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Lafci Büyükkahraman M, Chen H, Chen-Charpentier BM, Liao J, Kojouharov HV. A Mathematical Exploration of the Effects of Ischemia-Reperfusion Injury After a Myocardial Infarction. Bioengineering (Basel) 2025; 12:177. [PMID: 40001696 PMCID: PMC11851514 DOI: 10.3390/bioengineering12020177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 01/20/2025] [Accepted: 01/27/2025] [Indexed: 02/27/2025] Open
Abstract
INTRODUCTION After myocardial infarction (MI), the heart undergoes necrosis, inflammation, scar formation, and remodeling. While restoring blood flow is crucial, it can cause ischemia-reperfusion (IR) injury, driven by reactive oxygen species (ROSs), which exacerbate cell death and tissue damage. This study introduces a mathematical model capturing key post-MI dynamics, including inflammatory responses, IR injury, cardiac remodeling, and stem cell therapy. The model uses nonlinear ordinary differential equations to simulate these processes under varying conditions, offering a predictive tool to understand MI pathophysiology better and optimize treatments. METHODS After myocardial infarction (MI), left ventricular remodeling progresses through three distinct yet interconnected phases. The first phase captures the immediate dynamics following MI, prior to any medical intervention. This stage is mathematically modeled using the system of ordinary differential equations: The second and third stages of the remodeling process account for the system dynamics of medical treatments, including oxygen restoration and subsequent stem cell injection at the injury site. RESULTS We simulate heart tissue and immune cell dynamics over 30 days for mild and severe MI using the novel mathematical model under medical treatment. The treatment involves no intervention until 2 h post-MI, followed by oxygen restoration and stem cell injection at day 7, which is shown experimentallyand numerically to be optimal. The simulation incorporates a baseline ROS threshold (Rc) where subcritical ROS levels do not cause cell damage. CONCLUSION This study presents a novel mathematical model that extends a previously published framework by incorporating three clinically relevant parameters: oxygen restoration rate (ω), patient risk factors (γ), and neutrophil recruitment profile (δ). The model accounts for post-MI inflammatory dynamics, ROS-mediated ischemia-reperfusion (IR) injury, cardiac remodeling, and stem cell therapy. The model's sensitivity highlights critical clinical insights: while oxygen restoration is vital, excessive rates may exacerbate ROS-driven IR injury. Additionally, heightened patient risk factors (e.g., smoking, obesity) and immunodeficiency significantly impact tissue damage and recovery. This predictive tool offers valuable insights into MI pathology and aids in optimizing treatment strategies to mitigate IR injury and improve post-MI outcomes.
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Affiliation(s)
| | - Houjia Chen
- Department of Bioengineering, The University of Texas at Arlington, Arlington, TX 76010-0138, USA; (H.C.); (J.L.)
| | - Benito M. Chen-Charpentier
- Department of Mathematics, The University of Texas at Arlington, Arlington, TX 76019-0408, USA; (B.M.C.-C.); (H.V.K.)
| | - Jun Liao
- Department of Bioengineering, The University of Texas at Arlington, Arlington, TX 76010-0138, USA; (H.C.); (J.L.)
| | - Hristo V. Kojouharov
- Department of Mathematics, The University of Texas at Arlington, Arlington, TX 76019-0408, USA; (B.M.C.-C.); (H.V.K.)
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Matta A, Ohlmann P, Nader V, Moussallem N, Carrié D, Roncalli J. A review of therapeutic approaches for post-infarction left ventricular remodeling. Curr Probl Cardiol 2024; 49:102562. [PMID: 38599556 DOI: 10.1016/j.cpcardiol.2024.102562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Accepted: 04/07/2024] [Indexed: 04/12/2024]
Abstract
Left ventricular remodeling is an adaptive process initially developed in response to acute myocardial infarction (AMI), but it ends up with negative adverse outcomes such as infarcted wall thinning, ventricular dilation, and cardiac dysfunction. A prolonged excessive inflammatory reaction to cardiomyocytes death and necrosis plays the crucial role in the pathophysiological mechanisms. The pharmacological treatment includes nitroglycerine, β-blockers, ACEi/ARBs, SGLT2i, mineralocorticoid receptor antagonists, and some miscellaneous aspects. Stem cells therapy, CD34+ cells transplantation and gene therapy constitute the promissing therapeutic approaches for post AMI cardiac remodeling, thereby enhancing angiogenesis, cardiomyocytes differenciation and left ventricular function on top of inhibiting apoptosis, inflammation, and collagen deposition. All these lead to reduce infarct size, scar formation and myocardial fibrosis.
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Affiliation(s)
- Anthony Matta
- Department of Cardiology, Civilian Hospitals of Colmar, Colmar, France; School of Medicine and Medical Sciences, Holy Spirit University of Kaslik, P.O.Box 446, Jounieh, Lebanon.
| | - Patrick Ohlmann
- Department of Cardiology, Strasbourg University Hospital, Strasbourg, France
| | - Vanessa Nader
- Department of Cardiology, Civilian Hospitals of Colmar, Colmar, France
| | - Nicolas Moussallem
- School of Medicine and Medical Sciences, Holy Spirit University of Kaslik, P.O.Box 446, Jounieh, Lebanon
| | - Didier Carrié
- Department of Cardiology, Toulouse University Hospital, Toulouse, France
| | - Jerome Roncalli
- Department of Cardiology, Toulouse University Hospital, Toulouse, France
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Differentiation of embryonic stem cells into a putative hair cell-progenitor cells via co-culture with HEI-OC1 cells. Sci Rep 2021; 11:13893. [PMID: 34230535 PMCID: PMC8260610 DOI: 10.1038/s41598-021-93049-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 06/17/2021] [Indexed: 12/14/2022] Open
Abstract
Several studies have shown how different cell lines can influence the differentiation of stem cells through co-culture systems. The House Ear Institute-Organ of Corti 1 (HEI-OC1) is considered an important cell line for in vitro auditory research. However, it is unknown if HEI-OC1 cells can promote the differentiation of embryonic stem cells (ESCs). In this study, we investigated whether co-culture of ESCs with HEI-OC1 cells promotes differentiation. To this end, we developed a co-culture system of mouse ESCs with HEI-OC1 cells. Dissociated or embryonic bodies (EBs) of ESCs were introduced to a conditioned and inactivated confluent layer of HEI-OC1 cells for 14 days. The dissociated ESCs coalesced into an EB-like form that was smaller than the co-cultured EBs. Contact co-culture generated cells expressing several otic progenitor markers as well as hair cell specific markers. ESCs and EBs were also cultured in non-contact setup but using conditioned medium from HEI-OC1 cells, indicating that soluble factors alone could have a similar effect. The ESCs did not form into aggregates but were still Myo7a-positive, while the EBs degenerated. However, in the fully differentiated EBs, evidence to prove mature differentiation of inner ear hair cell was still rudimentary. Nevertheless, these results suggest that cellular interactions between ESCs and HEI-OC1 cells may both stimulate ESC differentiation.
