, NHS Blood and Transplant, Oxford, UK (S.A.F., C.D.); Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, UK (S.A.F., C.D., E.M.-R.); Department of Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK (A.M.); and Stem Cell Research Laboratory, R&D Department, NHS Blood and Transplant, Oxford, UK (E.M.-R.)
| | - Anthony Mathur
- From the Systematic Review Group, R&D Department, NHS Blood and Transplant, Oxford, UK (S.A.F., C.D.); Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, UK (S.A.F., C.D., E.M.-R.); Department of Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK (A.M.); and Stem Cell Research Laboratory, R&D Department, NHS Blood and Transplant, Oxford, UK (E.M.-R.)
| | - Enca Martin-Rendon
- From the Systematic Review Group, R&D Department, NHS Blood and Transplant, Oxford, UK (S.A.F., C.D.); Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, UK (S.A.F., C.D., E.M.-R.); Department of Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK (A.M.); and Stem Cell Research Laboratory, R&D Department, NHS Blood and Transplant, Oxford, UK (E.M.-R.)
| |
Collapse
|
|
29
|
Guan LX, Guan H, Li HB, Ren CA, Liu L, Chu JJ, Dai LJ. Therapeutic efficacy of umbilical cord-derived mesenchymal stem cells in patients with type 2 diabetes. Exp Ther Med 2015; 9:1623-1630. [PMID: 26136869 DOI: 10.3892/etm.2015.2339] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2014] [Accepted: 02/11/2015] [Indexed: 12/19/2022] Open
Abstract
Type 2 diabetes (T2D) is characterized by progressive and inexorable β-cell dysfunction, leading to insulin deficiency. Novel strategies to preserve the remaining β-cells and restore β-cell function for the treatment of diabetes are urgently required. Mesenchymal stem cells (MSCs) have been exploited in a variety of clinical trials aimed at reducing the burden of immune-mediated disease. The aim of the present clinical trial was to assess the safety and efficacy of umbilical cord-derived MSC (UCMSC) transplantation for patients with T2D. The safety and efficacy of UCMSC application were evaluated in six patients with T2D during a minimum of a 24-month follow-up period. Following transplantation, the levels of fasting C-peptide, the peak value and the area under the C-peptide release curve increased significantly within one month and remained high during the follow-up period (P<0.05). Three of the six patients became insulin free for varying lengths of time between 25 and 43 months, while the additional three patients continued to require insulin injections, although with a reduced insulin requirement. Fasting plasma glucose and 2-h postprandial blood glucose levels were relatively stable in all the patients following transplantation. There was no immediate or delayed toxicity associated with the cell administration within the follow-up period. Therefore, the results indicated that transplantation of allogeneic UCMSCs may be an approach to improve islet function in patients with T2D. There were no safety issues observed during infusion and the long-term monitoring period.
Collapse
Affiliation(s)
- Li-Xue Guan
- Central Laboratory, Weifang People's Hospital, Weifang Medical College, Weifang, Shandong 261042, P.R. China
| | - Hui Guan
- College of Management, Weifang Medical University, Weifang, Shandong 261053, P.R. China
| | - Hai-Bo Li
- Central Laboratory, Weifang People's Hospital, Weifang Medical College, Weifang, Shandong 261042, P.R. China
| | - Cui-Ai Ren
- Department of Hematology, Weifang People's Hospital, Weifang Medical University, Weifang, Shandong 261042, P.R. China
| | - Lin Liu
- Department of Endocrinology, Weifang People's Hospital, Weifang Medical University, Weifang, Shandong 261042, P.R. China
| | - Jin-Jin Chu
- Central Laboratory, Weifang People's Hospital, Weifang Medical College, Weifang, Shandong 261042, P.R. China
| | - Long-Jun Dai
- Central Laboratory, Weifang People's Hospital, Weifang Medical College, Weifang, Shandong 261042, P.R. China ; Department of Surgery, University of British Columbia, Vancouver, BC V5Z 1L8, Canada
| |
Collapse
|
|
30
|
Mozid A, Yeo C, Arnous S, Ako E, Saunders N, Locca D, Brookman P, Archbold RA, Rothman M, Mills P, Agrawal S, Martin J, Mathur A. Safety and feasibility of intramyocardial versus intracoronary delivery of autologous cell therapy in advanced heart failure: the REGENERATE-IHD pilot study. Regen Med 2015; 9:269-78. [PMID: 24935040 DOI: 10.2217/rme.14.3] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
AIM This study presents an interim safety and feasibility analysis of the REGENERATE-IHD randomized controlled trial, which is examining the safety and efficacy of three different delivery routes of bone marrow-derived stem cells (BMSCs) in patients with ischemic heart failure. METHODS & RESULTS The first 58 patients recruited to the REGENERATE-IHD study are included in this interim analysis (pilot). Symptomatic patients with ischemic heart failure were randomized to receive subcutaneous granulocyte colony-stimulating factor or saline injections only; or subcutaneous granulocyte colony-stimulating factor injections followed by intracoronary or intramyocardial injections of BMSCs or serum (control). No significant differences were found in terms of safety and feasibility between the different delivery routes, with no significant difference in procedural complications or major adverse cardiac events. There was a signal towards improved heart failure symptoms in the patients treated with intramyocardial injection of mobilized BMSCs. CONCLUSION Peripheral mobilization of BMSCs with or without subsequent direct myocardial delivery appears safe and feasible in patients with chronic ischemic heart failure.
