Heart Disease and Stem Cells

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Clinical study using adipose-derived mesenchymal-like stem cells in acute myocardial infarction and heart failure

Methods Mol Biol. 2013;1036:207-12
Authors: Panfilov IA, de Jong R, Takashima S, Duckers HJ

Adipose tissue represents an abundant, accessible source of regenerative cells that can be easily obtained in sufficient amount for therapy. Adipose-derived regenerative cells (ADRC) are comprised of leukocytes, smooth muscles, endothelial cells, and mesenchymal stem cells. In contrast to bone-marrow-derived MSC, the abundance of adipose tissue in patients and the higher frequency per unit mass of regenerative cells allow for the isolation of cells in therapeutic meaningful amounts in less than 2h after donor tissue acquisition.Harvest of adipose tissue can thus follow primary PCI, allowing efficient treatment within 24h. This obviates the need for extensive cell culturing in GMP clean room facilities and makes ADSCs a promising and practical autologous cell source. In the following chapter, we will describe the liposuction procedure for stem cell harvest, two cell delivery techniques, and pressure/volume loop analysis for the follow-up of our patients enrolled in the clinical studies.

PMID: 23807797 [PubMed – indexed for MEDLINE]

Cardiac-derived stem cell-based therapy for heart failure: progress and clinical applications

Exp Biol Med (Maywood). 2013 Mar;238(3):294-300
Authors: Tang YL, Wang YJ, Chen LJ, Pan YH, Zhang L, Weintraub NL

Stem cell-based therapy is emerging as a promising strategy to treat end-stage heart failure, a leading cause of morbidity and mortality. Stem cells can be isolated from a variety of sources and exhibit unique characteristics that impact their potential therapeutic utility. The adult heart contains small populations of committed, multipotent cardiac stem cells (CSC), which are adapted to the cardiac microenvironment and participate in postnatal physiological and pathological cardiac renewal or repair. These cells can be isolated, expanded in culture, and administered therapeutically to improve cardiac function in the setting of heart failure. CSC can be differentiated into three distinct cardiovascular lineages and exhibit enhanced paracrine factor production and engraftment as compared with other types of mesenchymal stem cells, which in turn may translate into improved therapeutic efficacy. The cell surface marker expression and phenotype of these CSC, however, depends on the method of isolation, selection and propagation, which likely explains the variable experimental results obtained to date. Moreover, invasive procedures are required to obtain CSC from humans. Early trials using autologous CSC in patients with ischemic cardiomyopathy have demonstrated feasibility and safety, along with variable degrees of therapeutic efficacy in terms of enhancing myocardial viability and cardiac function. Further studies are needed to optimize methods of CSC isolation, manipulation and delivery. If fully realized, the potential of CSC therapy could fundamentally change the approach to the treatment of end-stage heart failure.

PMID: 23598975 [PubMed – indexed for MEDLINE]

Cardiopoietic stem cell therapy in heart failure: the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) multicenter randomized trial with lineage-specified biologics.

J Am Coll Cardiol. 2013 Jun 11;61(23):2329-38
Authors: Bartunek J, Behfar A, Dolatabadi D, Vanderheyden M, Ostojic M, Dens J, El Nakadi B, Banovic M, Beleslin B, Vrolix M, Legrand V, Vrints C, Vanoverschelde JL, Crespo-Diaz R, Homsy C, Tendera M, Waldman S, Wijns W, Terzic A

OBJECTIVES: This study sought to evaluate the feasibility and safety of autologous bone marrow-derived and cardiogenically oriented mesenchymal stem cell therapy and to probe for signs of efficacy in patients with chronic heart failure.

BACKGROUND: In pre-clinical heart failure models, cardiopoietic stem cell therapy improves left ventricular function and blunts pathological remodeling.