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Razeghian-Jahromi I, Matta AG, Canitrot R, Zibaeenezhad MJ, Razmkhah M, Safari A, Nader V, Roncalli J. Surfing the clinical trials of mesenchymal stem cell therapy in ischemic cardiomyopathy. Stem Cell Res Ther 2021; 12:361. [PMID: 34162424 PMCID: PMC8220796 DOI: 10.1186/s13287-021-02443-1] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 06/09/2021] [Indexed: 12/15/2022] Open
Abstract
While existing remedies failed to fully address the consequences of heart failure, stem cell therapy has been introduced as a promising approach. The present review is a comprehensive appraisal of the impacts of using mesenchymal stem cells (MSCs) in clinical trials mainly conducted on ischemic cardiomyopathy. The benefits of MSC therapy for dysfunctional myocardium are likely attributed to numerous secreted paracrine factors and immunomodulatory effects. The positive outcomes associated with MSC therapy are scar size reduction, reverse remodeling, and angiogenesis. Also, a decreasing in the level of chronic inflammatory markers of heart failure progression like TNF-α is observed. The intense inflammatory reaction in the injured myocardial micro-environment predicts a poor response of scar tissue to MSC therapy. Subsequently, the interval delay between myocardial injury and MSC therapy is not yet determined. The optimal requested dose of cells ranges between 100 to 150 million cells. Allogenic MSCs have different advantages compared to autogenic cells and intra-myocardial injection is the preferred delivery route. The safety and efficacy of MSCs-based therapy have been confirmed in numerous studies, however several undefined parameters like route of administration, optimal timing, source of stem cells, and necessary dose are limiting the routine use of MSCs therapeutic approach in clinical practice. Lastly, pre-conditioning of MSCs and using of exosomes mediated MSCs or genetically modified MSCs may improve the overall therapeutic effect. Future prospective studies establishing a constant procedure for MSCs transplantation are required in order to apply MSC therapy in our daily clinical practice and subsequently improving the overall prognosis of ischemic heart failure patients.
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Affiliation(s)
| | - Anthony G Matta
- Department of Cardiology, Institute CARDIOMET, University Hospital of Toulouse, Toulouse, France.,Faculty of medicine, Holy Spirit University of Kaslik, Kaslik, Lebanon
| | - Ronan Canitrot
- Department of Cardiology, Institute CARDIOMET, University Hospital of Toulouse, Toulouse, France
| | | | - Mahboobeh Razmkhah
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Anahid Safari
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Vanessa Nader
- Department of Cardiology, Institute CARDIOMET, University Hospital of Toulouse, Toulouse, France.,Faculty of Pharmacy, Lebanese University, Beirut, Lebanon
| | - Jerome Roncalli
- Department of Cardiology, Institute CARDIOMET, University Hospital of Toulouse, Toulouse, France. .,Service de Cardiologie A, CHU de Toulouse, Hôpital de Rangueil, 1 avenue Jean Poulhès, TSA 50032, 31059, Toulouse Cedex 9, France.
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Chrostek MR, Fellows EG, Crane AT, Grande AW, Low WC. Efficacy of stem cell-based therapies for stroke. Brain Res 2019; 1722:146362. [PMID: 31381876 PMCID: PMC6815222 DOI: 10.1016/j.brainres.2019.146362] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 07/30/2019] [Accepted: 07/31/2019] [Indexed: 02/08/2023]
Abstract
Stroke remains a prevalent disease with limited treatment options. Available treatments offer little in the way of enhancing neurogenesis and recovery. Because of the limitations of available treatments, new therapies for stroke are needed. Stem cell-based therapies for stroke offer promise because of their potential to provide neurorestorative benefits. Stem cell-based therapies aim to promote neurogenesis and replacement of lost neurons or protect surviving neurons in order to improve neurological recovery. The mechanism through which stem cell treatments mediate their therapeutic effect is largely dependent on the type of stem cell and route of administration. Neural stem cells have been shown in pre-clinical and clinical trials to promote functional recovery when used in intracerebral transplantations. The therapeutic effects of neural stem cells have been attributed to their formation of new neurons and promotion of neuroregeneration. Bone marrow stem cells (BMSC) and mesenchymal stem cells (MSC) have been shown to enhance neurogenesis in pre-clinical models in intracerebral transplantations, but lack clinical evidence to support this therapeutic approach in patients and appear to be less effective than neural stem cells. Intravenous and intra-arterial administration of BMSC and MSC have shown more promise, where their effects are largely mediated through neuroprotective mechanisms. The immune system has been implicated in exacerbating initial damage caused by stroke, and BMSC and MSC have demonstrated immunomodulatory properties capable of dampening post-stroke inflammation and potentially improving recovery. While still in development, stem cell therapies may yield new treatments for stroke which can improve neurological recovery.
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Affiliation(s)
- Matthew R Chrostek
- Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Emily G Fellows
- Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Andrew T Crane
- Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Andrew W Grande
- Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Stem Cell Institute, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Walter C Low
- Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Stem Cell Institute, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
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Retention and Functional Effect of Adipose-Derived Stromal Cells Administered in Alginate Hydrogel in a Rat Model of Acute Myocardial Infarction. Stem Cells Int 2018; 2018:7821461. [PMID: 29765421 PMCID: PMC5892231 DOI: 10.1155/2018/7821461] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 01/05/2018] [Accepted: 01/18/2018] [Indexed: 01/12/2023] Open
Abstract
Background Cell therapy for heart disease has been proven safe and efficacious, despite poor cell retention in the injected area. Improving cell retention is hypothesized to increase the treatment effect. In the present study, human adipose-derived stromal cells (ASCs) were delivered in an in situ forming alginate hydrogel following acute myocardial infarction (AMI) in rats. Methods ASCs were transduced with luciferase and tested for ASC phenotype. AMI was inducted in nude rats, with subsequent injection of saline (controls), 1 × 106 ASCs in saline or 1 × 106 ASCs in 1% (w/v) alginate hydrogel. ASCs were tracked by bioluminescence and functional measurements were assessed by magnetic resonance imaging (MRI) and 82rubidium positron emission tomography (PET). Results ASCs in both saline and alginate hydrogel significantly increased the ejection fraction (7.2% and 7.8% at 14 days and 7.2% and 8.0% at 28 days, resp.). After 28 days, there was a tendency for decreased infarct area and increased perfusion, compared to controls. No significant differences were observed between ASCs in saline or alginate hydrogel, in terms of retention and functional salvage. Conclusion ASCs improved the myocardial function after AMI, but administration in the alginate hydrogel did not further improve retention of the cells or myocardial function.