Collapse
Affiliation(s)
- Abdul Mozid
- Department of Cardiology, London Chest Hospital, Barts Health Trust, London, E2 9JX, UK
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Armstrong PW, Willerson JT. Treatment of Acute ST-Elevation Myocardial Infarction. Coron Artery Dis 2015. [DOI: 10.1007/978-1-4471-2828-1_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
|
|
32
|
Kindzelski BA, Zhou Y, Horvath KA. Transmyocardial revascularization devices: technology update. MEDICAL DEVICES-EVIDENCE AND RESEARCH 2014; 8:11-9. [PMID: 25565905 PMCID: PMC4274152 DOI: 10.2147/mder.s51591] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Transmyocardial laser revascularization (TMR) emerged as treatment modality for patients with diffuse coronary artery disease not amendable to percutaneous or surgical revascularization. The procedure entails the creation of laser channels within ischemic myocardium in an effort to better perfuse these areas. Currently, two laser devices are approved by the US Food and Drug Administration for TMR – holmium:yttrium–aluminum–garnet and CO2. The two devices differ in regard to energy outputs, wavelengths, ability to synchronize with the heart cycle, and laser–tissue interactions. These differences have led to studies showing different efficacies between the two laser devices. Over 50,000 procedures have been performed worldwide using TMR. Improvements in angina stages, quality of life, and perfusion of the myocardium have been demonstrated with TMR. Although several mechanisms for these improvements have been suggested, evidence points to new blood vessel formation, or angiogenesis, within the treated myocardium, as the major contributory factor. TMR has been used as sole therapy and in combination with coronary artery bypass grafting. Clinical studies have demonstrated that TMR is both safe and effective in angina relief long term. The objective of this review is to present the two approved laser devices and evidence for the safety and efficacy of TMR, along with future directions with this technology.
Collapse
Affiliation(s)
- Bogdan A Kindzelski
- Cardiothoracic Surgery Research Program, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Yifu Zhou
- Cardiothoracic Surgery Research Program, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Keith A Horvath
- Cardiothoracic Surgery Research Program, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| |
Collapse
|
|
33
|
Zhou Y, Wang S, Yu Z, Hoyt RF, Hunt T, Kindzelski B, Shou D, Xie W, Du Y, Liu C, Horvath KA. Induced pluripotent stem cell transplantation in the treatment of porcine chronic myocardial ischemia. Ann Thorac Surg 2014; 98:2130-7. [PMID: 25443017 DOI: 10.1016/j.athoracsur.2014.07.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 06/30/2014] [Accepted: 07/01/2014] [Indexed: 01/14/2023]
Abstract
BACKGROUND This study was designed to test the effects of induced pluripotent stem cell (iPSC) in the treatment of chronic myocardial ischemia. METHODS The reprogramming of passage 3 myocardial fibroblasts was performed by using the lentiviral vector containing 4 human factors: OCT4, SOX2, KLF4, and c-MYC. The iPSC colonies at P12-17 were allogeneically transplanted into ischemic myocardium of 10 swine by direct injection. Cohorts of 2 animals were sacrificed at 2, 4, 6, 8, and 12 weeks after injection. RESULTS No signs of graft versus host disease were evident at any time points. At 2 weeks, clusters of SSEA-4-positive iPSCs were detected in the injected area. At 4 to 8 weeks, these cells started to proliferate into small spheres surrounded by thin capsules. At 12 weeks the cell clusters still existed, but decreased in size and numbers. The cells inside these masses were homogeneous with no sign of differentiation into any specific lineage. Increased smooth muscle actin or vWF positive cells were found inside and around the iPSC clusters, compared with non-injected areas. By real-time polymerase chain reaction, the levels of VEGF, basic FGF, and ANRT expression were significantly higher in the iPSC-treated myocardium compared with untreated areas. These results suggest that iPSCs contributed to angiogenesis. CONCLUSIONS Allogeneically transplanted pig iPSCs proliferated despite an ischemic environment in the first 2 months and survived for at least 3 months in immunocompetent hosts. Transplanted iPSCs were also proangiogenic and thus might have beneficial effects on the ischemic heart diseases.