METHODS: The C-CURE (Cardiopoietic stem Cell therapy in heart failURE) trial, a prospective, multicenter, randomized trial, was conducted in patients with heart failure of ischemic origin who received standard of care or standard of care plus lineage-specified stem cells. In the cell therapy arm, bone marrow was harvested and isolated mesenchymal stem cells were exposed to a cardiogenic cocktail. Derived cardiopoietic stem cells, meeting release criteria under Good Manufacturing Practice, were delivered by endomyocardial injections guided by left ventricular electromechanical mapping. Data acquisition and analysis were performed in blinded fashion. The primary endpoint was feasibility/safety at 2-year follow-up. Secondary endpoints included cardiac structure/function and measures of global clinical performance 6 months post-therapy.

RESULTS: Mesenchymal stem cell cocktail-based priming was achieved for each patient with the dose attained in 75% and delivery without complications in 100% of cases. There was no evidence of increased cardiac or systemic toxicity induced by cardiopoietic cell therapy. Left ventricular ejection fraction was improved by cell therapy (from 27.5 ± 1.0% to 34.5 ± 1.1%) versus standard of care alone (from 27.8 ± 2.0% to 28.0 ± 1.8%, p < 0.0001) and was associated with a reduction in left ventricular end-systolic volume (-24.8 ± 3.0 ml vs. -8.8 ± 3.9 ml, p < 0.001). Cell therapy also improved the 6-min walk distance (+62 ± 18 m vs. -15 ± 20 m, p < 0.01) and provided a superior composite clinical score encompassing cardiac parameters in tandem with New York Heart Association functional class, quality of life, physical performance, hospitalization, and event-free survival. CONCLUSIONS: The C-CURE trial implements the paradigm of lineage guidance in cell therapy. Cardiopoietic stem cell therapy was found feasible and safe with signs of benefit in chronic heart failure, meriting definitive clinical evaluation. (C-Cure Clinical Trial; NCT00810238). PMID: 23583246 [PubMed - indexed for MEDLINE]

Current status of cell-based therapy for heart failure

Curr Heart Fail Rep. 2013 Jun;10(2):165-76
Authors: Jakob P, Landmesser U

In the last two decades, morbidity and mortality of patients with chronic heart failure could be further reduced by improved pharmacological and cardiac device therapies. However, despite these advances, there is a substantial unmet need for novel therapies, ideally specifically addressing repair and regeneration of the damaged or lost myocardium and its vasculature, given the limited endogenous potential for renewal of cardiomyocytes in adults. In this respect, cardiac cell-based therapies have gained substantial attention and have entered clinical feasibility and safety studies a decade ago. Different cell-types have been used, including bone marrow-derived mononuclear cells, bone marrow-derived mesenchymal stem cells, mobilized CD34+ cells, and more recently cardiac-derived c-kit+ stem cells and cardiosphere-derived cells. Some of these studies have suggested a potential of cell-based therapies to reduce cardiac scar size and to improve cardiac function in patients with ischemic cardiomyopathy. While first clinical trials examining the impact of cardiac cell-based therapy on clinical outcome have now been initiated, improved understanding of underlying mechanisms of action of cell-based therapies may lead to strategies for optimization of the cardiac repair potential of the applied cells. In experimental studies, direct in vivo reprogramming of cardiac fibroblasts towards cardiomyocytes, and microRNA-based promotion of cardiomyocyte proliferation and cardiac repair have recently been reported that may represent novel therapeutic approaches for cardiac regeneration that would not need cell-administration but rather directly stimulate endogenous cardiac regeneration. This review will focus mainly on recently completed clinical trials (within the last 2 years) investigating cardiac cell-based therapies and the current status of experimental studies for cardiac cell-based repair and regeneration with a potential for later translation into clinical studies in the future.

PMID: 23504442 [PubMed – indexed for MEDLINE]

CT for evaluation of myocardial cell therapy in heart failure: a comparison with CMR imaging

JACC Cardiovasc Imaging. 2011 Dec;4(12):1284-93
Authors: Schuleri KH, Centola M, Choi SH, Evers KS, Dawoud F, George RT, Lima JA, Lardo AC

OBJECTIVES: The aim of this study was to use multidetector computed tomography (MDCT) to assess therapeutic effects of myocardial regenerative cell therapies.
BACKGROUND: Cell transplantation is being widely investigated as a potential therapy in heart failure. Noninvasive imaging techniques are frequently used to investigate therapeutic effects of cell therapies in the preclinical and clinical settings. Previous studies have shown that cardiac MDCT can accurately quantify myocardial scar tissue and determine left ventricular (LV) volumes and ejection fraction (LVEF).