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Petrov VN, Agaeva EV, Popovkina OE, Konoplyannikov AG, Kaplan MA, Lepekhina LA, Sayapina EV, Semenkova IV. Modifying Effect of Autotransfusion of Mesenchymal Stromal Cells on the Production of Reactive Oxygen Species and Cytokines by Mononuclear Cells in Patients with Chronic Heart Failure. Bull Exp Biol Med 2017; 164:233-240. [PMID: 29181671 DOI: 10.1007/s10517-017-3965-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Indexed: 12/29/2022]
Abstract
We studied in vivo modifying effect of autotransfusion of human bone marrow mesenchymal stromal cells on ROS generation and production of cytokines (TNFα,TNFβ, IL-1α, IL-10, IFNγ, and GM-CSF) and PGE2 by mononuclear cells of patients (N=21) with chronic heart failure. These parameters were evaluated prior to (control) and after (immediately and on day 14) intravenous administration of stromal cells in doses of 100-200×106. Immediately after autotransfusion, significant increase of in vitro zymosan-induced chemiluminescence of blood mononuclear cells from 10 patients was observed. At later terms after autotransfusion (day 14), inhibition of chemiluminescent activity of blood mononuclear cells was revealed in 50% patients. We discuss possible mechanisms of involvement of transplanted autologous bone marrow mesenchymal stromal cells in reprogramming of blood mononuclear phagocytes from the pro- to anti-inflammatory phenotype under conditions of their in vivo interaction manifesting in transition from activation to inhibition of ROS-producing activity of macrophages and significant suppression of in vitro LPS-induced production of TNFα and GM-CSF by blood mononuclears against the background of significantly elevated TNFβ, IL-10, and IL-1α concentrations.
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Affiliation(s)
- V N Petrov
- A. F. Tsyb Medical Radiological Research Center, Affiliated Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Obninsk, Russia
| | - E V Agaeva
- A. F. Tsyb Medical Radiological Research Center, Affiliated Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Obninsk, Russia.
| | - O E Popovkina
- A. F. Tsyb Medical Radiological Research Center, Affiliated Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Obninsk, Russia
| | - A G Konoplyannikov
- A. F. Tsyb Medical Radiological Research Center, Affiliated Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Obninsk, Russia
| | - M A Kaplan
- A. F. Tsyb Medical Radiological Research Center, Affiliated Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Obninsk, Russia
| | - L A Lepekhina
- A. F. Tsyb Medical Radiological Research Center, Affiliated Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Obninsk, Russia
| | - E V Sayapina
- A. F. Tsyb Medical Radiological Research Center, Affiliated Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Obninsk, Russia
| | - I V Semenkova
- A. F. Tsyb Medical Radiological Research Center, Affiliated Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Obninsk, Russia
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Liu X, Cai J, Jiao X, Yu X, Ding X. Therapeutic potential of mesenchymal stem cells in acute kidney injury is affected by administration timing. Acta Biochim Biophys Sin (Shanghai) 2017; 49:338-348. [PMID: 28338909 DOI: 10.1093/abbs/gmx016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Indexed: 12/22/2022] Open
Abstract
Mesenchymal stem cell (MSC) transplantation is a promising therapy for acute kidney injury; however, the efficacy is limited due to poor survival after transplantation. In this study, we investigated how MSC transplantation timing affected the survival and therapeutic potential of MSCs in the kidney ischemia-reperfusion (I/R) injury model. After kidney I/R injury, the inflammatory process and tissue damage were characterized over 1 week post-I/R, we found that inflammation peaked at 12-24 h post-I/R (h.p.i.), and urine neutrophil gelatinase-associated lipocalin (NGAL) measurements correlated highly with measures of inflammation. We cultured MSCs with supernatants from I/R injured kidney tissue homogenates collected at different time points and found that kidney homogenates from 12 and 24 h.p.i. were most toxic to MSCs, whereas homogenates from 1 h.p.i. were not as cytotoxic as those from 12 and 24 h.p.i. Compared with MSCs administered at 12, or 24 h.p.i., cells administered immediately after ischemia or 1 h.p.i. yielded the highest renoprotective and anti-inflammatory effects. Our findings indicate that MSC treatment for acute kidney injury is most effective when applied prior to the development of a potent inflammatory microenvironment, and urine NGAL may be helpful for detecting inflammation and selecting MSC transplantation timing in I/R kidney injury.
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Affiliation(s)
- Xiaoyan Liu
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Department of nephrology, The Second Affiliated Hospital of Dalian Medical University, Dalian 116027, China
- Shanghai Institute of Kidney Disease and Dialysis, Shanghai 200032, China
| | - Jieru Cai
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Kidney Disease and Dialysis, Shanghai 200032, China
| | - Xiaoyan Jiao
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Kidney Disease and Dialysis, Shanghai 200032, China
| | - Xiaofang Yu
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Kidney Disease and Dialysis, Shanghai 200032, China
| | - Xiaoqiang Ding
- Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Institute of Kidney Disease and Dialysis, Shanghai 200032, China
- Shanghai Key Laboratory of Kidney disease and Blood Purification, Shanghai 200032, China
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Shalaby SM, El-Shal AS, Zidan HE, Mazen NF, Abd El-Haleem MR, Abd El Motteleb DM. Comparing the effects of MSCs and CD34+ cell therapy in a rat model of myocardial infarction. IUBMB Life 2016; 68:343-54. [DOI: 10.1002/iub.1487] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 02/05/2016] [Indexed: 12/11/2022]
Affiliation(s)
- Sally M. Shalaby
- Medical Biochemistry Department; Faculty of Medicine, Zagazig University; Zagazig Egypt
| | - Amal S. El-Shal
- Medical Biochemistry Department; Faculty of Medicine, Zagazig University; Zagazig Egypt
| | - Haidy E. Zidan
- Medical Biochemistry Department; Faculty of Medicine, Zagazig University; Zagazig Egypt
| | - Nehad F. Mazen
- Histology and Cell Biology Department; Faculty of Medicine, Zagazig University; Zagazig Egypt
| | - Manal R. Abd El-Haleem
- Histology and Cell Biology Department; Faculty of Medicine, Zagazig University; Zagazig Egypt
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Alestalo K, Miettinen JA, Vuolteenaho O, Huikuri H, Lehenkari P. Bone Marrow Mononuclear Cell Transplantation Restores Inflammatory Balance of Cytokines after ST Segment Elevation Myocardial Infarction. PLoS One 2015; 10:e0145094. [PMID: 26690350 PMCID: PMC4687062 DOI: 10.1371/journal.pone.0145094] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Accepted: 11/29/2015] [Indexed: 01/10/2023] Open
Abstract
Background Acute myocardial infarction (AMI) launches an inflammatory response and a repair process to compensate cardiac function. During this process, the balance between proinflammatory and anti-inflammatory cytokines is important for optimal cardiac repair. Stem cell transplantation after AMI improves tissue repair and increases the ventricular ejection fraction. Here, we studied in detail the acute effect of bone marrow mononuclear cell (BMMNC) transplantation on proinflammatory and anti-inflammatory cytokines in patients with ST segment elevation myocardial infarction (STEMI). Methods Patients with STEMI treated with thrombolysis followed by percutaneous coronary intervention (PCI) were randomly assigned to receive either BMMNC or saline as an intracoronary injection. Cardiac function was evaluated by left ventricle angiogram during the PCI and again after 6 months. The concentrations of 27 cytokines were measured from plasma samples up to 4 days after the PCI and the intracoronary injection. Results Twenty-six patients (control group, n = 12; BMMNC group, n = 14) from the previously reported FINCELL study (n = 80) were included to this study. At day 2, the change in the proinflammatory cytokines correlated with the change in the anti-inflammatory cytokines in both groups (Kendall’s tau, control 0.6; BMMNC 0.7). At day 4, the correlation had completely disappeared in the control group but was preserved in the BMMNC group (Kendall’s tau, control 0.3; BMMNC 0.7). Conclusions BMMNC transplantation is associated with preserved balance between pro- and anti-inflammatory cytokines after STEMI in PCI-treated patients. This may partly explain the favorable effect of stem cell transplantation after AMI.