Collapse
Affiliation(s)
- Yifu Zhou
- Cellular Biology Section, Cardiothoracic Surgery Research Program/National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
| | - Suna Wang
- Cellular Biology Section, Cardiothoracic Surgery Research Program/National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Zuxi Yu
- Cellular Biology Section, Cardiothoracic Surgery Research Program/National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Robert F Hoyt
- Cellular Biology Section, Cardiothoracic Surgery Research Program/National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Timothy Hunt
- Cellular Biology Section, Cardiothoracic Surgery Research Program/National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Bogdan Kindzelski
- Cellular Biology Section, Cardiothoracic Surgery Research Program/National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - David Shou
- Cellular Biology Section, Cardiothoracic Surgery Research Program/National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Wen Xie
- Cellular Biology Section, Cardiothoracic Surgery Research Program/National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Yubin Du
- Cellular Biology Section, Cardiothoracic Surgery Research Program/National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Chengyu Liu
- Cellular Biology Section, Cardiothoracic Surgery Research Program/National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Keith A Horvath
- Cellular Biology Section, Cardiothoracic Surgery Research Program/National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| |
Collapse
|
|
34
|
Abstract
PURPOSE OF REVIEW Surgical advances over the past few decades have transformed the clinical management of congenital heart disease, such as hypoplastic left heart syndrome. Congenital heart disease affects more than 1% of liveborn infants and accounts for more than 2.5 million affected children per year worldwide. The cost and availability of complex medical management for these children becomes bluntly realized when heart failure progresses and only palliative options remain. Cell-based cardiac regeneration has been the focus of intensive efforts in adult heart disease for more than a decade and now has promise for pediatrics. RECENT FINDINGS Innate cardiac regeneration in the pediatric setting is measurable and potentially modifiable in the early stages of development. Repurposing cell-based manufactured products to promote cardiac regeneration in congenital heart disease has demonstrated significant improvement in cases of dilated cardiomyopathy and structural heart disease in infants. SUMMARY A focus on preemptive cardiac regeneration in the pediatric setting may offer new insights into the timing of surgery, location of cell-based delivery, and type of cell-based regeneration that could further inform acquired cardiac disease applications. The concept of cell-based pediatric cardiac regenerative surgery could transform the management of congenital heart disease when cost-effective strategies produce a valuable adjunctive solution to improve outcomes of cardiac surgery.
Collapse
|
|
35
|
Ghodsizad A, Ruhparwar A, Bordel V, Mirsaidighazi E, Klein HM, Koerner MM, Karck M, El-Banayosy A. Clinical application of adult stem cells for therapy for cardiac disease. Cardiovasc Ther 2014; 31:323-34. [PMID: 23773460 DOI: 10.1111/1755-5922.12032] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
INTRODUCTION Cardiovascular disease is a major cause of death worldwide. Different medical and surgical therapeutic options are well established, but a significant number of patients are not amenable to standard therapeutic options. Cell-based therapies after clinical application have shown different results in recent years. Here, we are giving a comprehensive overview on major available clinical data regarding cell therapy. BACKGROUND Cell-based therapies and tissue engineering provide new promising platforms to develop upcoming therapeutic options. Initial clinical trials were able to generate promising results. A variety of different stem cell types have been used for the clinical application. Different adult cardiac stem cells and progenitor cells, including mesenchymal, CD34(+) and CD133(+) autologous human bone marrow-derived stem cells (BMCs), human myoblasts, and peripheral blood-derived stem and progenitor cells (PBSCs) have been used for the therapy for end-stage heart failure. Future experiments will show the importance of novel cell populations and clarify the mechanism causing cell therapy-mediated observed effects. CONCLUSION Several clinical trials have reported on sole therapy, as well as combined application of autologous adult stem cells with conventional revascularization. The reported promising findings encourage further research in the field of the translational research.
Collapse
Affiliation(s)
- Ali Ghodsizad
- Heart and Vascular Institute, Milton S. Hershey Medical Center, College of Medicine, The Pennsylvania State University, Hershey, PA, USA; Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
| | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Hansen M, Nyby S, Eifer Møller J, Videbæk L, Kassem M, Barington T, Thayssen P, Diederichsen ACP. Intracoronary injection of CD34-cells in chronic ischemic heart failure: 7 years follow-up of the DanCell study. Cardiology 2014; 129:69-74. [PMID: 25116577 DOI: 10.1159/000363133] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Accepted: 04/24/2014] [Indexed: 11/19/2022]
Abstract
OBJECTIVES Seven years ago, the DanCell study was carried out to test the hypothesis of improvement in left ventricular ejection fraction (LVEF) following repeated intracoronary injections of autologous bone marrow-derived stem cells (BMSCs) in patients suffering from chronic ischemic heart failure. In this post hoc analysis, the long-term effect of therapy is assessed. METHODS 32 patients [mean age 61 (SD ± 9), 81% males] with systolic dysfunction (LVEF 33 ± 9%) received two repeated intracoronary infusions (4 months apart) of autologous BMSCs (1,533 ± 765 × 10(6) BMSCs including 23 ± 11 × 10(6) CD34(+) cells and 14 ± 7 × 10(6) CD133(+) cells). Patients were followed for 7 years and deaths were recorded. RESULTS During follow-up, 10 patients died (31%). In univariate regression analysis, the total number of BMSCs, CD34(+) cell count and CD133(+) cell count did not significantly correlate with survival (hazard ratio: 0.999, 95% CI: 0.998-1.000, p = 0.24; hazard ratio: 0.94, 95% CI: 0.88-1.01, p = 0.10, and hazard ratio: 0.96, 95% CI: 0.87-1.07, p = 0.47, respectively). After adjustment for baseline variables in multivariate regression analysis, the CD34(+) cell count was significantly associated with survival (hazard ratio: 0.90, 95% CI: 0.82-1.00, p = 0.04). CONCLUSIONS Intracoronary injections of a high number of CD34(+) cells may have a beneficial effect on chronic ischemic heart failure in terms of long-term survival.