METHODS: Twenty-two minipigs were randomized to intramyocardial injection of phosphate-buffered saline (placebo, n = 9) or 200 million mesenchymal stem cells (MSC, n = 13) 12 weeks after myocardial infarction (MI). Cardiac magnetic resonance and MDCT acquisitions were performed before randomization (12 weeks after MI induction) and at the study endpoint 24 weeks after MI induction. None of the animals received medication to control the intrinsic heart rate during first-pass acquisitions for assessment of LV volumes and LVEF. Delayed-enhancement MDCT imaging was performed 10 min after contrast delivery. Two blinded observers analyzed MDCT acquisitions.

RESULTS: MDCT demonstrated that MSC therapy resulted in a reduction of infarct size from 14.3 ± 1.2% to 10.3 ± 1.5% of LV mass (p = 0.005), whereas infarct size increased in nontreated animals (from 13.8 ± 1.3% to 16.5 ± 1.5%; p = 0.02) (placebo vs. MSC; p = 0.003). Both observers had excellent agreement for infarct size (r = 0.96; p < 0.001). LVEF increased from 32.6 ± 2.2% to 36.9 ± 2.7% in MSC-treated animals (p = 0.03) and decreased in placebo animals (from 33.3 ± 1.4% to 29.1 ± 1.5%; p = 0.01; at week 24: placebo vs. MSC; p = 0.02). Infarct size, end-diastolic LV volume, and LVEF assessed by MDCT compared favorably with those assessed by cardiac magnetic resonance acquisitions (r = 0.70, r = 0.82, and r = 0.902, respectively; p < 0.001). CONCLUSIONS: This study demonstrated that cardiac MDCT can be used to evaluate infarct size, LV volumes, and LVEF after intramyocardial-delivered MSC therapy. These findings support the use of cardiac MDCT in preclinical and clinical studies for novel myocardial therapies. PMID: 22172785 [PubMed - indexed for MEDLINE]

Circulating stem cell vary with NYHA stage in heart failure patients

J Cell Mol Med. 2011 Aug;15(8):1726-36
Authors: Fortini C, Toffoletto B, Fucili A, Puppato E, Olivares A, Beltrami AP, Fiorelli V, Bergamin N, Cesselli D, Morelli C, Francolini G, Ferrari R, Beltrami CA

We have investigated the blood levels of sub-classes of stem cells (SCs) [mesenchymal stem cells (MSCs), haematopoietic stem cells (HSCs), endothelial progenitor cells/circulating endothelial cells (EPCs/CECs) and tissue-committed stem cells (TCSCs)] in heart failure (HF) patients at different stage of pathology and correlated it with plasmatic levels of proangiogenic cytokines. Peripheral blood level of SCs were analysed in 97 HF patients (24 in NYHA class I, 41 in class II, 17 in class III and 15 in class IV) and in 23 healthy controls. Plasmatic levels of PDGF-BB, bFGF, HGF, vascular endothelial growth factor (VEGF), SDF-1α, TNF-α and NTproBNP were also measured. Compared with healthy individuals, MSC, and in particular the sub-classes CD45(-) CD34(-) CD90(+) , CD45(-) CD34(-) CD105(+) and CD45(-) CD34(-) CXCR4(+) were significantly enhanced in NYHA class IV patients (16.8-, 6.4- and 2.7-fold, respectively). Level of CD45(-) CD34(-) CD90(+) CXCR4(+) cells progressively increased from class II to class IV (fold increases compared with controls: 8.5, 12 and 21.5, respectively). A significant involvement of CXCR4(+) subpopulation of HSC (CD45(+) CD34(+) CD90(+) CXCR4(+) , 1.4 versus 13.3 cells/μl in controls and NYHA class III patients, respectively) and TCSC (CD45(-) CD34(+) CXCR4(+) , 1.5 cells/ μl in controls versus 12.4 and 28.6 cells/μl in NYHA classes II and IV, respectively) were also observed. All tested cytokines were enhanced in HF patients. In particular, for PDGF-BB and SDF-1α we studied specific ligand/receptors pairs. Interestingly, the first one positively correlated with TCSCs expressing PDGFR (r = 0.52, P = 0.001), whereas the second one correlated with TCSCs (r = 0.34, P = 0.005) and with MSCs CD90(+) expressing CXCR4 (r = 0.39, P = 0.001). HF is characterized by the increase in the circulating levels of different MSC, HSC, EPC and TCSC subsets. Both the entity and kinetic of this process varied in distinct cell subsets. Specifically, differently from HSCs and EPCs/CECs, MSCs and TCSCs significantly increased with the progression of the disease, suggesting a possible distinct role of these cells in the pathophysiology of HF.