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Affiliation(s)
- Kirsi Alestalo
- Surgery Clinic, Medical Research Center, Oulu University Hospital, Oulu, Finland
- Department of Anatomy and Cell Biology, Medical Research Center, University of Oulu, Oulu, Finland
- * E-mail:
| | - Johanna A. Miettinen
- Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Olli Vuolteenaho
- Department of Physiology, Institute of Biomedicine, University of Oulu, Oulu, Finland
| | - Heikki Huikuri
- Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Petri Lehenkari
- Surgery Clinic, Medical Research Center, Oulu University Hospital, Oulu, Finland
- Department of Anatomy and Cell Biology, Medical Research Center, University of Oulu, Oulu, Finland
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Zamilpa R, Navarro MM, Flores I, Griffey S. Stem cell mechanisms during left ventricular remodeling post-myocardial infarction: Repair and regeneration. World J Cardiol 2014; 6:610-620. [PMID: 25068021 PMCID: PMC4110609 DOI: 10.4330/wjc.v6.i7.610] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2013] [Revised: 02/21/2014] [Accepted: 05/14/2014] [Indexed: 02/06/2023] Open
Abstract
Post-myocardial infarction (MI), the left ventricle (LV) undergoes a series of events collectively referred to as remodeling. As a result, damaged myocardium is replaced with fibrotic tissue consequently leading to contractile dysfunction and ultimately heart failure. LV remodeling post-MI includes inflammatory, fibrotic, and neovascularization responses that involve regulated cell recruitment and function. Stem cells (SCs) have been transplanted post-MI for treatment of LV remodeling and shown to improve LV function by reduction in scar tissue formation in humans and animal models of MI. The promising results obtained from the application of SCs post-MI have sparked a massive effort to identify the optimal SC for regeneration of cardiomyocytes and the paradigm for clinical applications. Although SC transplantations are generally associated with new tissue formation, SCs also secrete cytokines, chemokines and growth factors that robustly regulate cell behavior in a paracrine fashion during the remodeling process. In this review, the different types of SCs used for cardiomyogenesis, markers of differentiation, paracrine factor secretion, and strategies for cell recruitment and delivery are addressed.
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Fan CQ, Leu S, Sheu JJ, Zhen YY, Tsai TH, Chen YL, Chung SY, Chai HT, Sun CK, Yang JL, Chang HW, Ko SF, Yip HK. Prompt bone marrow-derived mesenchymal stem cell therapy enables early porcine heart function recovery from acute myocardial infarction. Int Heart J 2014; 55:362-71. [PMID: 24965596 DOI: 10.1536/ihj.14-007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Impact of early bone marrow-derived mesenchymal stem cell (BMDMSC) implantation on left ventricular (LV) function after AMI was studied.Twelve mini-pigs were equally divided into placebo (AMI through left coronary artery ligation) and cell-treated groups [BMDMSCs (3.0 × 10(7)) implanted into infarct area (IA)] with myocardium harvested by post-AMI day 90. Six healthy animals served as controls.On post-AMI day 90, magnetic resonance imaging showed a lower LV ejection fraction but higher LV dimensions in the placebo group (P < 0.003) that also had increased IAs but reduced wall thickness (P < 0.005). Pro-apoptotic gene expressions (Bax, caspase-3) and apoptotic nucleus number in IAs and peri-IAs were highest in the placebo group (P < 0.001). Inflammatory biomarker expressions (MMP-9, oxidized protein, CD40+ cells) were highest, whereas those of angiogenesis (VEGF, CD31+ cells, SDF-1α, CXCR4) and myocardium-preservation (connexin43, troponin-I, cytochrome-C) were lowest in the placebo group (P < 0.01).BMDMSC implantation preserved LV function and alleviated remodeling at post-AMI day 90.
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Affiliation(s)
- Chang-Qing Fan
- Division of Cardiology, Department of Internal Medicine, Xiamen Chang Gung Memorial Hospital
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Yan J, Tie G, Xu TY, Cecchini K, Messina LM. Mesenchymal stem cells as a treatment for peripheral arterial disease: current status and potential impact of type II diabetes on their therapeutic efficacy. Stem Cell Rev Rep 2014; 9:360-72. [PMID: 23475434 DOI: 10.1007/s12015-013-9433-8] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Mesenchymal stem cells (MSCs), due to their paracrine, transdifferentiation, and immunosuppressive effects, hold great promise as a therapy for peripheral arterial disease. Diabetes is an important risk factor for peripheral arterial disease; however, little is known of how type II diabetes affects the therapeutic function of MSCs. This review summarizes the current status of preclinical and clinical studies that have been performed to determine the efficacy of MSCs in the treatment of peripheral arterial disease. We also present findings from our laboratory regarding the impact of type II diabetes on the therapeutic efficacy of MSCs neovascularization after the induction of hindlimb ischemia. In our studies, we documented that experimental type II diabetes in db/db mice impaired MSCs' therapeutic function by favoring their differentiation towards adipocytes, while limiting their differentiation towards endothelial cells. Moreover, type II diabetes impaired the capacity of MSCs to promote neovascularization in the ischemic hindlimb. We further showed that these impairments of MSC function and multipotency were secondary to hyperinsulinemia-induced, Nox4-dependent oxidant stress in db/db MSCs. Should human MSCs display similar oxidant stress-induced impairment of function, these findings might permit greater leverage of the potential of MSC transplantation, particularly in the setting of diabetes or other cardiovascular risk factors, as well as provide a therapeutic approach by reversing the oxidant stress of MSCs prior to transplantation.