Collapse
Affiliation(s)
- Morten Hansen
- Department of Cardiology, Odense University Hospital, Odense, Denmark
| | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Affiliation(s)
- E E van der Wall
- Interuniversity Cardiology Institute of the Netherlands (ICIN), Netherlands Heart Institute, Catherijnesingel 52, P.O. Box 19258, 3501 DG, Utrecht, the Netherlands,
| |
Collapse
|
|
38
|
Pavo N, Charwat S, Nyolczas N, Jakab A, Murlasits Z, Bergler-Klein J, Nikfardjam M, Benedek I, Benedek T, Pavo IJ, Gersh BJ, Huber K, Maurer G, Gyöngyösi M. Cell therapy for human ischemic heart diseases: critical review and summary of the clinical experiences. J Mol Cell Cardiol 2014; 75:12-24. [PMID: 24998410 DOI: 10.1016/j.yjmcc.2014.06.016] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Revised: 05/23/2014] [Accepted: 06/26/2014] [Indexed: 12/24/2022]
Abstract
A decade ago, stem or progenitor cells held the promise of tissue regeneration in human myocardium, with the expectation that these therapies could rescue ischemic myocyte damage, enhance vascular density and rebuild injured myocardium. The accumulated evidence in 2014 indicates, however, that the therapeutic success of these cells is modest and the tissue regeneration involves much more complex processes than cell-related biologics. As the quest for the ideal cell or combination of cells continues, alternative cell types, such as resident cardiac cells, adipose-derived or phenotypic modified stem or progenitor cells have also been applied, with the objective of increasing both the number and the retention of the reparative cells in the myocardium. Two main delivery routes (intracoronary and percutaneous intramyocardial) of stem cells are currently used preferably for patients with recent acute myocardial infarction or ischemic cardiomyopathy. Other delivery modes, such as surgical or intravenous via peripheral veins or coronary sinus have also been utilized with less success. Due to the difficult recruitment of patients within conceivable timeframe into cardiac regenerative trials, meta-analyses of human cardiac cell-based studies have tried to gather sufficient number of subjects to present a statistical compelling statement, reporting modest success with a mean increase of 0.9-6.1% in left ventricular global ejection fraction. Additionally, nearly half of the long-term studies reported the disappearance of the initial benefit of this treatment. Beside further extensive efforts to increase the efficacy of currently available methods, pre-clinical experiments using new techniques such as tissue engineering or exploiting paracrine effect hold promise to regenerate injured human cardiac tissue.
Collapse
Affiliation(s)
- Noemi Pavo
- Department of Cardiology, Medical University of Vienna, Austria
| | - Silvia Charwat
- Department of Cardiology, Medical University of Vienna, Austria
| | - Noemi Nyolczas
- Department of Cardiology, Medical University of Vienna, Austria
| | - András Jakab
- Department of Biomedical Laboratory and Imaging Science, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zsolt Murlasits
- Exercise Biochemistry Laboratory, The University of Memphis, Department of Health and Sport Sciences, Memphis, TN, USA
| | | | | | - Imre Benedek
- Department of Cardiology, University of Medicine and Pharmacy Tirgu Mures, Romania
| | - Teodora Benedek
- Department of Cardiology, University of Medicine and Pharmacy Tirgu Mures, Romania
| | - Imre J Pavo
- Department of Cardiology, Medical University of Vienna, Austria
| | - Bernard J Gersh
- Internal Medicine, Mayo Graduate School of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Kurt Huber
- 3(rd) Dept. Cardiology and Emergency Medicine, Wilhelminen hospital, Vienna, Austria
| | - Gerald Maurer
- Department of Cardiology, Medical University of Vienna, Austria
| | | |
Collapse
|
|
39
|
Zhou Y, Singh AK, Hoyt RF, Wang S, Yu Z, Hunt T, Kindzelski B, Corcoran PC, Mohiuddin MM, Horvath KA. Regulatory T cells enhance mesenchymal stem cell survival and proliferation following autologous cotransplantation in ischemic myocardium. J Thorac Cardiovasc Surg 2014; 148:1131-7; discussiom 1117. [PMID: 25052825 DOI: 10.1016/j.jtcvs.2014.06.029] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Revised: 06/06/2014] [Accepted: 06/13/2014] [Indexed: 12/29/2022]
Abstract
OBJECTIVES We sought to investigate if autologous freshly isolated regulatory T cells (Tregs) provide a protective and supportive role when cotransplanted with mesenchymal stem cells (MSCs). METHODS In a porcine model of chronic ischemia, autologous MSCs were isolated and expanded ex vivo for 4 weeks. Autologous Treg cells were freshly isolated from 100 mL peripheral blood and purified by fluorescence-activated cell sorting. MSCs and Treg cells were then cotransplanted into the chronic ischemic myocardium of Yorkshire pigs by direct intramyocardial injection (1.2 × 10(8) MSCs plus an average of 1.5 million Treg cells in 25 injection sites). Animals were killed 6 weeks postinjection to study the fate of the cells and compare the effect of combined MSCs + Treg cells transplantation versus MSCs alone. RESULTS The coinjection of MSCs along with Tregs was safe and no deleterious side effects were observed. Six weeks after injection of the cell combination, spherical MSCs clusters with thin layer capsules were found in the injected areas. In animals treated with MSCs only, the MSC clusters were less organized and not encapsulated. Immunofluorescent staining showed CD25+ cells among the CD90+ (MSC marker) cells, suggesting that the injected Treg cells remained present locally, and survived. Factor VIII+ cells were also prevalent suggesting new angiogenesis. We found no evidence that coinjections were associated with the generation of cardiac myocytes. CONCLUSIONS The cotransplantation of Treg cells with MSCs dramatically increased the MSC survival rate, proliferation, and augmented their role in angiogenesis, which suggests a new way for future clinical application of cell-based therapy.