PMID: 21029373 [PubMed – indexed for MEDLINE]

Heart failure therapy mediated by the trophic activities of bone marrow mesenchymal stem cells: a noninvasive therapeutic regimen

Am J Physiol Heart Circ Physiol. 2009 Jun;296(6):H1888-97
Authors: Shabbir A, Zisa D, Suzuki G, Lee T

Heart failure carries a poor prognosis with few treatment options. While myocardial stem cell therapeutic trials have traditionally relied on intracoronary infusion or intramyocardial injection routes, these cell delivery methods are invasive and can introduce harmful scar tissue, arrhythmia, calcification, or microinfarction in the heart. Given that patients with heart failure are at an increased surgical risk, the development of a noninvasive stem cell therapeutic approach is logistically appealing. Taking advantage of the trophic effects of bone marrow mesenchymal stem cells (MSCs) and using a hamster heart failure model, the present study demonstrates a novel noninvasive therapeutic regimen via the direct delivery of MSCs into the skeletal muscle bed. Intramuscularly injected MSCs and MSC-conditioned medium each significantly improved ventricular function 1 mo after MSC administration. MSCs at 4 million cells/animal increased fractional shortening by approximately 40%, enhanced capillary and myocyte nuclear density by approximately 30% and approximately 80%, attenuated apoptosis by approximately 60%, and reduced fibrosis by approximately 50%. Myocyte regeneration was evidenced by an approximately twofold increase in the expression of cell cycle markers (Ki67 and phosphohistone H(3)) and an approximately 13% reduction in mean myocyte diameter. Increased circulating levels of hepatocyte growth factor (HGF), leukemia inhibitory factor, and macrophage colony-stimulating factor were associated with the mobilization of c-Kit-positive, CD31-positive, and CD133-positive progenitor cells and a subsequent increase in myocardial c-Kit-positive cells. Trophic effects of MSCs further activated the expression of HGF, IGF-II, and VEGF in the myocardium. The work highlights a cardiac repair mechanism mediated by trophic cross-talks among the injected MSCs, bone marrow, and heart that can be explored for noninvasive stem cell therapy.

PMID: 19395555 [PubMed – indexed for MEDLINE]

Regenerative medicine for heart failure

Nihon Rinsho. 2008 May;66(5):978-83
Authors: Nagaya N, Kitamura S

Heart failure is one of the most important cardiovascular health problems throughout the world and has high mortality, and there is a need to develop more effective therapeutic strategies to replace such specialized treatment as mechanical circulatory support and cardiac transplantation. Mesenchymal stem cells (MSC) are multipotent plastic-adherent cells obtained from bone marrow, adipose tissue, and other tissues and can be easily expanded in culture. MSC exert their role in cardiac regeneration not only by differentiating into specific cell types such as cardiomyocytes and vascular endothelial cells but also through paracrine effects via secretion of angiogenic and antiapoptotic factors. On the basis of information obtained from basic and translational research, several clinical trials have recently been started to evaluate the safety and efficacy of autologous MSC for heart failure.