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Affiliation(s)
- Jinglian Yan
- Division of Vascular and Endovascular Surgery, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA
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The role of bioactive lipids in stem cell mobilization and homing: novel therapeutics for myocardial ischemia. BIOMED RESEARCH INTERNATIONAL 2014; 2014:653543. [PMID: 24672794 PMCID: PMC3930186 DOI: 10.1155/2014/653543] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Revised: 08/13/2013] [Accepted: 10/11/2013] [Indexed: 11/25/2022]
Abstract
Despite significant advances in medical therapy and interventional strategies, the prognosis of millions of patients with acute myocardial infarction (AMI) and ischemic heart disease (IHD) remains poor. Currently, short of heart transplantation with all of its inherit limitations, there are no available treatment strategies that replace the infarcted myocardium. It is now well established that cardiomyocytes undergo continuous renewal, with contribution from bone marrow (BM)-derived stem/progenitor cells (SPCs). This phenomenon is upregulated during AMI by initiating multiple innate reparatory mechanisms through which BMSPCs are mobilized towards the ischemic myocardium and contribute to myocardial regeneration. While a role for the SDF-1/CXCR4 axis in retention of BMSPCs in bone marrow is undisputed, its exclusive role in their mobilization and homing to a highly proteolytic microenvironment, such as the ischemic/infarcted myocardium, is currently being challenged. Recent evidence suggests a pivotal role for bioactive lipids in the mobilization of BMSPCs at the early stages following AMI and their homing towards ischemic myocardium. This review highlights the recent advances in our understanding of the mechanisms of stem cell mobilization, provides newer evidence implicating bioactive lipids in BMSPC mobilization and differentiation, and discusses their potential as therapeutic agents in the treatment of IHD.
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Grawish MEA, Khounganian R, Hamam MK, Zaher AR, Hegazy D, El-Negoly SAER, Hassan G, Zyada MM. Altered coronal tissue of the human dental pulp in chronic hepatitis C virus infected patients. J Endod 2013; 39:752-758. [PMID: 23683274 DOI: 10.1016/j.joen.2012.11.031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Revised: 11/07/2012] [Accepted: 11/12/2012] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Hepatitis C virus (HCV) infection is characterized by a high rate of chronicity and concerns 170 million individuals worldwide. Extrahepatic manifestations are frequently observed in patients with chronic viral hepatitis. Although extrahepatic manifestations do exist with all hepatitis viruses, they are more commonly associated with chronic HCV infection. This study aimed to evaluate qualitatively and quantitatively the effect of chronic HCV infection on the coronal tissue of the human dental pulp. METHODS Thirty sound impacted teeth were obtained from healthy individuals as healthy controls. The patient group included another 30 sound impacted teeth obtained from chronic HCV-infected patients. The coronal pulp tissues were carefully removed, fixed, and processed to be stained with hematoxylin-eosin, alcian blue (2.5)/periodic acid-Schiff, van Gieson, and fibronectin. RESULTS The tissue sections of chronic HCV patients revealed disorganized pulp tissue, chronic inflammatory cell infiltrate, thickening, stenosis and occlusion of large-sized blood vessel arteriole, and collapsed venule and lymphatic system. The acidic, neutral, and mixed mucins were increased, whereas the amount of collagen was decreased, accompanied with marked decrease in the distribution and quantity of fibronectin glycoprotein. Application of Kruskal-Wallis test showed that there were statistically significant changes between the 2 groups (P ≤ .05). CONCLUSIONS The coronal tissue of the dental pulp, like any other body tissues, is affected by chronic HCV infection, with an inappropriate cellularity, vasculature, and extracellular matrix proteins. The clinician should be alerted to these histologic changes and their subsequent implications.
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Affiliation(s)
- Mohammed El-Awady Grawish
- Department of Oral Medicine and Diagnostic Science, College of Dentistry, King Saud University, Riyadh, Saudi Arabia
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Song L, Yang YJ, Dong QT, Qian HY, Gao RL, Qiao SB, Shen R, He ZX, Lu MJ, Zhao SH, Geng YJ, Gersh BJ. Atorvastatin enhance efficacy of mesenchymal stem cells treatment for swine myocardial infarction via activation of nitric oxide synthase. PLoS One 2013; 8:e65702. [PMID: 23741509 PMCID: PMC3669282 DOI: 10.1371/journal.pone.0065702] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2013] [Accepted: 04/26/2013] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND In a swine model of acute myocardial infarction (AMI), Statins can enhance the therapeutic efficacy of mesenchymal stem cell (MSCs) transplantation. However, the mechanisms remain unclear. This study aims at assessing whether atorvastatin (Ator) facilitates the effects of MSCs through activation of nitric oxide synthase (NOS), especially endothelial nitric oxide synthase (eNOS), which is known to protect against ischemic injury. METHODS AND RESULTS 42 miniswines were randomized into six groups (n = 7/group): Sham operation; AMI control; Ator only; MSC only, Ator+MSCs and Ator+MSCs+NG-nitrol-L-arginine (L-NNA), an inhibitor of NOS. In an open-heart surgery, swine coronary artery ligation and reperfusion model were established, and autologous bone-marrow MSCs were injected intramyocardium. Four weeks after transplantation, compared with the control group, Ator+MSCs animals exhibited decreased defect areas of both "perfusion" defined by Single-Photon Emission Computed Tomography (-6.2±1.8% vs. 2.0±5.1%, P = 0.0001) and "metabolism" defined by Positron Emission Tomography (-3.00±1.41% vs. 4.20±4.09%, P = 0.0004); Ejection fraction by Magnetic Resonance Imaging increased substantially (14.22±12.8% vs. 1.64±2.64%, P = 0.019). In addition, indices of inflammation, fibrosis, and apoptosis were reduced and survivals of MSCs or MSC-derived cells were increased in Ator+MSCs animals. In Ator or MSCs alone group, perfusion, metabolism, inflammation, fibrosis or apoptosis were reduced but there were no benefits in terms of heart function and cell survival. Furthermore, the above benefits of Ator+MSCs treatment could be partially blocked by L-NNA. CONCLUSIONS Atorvastatin facilitates survival of implanted MSCs, improves function and morphology of infarcted hearts, mediated by activation of eNOS and alleviated by NOS inhibitor. The data reveal the cellular and molecular mechanism for anti-AMI therapy with a combination of statin and stem cells.