Collapse
Affiliation(s)
- Yifu Zhou
- Cardiothoracic Surgery Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
| | - Avneesh K Singh
- Cardiothoracic Surgery Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md
| | - Robert F Hoyt
- Cardiothoracic Surgery Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md
| | - Suna Wang
- Cardiothoracic Surgery Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md
| | - Zuxi Yu
- Cardiothoracic Surgery Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md
| | - Timothy Hunt
- Cardiothoracic Surgery Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md
| | - Bogdan Kindzelski
- Cardiothoracic Surgery Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md
| | - Philip C Corcoran
- Cardiothoracic Surgery Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md
| | - Muhammad M Mohiuddin
- Cardiothoracic Surgery Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md
| | - Keith A Horvath
- Cardiothoracic Surgery Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md
| |
Collapse
|
|
40
|
Wang X, Zachman AL, Haglund NA, Maltais S, Sung HJ. Combined Usage of Stem Cells in End-Stage Heart Failure Therapies. J Cell Biochem 2014; 115:1217-24. [DOI: 10.1002/jcb.24782] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Accepted: 02/03/2014] [Indexed: 01/14/2023]
Affiliation(s)
- Xintong Wang
- Department of Biomedical Engineering; Vanderbilt University; Nashville Tennessee
| | - Angela L. Zachman
- Department of Biomedical Engineering; Vanderbilt University; Nashville Tennessee
| | | | - Simon Maltais
- Division of Cardiovascular Surgery; Vanderbilt University; Nashville Tennessee
| | - Hak-Joon Sung
- Department of Biomedical Engineering; Vanderbilt University; Nashville Tennessee
| |
Collapse
|
|
41
|
Lux CA, Mark P, Klopsch C, Laupheimer M, Tu-Rapp H, Li W, Ma N, Steinhoff G, David R. Impact of short-term liquid storage on human CD133(+) stem cells. Cell Transplant 2014; 24:2409-22. [PMID: 24800805 DOI: 10.3727/096368914x681577] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Stem cell transplantation is a viable strategy for regenerative medicine. However, it is inevitable to have cells undergo storage for several hours or days due to processing and transportation. Therefore, it is crucial to have rigidly controlled conditions ensuring the therapeutic benefit of isolated stem cells. In the present study, we investigated the impact of short-term storage on human CD133(+) cells. CD133(+) cells were isolated from human bone marrow and kept at standardized nonfreezing storage conditions for up to 72 h. Cell viability (apoptosis/necrosis) and expression of CD133 and CXCR4 were analyzed by flow cytometry. Metabolic activity was determined using an MTT assay; colony-forming ability, as well as endothelial-like differentiation, was further evaluated. A qRT-PCR array was employed to investigate the expression of stemness genes. CD133 and CXCR4 expressions were preserved at all time points. After 30 h, cell number and metabolic activity decreased, although no significant changes were detected in cell viability and proliferation as well as endothelial-like differentiation. Cell viability and proliferation decreased significantly only after 72 h of storage. Our results indicate that storage of isolated human CD133(+) bone marrow stem cells in liquid allows for high viability and functionality. However, storage time should be limited in order to avoid cell loss.
Collapse
Affiliation(s)
- Cornelia A Lux
- Reference and Translation Center for Cardiac Stem Cell Therapy, University of Rostock, Rostock, Germany
| | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Katsikis A, Koutelou M. Cardiac Stem Cell Imaging by SPECT and PET. CURRENT CARDIOVASCULAR IMAGING REPORTS 2014. [DOI: 10.1007/s12410-014-9265-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
|
|
43
|
Functional improvement in patients with dilated cardiomyopathy after the intracoronary infusion of autologous bone marrow mononuclear cells. ACTA ACUST UNITED AC 2014; 66:450-7. [PMID: 24776047 DOI: 10.1016/j.rec.2012.11.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Accepted: 11/10/2012] [Indexed: 01/14/2023]
Abstract
INTRODUCTION AND OBJECTIVES Different studies have shown improvement in patients with idiopathic nonischemic dilated cardiomyopathy treated with cell-therapy. However, factors influencing responsiveness are not well known. This trial investigates functional changes and factors influencing the 6-month gain in ejection fraction in 27 patients with dilated cardiomiopathy treated with intracoronary cell-therapy. METHODS Patients received intracoronary infusion of autologous bone-marrow mononuclear cells (mean infused, 10.2 [2.9]×10(8)). Flow cytometry and functional analyses of the cells were also performed. RESULTS The 6-month angiographic gain in ejection fraction ranged from -9% to 34% (mean, 9%). These changes were distinguished into 2 groups: 21 patients (78%) with a significant improvement at the 6-month evaluation (mean gain, 14 [7]%), and 6 patients who had no response (mean gain, -5 [3]%). The responders were younger as compared to the nonresponders (50 [12] years vs 62 [9] years; P<.04). There was an inverse correlation (r=-0.41; P<.003) between the gain in ejection fraction and the high density lipoprotein level, suggesting higher functional gain with low high density lipoprotein levels. The 24 h migratory capability of the infused cells was significantly reduced in the responders' group (5.4 [1.7]×10(8) vs 8.1 [2.3]×10(8); P<.009 for vascular endothelial growth factor and 5.8 [1.7]×10(8) vs 8.4 [2.9]×10(8); P<.002 for stromal cell-derived factor-1). CONCLUSIONS Younger patients with dilated cardiomiopathy and lower plasma high density lipoprotein levels gain greater benefit from intracoronary cell-therapy. Functional improvement also seems to be enhanced by a lower migratory capacity of the infused cells.
Collapse
|
|
44
|
Kanno Y, Mitsui T, Sano H, Kitta T, Moriya K, Nonomura K. Contribution of bone marrow-derived mesenchymal stem cells to the morphological changes in the bladder after partial outlet obstruction: A preliminary study. Int J Urol 2014; 21:714-8. [DOI: 10.1111/iju.12406] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Accepted: 01/07/2014] [Indexed: 01/14/2023]
Affiliation(s)
- Yukiko Kanno
- Department of Urology; Hokkaido University Graduate School of Medicine; Sapporo Japan
| | - Takahiko Mitsui
- Department of Urology; Hokkaido University Graduate School of Medicine; Sapporo Japan
| | - Hiroshi Sano
- Department of Urology; Hokkaido University Graduate School of Medicine; Sapporo Japan
| | - Takeya Kitta
- Department of Urology; Hokkaido University Graduate School of Medicine; Sapporo Japan
| | - Kimihiko Moriya
- Department of Urology; Hokkaido University Graduate School of Medicine; Sapporo Japan
| | - Katsuya Nonomura
- Department of Urology; Hokkaido University Graduate School of Medicine; Sapporo Japan
| |
Collapse
|
|
45
|
Nasseri BA, Ebell W, Dandel M, Kukucka M, Gebker R, Doltra A, Knosalla C, Choi YH, Hetzer R, Stamm C. Autologous CD133+ bone marrow cells and bypass grafting for regeneration of ischaemic myocardium: the Cardio133 trial. Eur Heart J 2014; 35:1263-74. [PMID: 24497345 DOI: 10.1093/eurheartj/ehu007] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
AIMS Intra-myocardial transplantation of CD133(+) bone marrow stem cells (BMC) yielded promising results in clinical pilot trials. We now performed the double-blinded, randomized, placebo-controlled CARDIO133 trial to determine its impact on left ventricular (LV) function and clinical symptoms. METHODS AND RESULTS Sixty patients with chronic ischaemic heart disease and impaired LV function (left ventricular ejection fraction, LVEF <35%) were randomized to undergo either coronary artery bypass grafting (CABG) and injection of CD133(+) BMC in the non-transmural, hypokinetic infarct border zone (CD133), or CABG and placebo injection (placebo). Pre-operative LVEF was 27 ± 6% in CD133 patients and 26 ± 6% in placebo patients. Outcome was assessed after 6 months, and the primary endpoint was LVEF measured by cardiac magnetic resonance imaging (MRI) at rest. The incidence of adverse events was similar in both groups. There was no difference in 6-min walking distance, Minnesota Living with Heart Failure score, or Canadian Cardiovascular Society (CCS) class between groups at follow-up, and New York Heart Association class improved more in the placebo group (P = 0.004). By cardiac MRI, LVEF at 6 months was 33 ± 8% in the placebo group and 31 ± 7% in verum patients (P = 0.3), with an average inter-group difference of -2.1% (95% CI -6.3 to 2.1). Systolic or diastolic LV dimensions at 6 months were not different, either. In the CD133 group, myocardial perfusion at rest recovered in more LV segments than in the placebo group (9 vs. 2%, P < 0.001). Scar mass decreased by 2.2 ± 5 g in CD133(+) patients (P = 0.05), but was unchanged in the placebo group (0.3 ± 4 g, P = 0.7; inter-group difference in change = 2 g (95% CI -1.1 to 5)). By speckle-tracking echocardiography, cell-treated patients showed a better recovery of regional wall motion when the target area was posterior. CONCLUSION Although there may be some improvements in scar size and regional perfusion, intra-myocardial injection of CD133(+) BMC has no effect on global LV function and clinical symptoms. Improvements in regional myocardial function are only detectable in patients with posterior infarction, probably because the interventricular septum after anterior infarction is not accessible by trans-epicardial injection. CLINICAL TRIAL REGISTRATION This trial was registered at http://www.clinicaltrials.gov under NCT00462774.