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Affiliation(s)
- Lei Song
- Coronary Heart Disease Center, Department of Cardiology, Fuwai Hospital and Cardiovascular Institute, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Yuan C, Yu G, Yang T, Li W, Ai Q, Deng L. Enhanced therapeutic effects on acute myocardial infarction with multiple intravenous transplantation of human cord blood mononuclear cells. Int J Cardiol 2013; 168:2767-73. [PMID: 23651828 DOI: 10.1016/j.ijcard.2013.03.131] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Revised: 03/19/2013] [Accepted: 03/26/2013] [Indexed: 12/20/2022]
Abstract
BACKGROUND Cell transplantation of human cord blood mononuclear progenitor cells (HCBMCs) is a new treatment that could restore cardiac functions after acute myocardial infarction (AMI). We hypothesize that multiple doses of HCBMCs might increase homing of transplanted cells to infarcted region, and improve outcome of AMI via inhibition of ischemic-induced inflammatory responses. METHODS AND RESULTS HCBMCs were injected intravenously to rabbits that previously underwent ligation of left anterior coronary artery (LAD). Single dose of HCBMCs was intravenously delivered on the 7th day or multiple doses of HCBMCs were delivered on the 7th, 9th, 11th and 13th day after AMI. Homing of HCBMCs was determined by 5-bromodeoxyuridine (BrdU) labeling. The amount of grafted cells homed and retained in the infarcted area was significantly increased in the rabbits that received multiple doses. More viable cardiomyocytes and less collagen deposition were observed also in the group with more injections. Cardiac functions were assessed by echocardiography and hemodynamics. Multiple doses of HCBMCs showed significant benefits in preservation of cardiac functions. In infarcted myocardium, multiple transplantations of HCBMCs showed a significant increase in the myocardial level of anti-inflammatory IL-10 and a marked decrease in the level of the pro-inflammatory IL-6. CONCLUSIONS Multiple injections of HCBMCs markedly increased the amount of grafted cells, beneficially improving cardiac functions after AMI. The findings suggest that multiple doses of HCBMCs might be a novel strategy in the cell therapy for AMI.
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Affiliation(s)
- Chunju Yuan
- Department of Cardiology, Xiangya Hospital, Central South University, Changsha 410008, PR China
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Karpov AA, Uspenskaya YK, Minasian SM, Puzanov MV, Dmitrieva RI, Bilibina AA, Anisimov SV, Galagudza MM. The effect of bone marrow- and adipose tissue-derived mesenchymal stem cell transplantation on myocardial remodelling in the rat model of ischaemic heart failure. Int J Exp Pathol 2013; 94:169-77. [PMID: 23560418 DOI: 10.1111/iep.12017] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2012] [Accepted: 01/11/2013] [Indexed: 12/27/2022] Open
Abstract
This study aimed to investigate the effect of bone marrow- and adipose tissue-derived mesenchymal stem cell (BM-MSC and AD-MSC respectively) transplantation on left ventricular function and infarct area (IA) in the rat model of ischaemic heart failure. In anaesthetized Wistar rats, the left coronary artery (LCA) was occluded for 40 min with subsequent reperfusion for 7 days. Seven days following surgery, the animals with LCA occlusion/reperfusion were randomized into three groups: (i) Controls received intramyocardial injection of vehicle at three different locations within the peri-infarct zone, (ii) BM-MSC: cells were injected in the same way as in previous group (10(6) ), (iii) AD-MSC: using the same protocol as used in the BM-MSC group. In addition there was also a sham-treated group that had no injection. Two weeks following MSC transplantation, the hearts were isolated and perfused according to the Langendorff method followed by 30-min global ischaemia and 90-min reperfusion. After this IA was determined histologically. During Langendorff perfusion initial and postischaemic LV functions were the same in all groups although LV pressure at the 10th minute of reperfusion was higher in the AD-MSC group compared to controls. However, LV pressure during 30-min global ischaemia was significantly higher in BM-MSC as compared to controls and AD-MSC. The sham treated animals showed the same results as those seen with BM-MSC. Thus, BM-MSC transplantation, in contrast to transplantation of AD-MSC, resulted in better preservation of the LV ability to contract during ischaemia. Furthermore, IA was significantly smaller in BM-MSC group as compared to the controls and the AD-MSC groups. Thus this study has demonstrated that treatment with BM-MSC both ameliorates LV function and reduces histological scar size.
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Affiliation(s)
- Andrey A Karpov
- Department of Pathophysiology, IP Pavlov Federal Medical University, St-Petersburg, Russia. a–
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Effects of bone marrow mesenchymal stem cells in a rat model of myocardial infarction. Resuscitation 2012; 83:1391-6. [DOI: 10.1016/j.resuscitation.2012.02.033] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2011] [Revised: 02/15/2012] [Accepted: 02/21/2012] [Indexed: 01/14/2023]
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Liew A, O'Brien T. Therapeutic potential for mesenchymal stem cell transplantation in critical limb ischemia. Stem Cell Res Ther 2012; 3:28. [PMID: 22846185 PMCID: PMC3580466 DOI: 10.1186/scrt119] [Citation(s) in RCA: 127] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The therapeutic potential of mesenchymal stem cell (MSC) transplantation for the treatment of ischemic conditions such as coronary artery disease, peripheral arterial disease, and stroke has been explored in animal models and early-phase clinical trials. A substantial database documents the safety profile of MSC administration to humans in a large number of disease states. The mechanism of the therapeutic effect of MSC transplantation in ischemic disease has been postulated to be due to paracrine, immunomodulatory, and differentiation effects. This review provides an overview of the potential role of MSC-based therapy for critical limb ischemia (CLI), the comparison of MSC cellular therapy with angiogenesis gene therapy in CLI, and the proposed mechanism of action of MSC therapy. Preclinical efficacy data in animal models of hindlimb ischemia, current early-phase human trial data, and considerations for future MSC-based therapy in CLI will also be discussed.