Collapse
Affiliation(s)
- Boris A Nasseri
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, Berlin 13353, Germany
| | - Wolfram Ebell
- Pediatric Bone Marrow Transplant Program, Charité, Universitätsmedizin Berlin, Berlin 10117, Germany
| | - Michael Dandel
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, Berlin 13353, Germany
| | - Marian Kukucka
- Department of Anesthesiology, Deutsches Herzzentrum Berlin, Berlin 13353, Germany
| | - Rolf Gebker
- Department of Internal Medicine/Cardiology, Deutsches Herzzentrum Berlin, Berlin 13353, Germany
| | - Adelina Doltra
- Department of Internal Medicine/Cardiology, Deutsches Herzzentrum Berlin, Berlin 13353, Germany
| | - Christoph Knosalla
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, Berlin 13353, Germany
| | - Yeong-Hoon Choi
- Berlin-Brandenburg Center for Regenerative Therapies, Berlin 13353, Germany
| | - Roland Hetzer
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, Berlin 13353, Germany
| | - Christof Stamm
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, Berlin 13353, Germany Berlin-Brandenburg Center for Regenerative Therapies, Berlin 13353, Germany
| |
Collapse
|
|
46
|
Diederichsen AC, Møller JE, Thayssen P, Junker AB, Videbaek L, Saekmose SG, Barington T, Kristiansen M, Kassem M. Effect of repeated intracoronary injection of bone marrow cells in patients with ischaemic heart failure☆ The Danish Stem Cell study-Congestive Heart Failure trial (DanCell-CHF). Eur J Heart Fail 2014; 10:661-7. [DOI: 10.1016/j.ejheart.2008.05.010] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2008] [Revised: 04/07/2008] [Accepted: 05/15/2008] [Indexed: 01/14/2023] Open
Affiliation(s)
| | - Jacob E. Møller
- Department of Cardiology; Odense University Hospital; Denmark
| | - Per Thayssen
- Department of Cardiology; Odense University Hospital; Denmark
| | | | - Lars Videbaek
- Department of Cardiology; Odense University Hospital; Denmark
| | | | - Torben Barington
- Department of Clinical Immunology; Odense University Hospital; Denmark
| | - Malthe Kristiansen
- Department of Endocrinology and Metabolism; Odense University Hospital; Denmark
| | - Moustapha Kassem
- Department of Endocrinology and Metabolism; Odense University Hospital; Denmark
| |
Collapse
|
|
47
|
Azene N, Fu Y, Maurer J, Kraitchman DL. Tracking of stem cells in vivo for cardiovascular applications. J Cardiovasc Magn Reson 2014; 16:7. [PMID: 24406054 PMCID: PMC3925252 DOI: 10.1186/1532-429x-16-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2012] [Accepted: 12/11/2013] [Indexed: 01/14/2023] Open
Abstract
In the past ten years, the concept of injecting stem and progenitor cells to assist with rebuilding damaged blood vessels and myocardial tissue after injury in the heart and peripheral vasculature has moved from bench to bedside. Non-invasive imaging can not only provide a means to assess cardiac repair and, thereby, cellular therapy efficacy but also a means to confirm cell delivery and engraftment after administration. In this first of a two-part review, we will review the different types of cellular labeling techniques and the application of these techniques in cardiovascular magnetic resonance and ultrasound. In addition, we provide a synopsis of the cardiac cellular clinical trials that have been performed to-date.
Collapse
Affiliation(s)
- Nicole Azene
- Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University, Baltimore, MD, USA
- Department of Molecular and Comparative Pathobiology, The Johns Hopkins University, Baltimore, MD, USA
| | - Yingli Fu
- Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University, Baltimore, MD, USA
| | - Jeremy Maurer
- Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University, Baltimore, MD, USA
| | - Dara L Kraitchman
- Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University, Baltimore, MD, USA
- Department of Molecular and Comparative Pathobiology, The Johns Hopkins University, Baltimore, MD, USA
- Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, 314 Park Building, Baltimore, MD 21287, USA
| |
Collapse
|
|
48
|
Lancaster JJ, Juneman E, Arnce SA, Johnson NM, Qin Y, Witte R, Thai H, Kellar RS, Ek Vitorin J, Burt J, Gaballa MA, Bahl JJ, Goldman S. An electrically coupled tissue-engineered cardiomyocyte scaffold improves cardiac function in rats with chronic heart failure. J Heart Lung Transplant 2013; 33:438-45. [PMID: 24560982 DOI: 10.1016/j.healun.2013.12.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2013] [Revised: 10/01/2013] [Accepted: 12/11/2013] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Varying strategies are currently being evaluated to develop tissue-engineered constructs for the treatment of ischemic heart disease. This study examines an angiogenic and biodegradable cardiac construct seeded with neonatal cardiomyocytes for the treatment of chronic heart failure (CHF). METHODS We evaluated a neonatal cardiomyocyte (NCM)-seeded 3-dimensional fibroblast construct (3DFC) in vitro for the presence of functional gap junctions and the potential of the NCM-3DFC to restore left ventricular (LV) function in an in vivo rat model of CHF at 3 weeks after permanent left coronary artery ligation. RESULTS The NCM-3DFC demonstrated extensive cell-to-cell connectivity after dye injection. At 5 days in culture, the patch contracted spontaneously in a rhythmic and directional fashion at 43 ± 3 beats/min, with a mean displacement of 1.3 ± 0.3 mm and contraction velocity of 0.8 ± 0.2 mm/sec. The seeded patch could be electrically paced at nearly physiologic rates (270 ± 30 beats/min) while maintaining coordinated, directional contractions. Three weeks after implantation, the NCM-3DFC improved LV function by increasing (p < 0.05) ejection fraction 26%, cardiac index 33%, dP/dt(+) 25%, dP/dt(-) 23%, and peak developed pressure 30%, while decreasing (p < 0.05) LV end diastolic pressure 38% and the time constant of relaxation (Tau) 16%. At 18 weeks after implantation, the NCM-3DFC improved LV function by increasing (p < 0.05) ejection fraction 54%, mean arterial pressure 20%, dP/dt(+) 16%, dP/dt(-) 34%, and peak developed pressure 39%. CONCLUSIONS This study demonstrates that a multicellular, electromechanically organized cardiomyocyte scaffold, constructed in vitro by seeding NCM onto 3DFC, can improve LV function long-term when implanted in rats with CHF.