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van Dijk A, Naaijkens BA, Jurgens WJFM, Nalliah K, Sairras S, van der Pijl RJ, Vo K, Vonk ABA, van Rossum AC, Paulus WJ, van Milligen FJ, Niessen HWM. Reduction of infarct size by intravenous injection of uncultured adipose derived stromal cells in a rat model is dependent on the time point of application. Stem Cell Res 2011; 7:219-29. [PMID: 21907165 DOI: 10.1016/j.scr.2011.06.003] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2010] [Revised: 06/14/2011] [Accepted: 06/16/2011] [Indexed: 01/08/2023] Open
Abstract
Stem cell therapy is a promising tool to improve outcome after acute myocardial infarction (AMI), but needs to be optimized since results from clinical applications remain ambiguous. A potent source of stem cells is the stromal vascular fraction of adipose tissue (SVF), which contains high numbers of adipose derived stem cells (ASC). We hypothesized that: 1) intravenous injection can be used to apply stem cells to the heart. 2) Uncultured SVF cells are easier and safer when cultured ASCs. 3) Transplantation after the acute inflammation period of AMI is favorable over early injection. For this, AMI was induced in rats by 40min of coronary occlusion. One or seven days after AMI, rats were intravenously injected with vehicle, 5×10(6) uncultured rat SVF cells or 1×10(6) rat ASCs. Rats were analyzed 35 days after AMI. Intravenous delivery of both fresh SVF cells and cultured ASCs 7 days after AMI significantly reduced infarct size compared to vehicle. Similar numbers of stem cells were found in the heart, after treatment with fresh SVF cells and cultured ASCs. Importantly, no adverse effects were found after injection of SVF cells. Using cultured ASCs, however, 3 animals had shortness of breath, and one animal died during injection. In contrast to application at 7 days post AMI, injection of SVF cells 1 day post AMI resulted in a small but non-significant infarct reduction (p=0.35). Taken together, intravenous injection of uncultured SVF cells subsequent to the acute inflammation period, is a promising stem cell therapy for AMI.
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Affiliation(s)
- A van Dijk
- Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands
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Mokashi SA, Guan J, Wang D, Tchantchaleishvili V, Brigham M, Lipsitz S, Lee LS, Schmitto JD, Bolman RM, Khademhosseini A, Liao R, Chen FY. Preventing cardiac remodeling: the combination of cell-based therapy and cardiac support therapy preserves left ventricular function in rodent model of myocardial ischemia. J Thorac Cardiovasc Surg 2010; 140:1374-80. [PMID: 21078426 DOI: 10.1016/j.jtcvs.2010.07.070] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2010] [Revised: 07/18/2010] [Accepted: 07/30/2010] [Indexed: 11/24/2022]
Abstract
OBJECTIVE Cellular and mechanical treatment to prevent heart failure each holds therapeutic promise but together have not been reported yet. The goal of the present study was to determine whether combining a cardiac support device with cell-based therapy could prevent adverse left ventricular remodeling, more than either therapy alone. METHODS The present study was completed in 2 parts. In the first part, mesenchymal stem cells were isolated from rodent femurs and seeded on a collagen-based scaffold. In the second part, myocardial infarction was induced in 60 rats. The 24 survivors were randomly assigned to 1 of 4 groups: control, stem cell therapy, cardiac support device, and a combination of stem cell therapy and cardiac support device. Left ventricular function was measured with biweekly echocardiography, followed by end-of-life histopathologic analysis at 6 weeks. RESULTS After myocardial infarction and treatment intervention, the ejection fraction remained preserved (74.9-80.2%) in the combination group at an early point (2 weeks) compared with the control group (66.2-82.8%). By 6 weeks, the combination therapy group had a significantly greater fractional area of change compared with the control group (69.2% ± 6.7% and 49.5% ± 6.1% respectively, P = .03). Also, at 6 weeks, the left ventricular wall thickness was greater in the combination group than in the stem cell therapy alone group (1.79 ± 0.11 and 1.33 ± 0.13, respectively, P = .02). CONCLUSIONS Combining a cardiac support device with stem cell therapy preserves left ventricular function after myocardial infarction, more than either therapy alone. Furthermore, stem cell delivery using a cardiac support device is a novel delivery approach for cell-based therapies.
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Affiliation(s)
- Suyog A Mokashi
- Division of Cardiac Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02115, USA
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Abstract
Multipotent mesenchymal stromal cells (MSCs) represent a rare heterogeneous subset of pluripotent stromal cells that can be isolated from many different adult tissues that exhibit the potential to give rise to cells of diverse lineages. Numerous studies have reported beneficial effects of MSCs in tissue repair and regeneration. After culture expansion and in vivo administration, MSCs home to and engraft to injured tissues and modulate the inflammatory response through synergistic downregulation of proinflammatory cytokines and upregulation of both prosurvival and antiinflammatory factors. In addition, MSCs possess remarkable immunosuppressive properties, suppressing T-cell, NK cell functions, and also modulating dentritic cell activities. Tremendous progress has been made in preclinical studies using MSCs, including the ability to use allogeneic cells, which has driven the application of MSCs toward the clinical setting. This review highlights our current understanding into the biology of MSCs with particular emphasis on the cardiovascular and renal applications, and provides a brief update on the clinical status of MSC-based therapy.
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Affiliation(s)
- Husein K Salem
- Centre for Translational Medicine and Therapeutics, The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Queen Mary-University of London, London, United Kingdom.
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Wang Y, Zhang D, Ashraf M, Zhao T, Huang W, Ashraf A, Balasubramaniam A. Combining neuropeptide Y and mesenchymal stem cells reverses remodeling after myocardial infarction. Am J Physiol Heart Circ Physiol 2009; 298:H275-86. [PMID: 19897711 DOI: 10.1152/ajpheart.00765.2009] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Neuropeptide Y (NPY) induced reentry of differentiated rat neonatal and adult cardiomyocytes into the cell cycle. NPY also induced differentiation of bone marrow-derived mesenchymal stem cells (MSC) into cardiomyocytes following transplantation into infarcted myocardium. Rat neonatal and adult cardiomyocytes were treated in vitro with vehicle, NPY, fibroblast growth factor (FGF; 100 ng/ml), or FGF plus NPY. DNA synthesis, mitosis, and cytokinesis were determined by immunocytochemistry. NPY-induced MSC gene expression, cell migration, tube formation, and endothelial cell differentiation were analyzed. Male rat green fluorescent protein-MSC (2 x 10(6)), pretreated with either vehicle or NPY (10(-8) M) for 72 h, were injected into the border zone of the female myocardium following left anterior descending artery ligation. On day 30, heart function was assessed, and hearts were harvested for histological and immunohistochemical analyses. NPY increased 5-bromo-2'-deoxy-uridine incorporation and promoted both cytokinesis and mitosis in rat neonatal and adult myocytes. NPY also upregulated several genes required for mitosis in MSC, including aurora B kinase, FGF-2, cycline A2, eukaryotic initiation factor 4 E, and stromal cell-derived factor-1alpha. NPY directly induced neonatal and adult cardiomyocyte cell-cycle reentry and enhanced the number of differentiated cardiomyocytes from MSC in the infarcted myocardium, which corresponded to improved cardiac function, reduced fibrosis, ventricular remodeling, and increased angiomyogenesis. It is concluded that a combined treatment of NPY with MSC is a novel approach for cardiac repair.
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Affiliation(s)
- Yigang Wang
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267-0529, USA.