Collapse
Affiliation(s)
- Jordan J Lancaster
- Cardiology and Medicine, Southern Arizona VA Health Care System; Sarver Heart Center; Department of Physiology.
| | - Elizabeth Juneman
- Cardiology and Medicine, Southern Arizona VA Health Care System; Sarver Heart Center
| | - Sarah A Arnce
- Cardiology and Medicine, Southern Arizona VA Health Care System; Sarver Heart Center
| | - Nicholle M Johnson
- Cardiology and Medicine, Southern Arizona VA Health Care System; Sarver Heart Center
| | - Yexian Qin
- Medical Imaging, University of Arizona, Tucson
| | | | - Hoang Thai
- Cardiology and Medicine, Southern Arizona VA Health Care System; Sarver Heart Center
| | | | | | | | | | - Joseph J Bahl
- Cardiology and Medicine, Southern Arizona VA Health Care System; Sarver Heart Center
| | - Steven Goldman
- Cardiology and Medicine, Southern Arizona VA Health Care System; Sarver Heart Center
| |
Collapse
|
|
49
|
Silvestre JS, Smadja DM, Lévy BI. Postischemic revascularization: from cellular and molecular mechanisms to clinical applications. Physiol Rev 2013; 93:1743-802. [PMID: 24137021 DOI: 10.1152/physrev.00006.2013] [Citation(s) in RCA: 171] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
After the onset of ischemia, cardiac or skeletal muscle undergoes a continuum of molecular, cellular, and extracellular responses that determine the function and the remodeling of the ischemic tissue. Hypoxia-related pathways, immunoinflammatory balance, circulating or local vascular progenitor cells, as well as changes in hemodynamical forces within vascular wall trigger all the processes regulating vascular homeostasis, including vasculogenesis, angiogenesis, arteriogenesis, and collateral growth, which act in concert to establish a functional vascular network in ischemic zones. In patients with ischemic diseases, most of the cellular (mainly those involving bone marrow-derived cells and local stem/progenitor cells) and molecular mechanisms involved in the activation of vessel growth and vascular remodeling are markedly impaired by the deleterious microenvironment characterized by fibrosis, inflammation, hypoperfusion, and inhibition of endogenous angiogenic and regenerative programs. Furthermore, cardiovascular risk factors, including diabetes, hypercholesterolemia, hypertension, diabetes, and aging, constitute a deleterious macroenvironment that participates to the abrogation of postischemic revascularization and tissue regeneration observed in these patient populations. Thus stimulation of vessel growth and/or remodeling has emerged as a new therapeutic option in patients with ischemic diseases. Many strategies of therapeutic revascularization, based on the administration of growth factors or stem/progenitor cells from diverse sources, have been proposed and are currently tested in patients with peripheral arterial disease or cardiac diseases. This review provides an overview from our current knowledge regarding molecular and cellular mechanisms involved in postischemic revascularization, as well as advances in the clinical application of such strategies of therapeutic revascularization.
Collapse
|
|
50
|
Francis DP, Mielewczik M, Zargaran D, Cole GD. Autologous bone marrow-derived stem cell therapy in heart disease: discrepancies and contradictions. Int J Cardiol 2013; 168:3381-403. [PMID: 23830344 DOI: 10.1016/j.ijcard.2013.04.152] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Revised: 04/11/2013] [Accepted: 04/12/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND Autologous bone marrow stem cell therapy is the greatest advance in the treatment of heart disease for a generation according to pioneering reports. In response to an unanswered letter regarding one of the largest and most promising trials, we attempted to summarise the findings from the most innovative and prolific laboratory. METHOD AND RESULTS Amongst 48 reports from the group, there appeared to be 5 actual clinical studies ("families" of reports). Duplicate or overlapping reports were common, with contradictory experimental design, recruitment and results. Readers cannot always tell whether a study is randomised versus not, open-controlled or blinded placebo-controlled, or lacking a control group. There were conflicts in recruitment dates, criteria, sample sizes, million-fold differences in cell counts, sex reclassification, fractional numbers of patients and conflation of competitors' studies with authors' own. Contradictory results were also common. These included arithmetical miscalculations, statistical errors, suppression of significant changes, exaggerated description of own findings, possible silent patient deletions, fractional numbers of coronary arteries, identical results with contradictory sample sizes, contradictory results with identical sample sizes, misrepresented survival graphs and a patient with a negative NYHA class. We tabulate over 200 discrepancies amongst the reports. The 5 family-flagship papers (Strauer 2002, STAR, IACT, ABCD, BALANCE) have had 2665 citations. Of these, 291 citations were to the pivotal STAR or IACT-JACC papers, but 97% of their eligible citing papers did not mention any discrepancies. Five meta-analyses or systematic reviews covered these studies, but none described any discrepancies and all resolved uncertainties by undisclosed methods, in mutually contradictory ways. Meta-analysts disagreed whether some studies were randomised or "accepter-versus-rejecter". Our experience of presenting the discrepancies to journals is that readers may remain unaware of such problems. CONCLUSIONS Modern reporting of clinical research can still be imperfect. The scientific literature absorbs such reports largely uncritically. Even meta-analyses seem to resolve contradictions haphazardly. Discrepancies communicated to journals are not guaranteed to reach the scientific community. Journals could consider prioritising systematic reporting of queries even if seemingly minor, and establishing a policy of "habeas data".
Collapse
|