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Nakamuta JS, Danoviz ME, Marques FLN, dos Santos L, Becker C, Gonçalves GA, Vassallo PF, Schettert IT, Tucci PJF, Krieger JE. Cell therapy attenuates cardiac dysfunction post myocardial infarction: effect of timing, routes of injection and a fibrin scaffold. PLoS One 2009; 4:e6005. [PMID: 19547700 PMCID: PMC2695782 DOI: 10.1371/journal.pone.0006005] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2009] [Accepted: 05/06/2009] [Indexed: 01/09/2023] Open
Abstract
Background Cell therapy approaches for biologic cardiac repair hold great promises, although basic fundamental issues remain poorly understood. In the present study we examined the effects of timing and routes of administration of bone marrow cells (BMC) post-myocardial infarction (MI) and the efficacy of an injectable biopolymer scaffold to improve cardiac cell retention and function. Methodology/Principal Findings 99mTc-labeled BMC (6×106 cells) were injected by 4 different routes in adult rats: intravenous (IV), left ventricular cavity (LV), left ventricular cavity with temporal aorta occlusion (LV+) to mimic coronary injection, and intramyocardial (IM). The injections were performed 1, 2, 3, or 7 days post-MI and cell retention was estimated by γ-emission counting of the organs excised 24 hs after cell injection. IM injection improved cell retention and attenuated cardiac dysfunction, whereas IV, LV or LV* routes were somewhat inefficient (<1%). Cardiac BMC retention was not influenced by timing except for the IM injection that showed greater cell retention at 7 (16%) vs. 1, 2 or 3 (average of 7%) days post-MI. Cardiac cell retention was further improved by an injectable fibrin scaffold at day 3 post-MI (17 vs. 7%), even though morphometric and function parameters evaluated 4 weeks later displayed similar improvements. Conclusions/Significance These results show that cells injected post-MI display comparable tissue distribution profile regardless of the route of injection and that there is no time effect for cardiac cell accumulation for injections performed 1 to 3 days post-MI. As expected the IM injection is the most efficient for cardiac cell retention, it can be further improved by co-injection with a fibrin scaffold and it significantly attenuates cardiac dysfunction evaluated 4 weeks post myocardial infarction. These pharmacokinetic data obtained under similar experimental conditions are essential for further development of these novel approaches.
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Affiliation(s)
- Juliana S. Nakamuta
- Heart Institute (InCor), University of São Paulo Medical School, São Paulo, São Paulo, Brazil
| | - Maria E. Danoviz
- Heart Institute (InCor), University of São Paulo Medical School, São Paulo, São Paulo, Brazil
| | - Fabio L. N. Marques
- Radiopharmacy Laboratory, Nuclear Medicine Center, University of São Paulo Medical School, São Paulo, São Paulo, Brazil
| | - Leonardo dos Santos
- Heart Institute (InCor), University of São Paulo Medical School, São Paulo, São Paulo, Brazil
- Cardiac Physiology and Pathophysiology Laboratory, Cardiology Division, Federal University of Sao Paulo, São Paulo, São Paulo, Brazil
| | - Claudia Becker
- Heart Institute (InCor), University of São Paulo Medical School, São Paulo, São Paulo, Brazil
| | - Giovana A. Gonçalves
- Heart Institute (InCor), University of São Paulo Medical School, São Paulo, São Paulo, Brazil
| | - Paula F. Vassallo
- Heart Institute (InCor), University of São Paulo Medical School, São Paulo, São Paulo, Brazil
| | - Isolmar T. Schettert
- Heart Institute (InCor), University of São Paulo Medical School, São Paulo, São Paulo, Brazil
| | - Paulo J. F. Tucci
- Cardiac Physiology and Pathophysiology Laboratory, Cardiology Division, Federal University of Sao Paulo, São Paulo, São Paulo, Brazil
| | - Jose E. Krieger
- Heart Institute (InCor), University of São Paulo Medical School, São Paulo, São Paulo, Brazil
- * E-mail:
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Wang JJ, Ye F, Cheng LJ, Shi YJ, Bao J, Sun HQ, Wang W, Zhang P, Bu H. Osteogenic differentiation of mesenchymal stem cells promoted by overexpression of connective tissue growth factor. J Zhejiang Univ Sci B 2009; 10:355-367. [PMID: 19434762 PMCID: PMC2676415 DOI: 10.1631/jzus.b0820252] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2008] [Accepted: 01/19/2009] [Indexed: 02/05/2023]
Abstract
OBJECTIVE Large segmental bone defect repair remains a clinical and scientific challenge with increasing interest focusing on combining gene transfection with tissue engineering techniques. The aim of this study is to investigate the effect of connective tissue growth factor (CTGF) on the proliferation and osteogenic differentiation of the bone marrow mesenchymal stem cells (MSCs). METHODS A CTGF-expressing plasmid (pCTGF) was constructed and transfected into MSCs. Then expressions of bone morphogenesis-related genes, proliferation rate, alkaline phosphatase activity, and mineralization were examined to evaluate the osteogenic potential of the CTGF gene-modified MSCs. RESULTS Overexpression of CTGF was confirmed in pCTGF-MSCs. pCTGF transfection significantly enhanced the proliferation rates of pCTGF-MSCs (P<0.05). CTGF induced a 7.5-fold increase in cell migration over control (P<0.05). pCTGF transfection enhanced the expression of bone matrix proteins, such as bone sialoprotein, osteocalcin, and collagen type I in MSCs. The levels of alkaline phosphatase (ALP) activities of pCTGF-MSCs at the 1st and 2nd weeks were 4.0- and 3.0-fold higher than those of MSCs cultured in OS-medium, significantly higher than those of mock-MSCs and normal control MSCs (P<0.05). Overexpression of CTGF in MSCs enhanced the capability to form mineralized nodules. CONCLUSION Overexpression of CTGF could improve the osteogenic differentiation ability of MSCs, and the CTGF gene-modified MSCs are potential as novel cell resources of bone tissue engineering.
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Affiliation(s)
- Jin-jing Wang
- Key Laboratory of Transplant Engineering and Immunology of Ministry of Health, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Feng Ye
- Key Laboratory of Transplant Engineering and Immunology of Ministry of Health, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Li-jia Cheng
- Key Laboratory of Transplant Engineering and Immunology of Ministry of Health, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yu-jun Shi
- Key Laboratory of Transplant Engineering and Immunology of Ministry of Health, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ji Bao
- Key Laboratory of Transplant Engineering and Immunology of Ministry of Health, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Huai-qiang Sun
- Key Laboratory of Transplant Engineering and Immunology of Ministry of Health, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Wei Wang
- Key Laboratory of Transplant Engineering and Immunology of Ministry of Health, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Peng Zhang
- Key Laboratory of Transplant Engineering and Immunology of Ministry of Health, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hong Bu
- Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China
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