PMID: 18464520 [PubMed – indexed for MEDLINE]

Stem cell therapy for heart failure: the science and current progress

Future Cardiol. 2008 May;4(3):285-98
Authors: Phillips MI, Tang YL, Pinkernell K

Cell therapy, particularly with stem cells, has created great interest as a solution to the fact that there are limited treatments for postischemic heart disease and none that can regenerate damaged heart cells to strengthen cardiac performance. From the first efforts with myoblasts to recent clinical trials with bone marrow-derived stem cells, early reports of cell therapy suggest improvement in cardiac performance as well as other clinical end points. Based on these exciting but tentative results, other stem cell types are being explored for their particular advantages as a source of adult stem cells. Autologous adipose-derived stem cells are multilinear and can be obtained relatively easily in large quantities from patients; cardiac-derived stem cells are highly appropriate for engraftment in their natural niche, the heart. Human umbilical cord blood cells are potentially forever young and allogenic adult mesenchymal stem cells appear not to evoke the graft versus host reaction. Human embryonic stem cells are effective and can be scaled up for supply purposes. The recent discovery of induced pluripotentcy in human adult stem cells, with only three transcription factor genes, opens a whole new approach to making autologous human pluripotent stem cells from skin or other available tissues. Despite the excitement, stem cells may have to be genetically modified with heme oxygenase, Akt or other genes to survive transplantation in a hypoxic environment. Homing factors and hormones secreted from transplanted stem cells may be more important than cells if they provide the necessary stimulus to trigger cardiac regrowth to replace scar tissue. As we await results from larger and more prolonged clinical trials, the science of stem cell therapy in cardiac disease keeps progressing.

PMID: 19804333 [PubMed]

Bone marrow-derived mesenchymal stem cells for treatment of heart failure: is it all paracrine actions and immunomodulation?

J Cardiovasc Med (Hagerstown). 2008 Feb;9(2):122-8
Authors: Mishra PK

Despite significant advances in medical and surgical management of heart failure, mostly of ischaemic origin, the mortality and morbidity associated with it continue to be high. Pluripotent stem cells are being evaluated for treatment of heart failure. Bone marrow-derived mesenchymal stem cells (MSCs) have been extensively studied. Emerging evidence suggests that locally delivered MSCs can lead to an improvement in ventricular function, but the cellular and molecular mechanisms involved remain unclear. Myocardial regeneration, as proposed by many researchers as the underlying mechanism, has failed to convince the scientific community. Recently some authors have ascribed improvement in ventricular function to paracrine actions of MSCs.A lot has been written about the host immune response triggered by embryonic stem cells and the consequent need for immunosuppression. Not enough work has been done on immune interactions involving allogeneic bone marrow cells. Full potential of stem cell therapy can be realised only when we are able to use allogeneic cells. The potential use of MSCs in cellular therapy has recently prompted researchers to look into their interaction with the host immune response. MSCs have immunomodulatory properties. They cause suppression of proliferation of alloreactive T cells in a dose-dependent manner.Tissue injury causes inflammation and release of several chemokines, cytokines and growth factors. They can cause recruitment of bone marrow-derived MSCs to the injured area. We review the literature on paracrine actions and immune interactions of allogeneic MSCs.

PMID: 18192802 [PubMed – indexed for MEDLINE]

Mesenchymal stem cells for the treatment of heart failure

Int J Hematol. 2007 Jul;86(1):17-21
Authors: Ohnishi S, Ohgushi H, Kitamura S, Nagaya N

Heart failure is one of the most important cardiovascular health problems throughout the world and has high mortality, and there is a need to develop more effective therapeutic strategies to replace such specialized treatment as mechanical circulatory support and cardiac transplantation. Mesenchymal stem cells (MSC) are multipotent plastic-adherent cells obtained from bone marrow, adipose tissue, and other tissues and can be easily expanded in culture. The ability of MSC to differentiate into a variety of cells, including cardiomyocytes and vascular endothelial cells, make them an attractive therapeutic tool for heart failure. Recent in vitro and in vivo studies have revealed the underlying mechanisms of MSC in cardiac repair. MSC exert their role in cardiac regeneration not only by differentiating into specific cell types such as cardiomyocytes and vascular endothelial cells but also through paracrine effects via secretion of a variety of angiogenic, antiapoptotic, and mitogenic factors. Endogenous MSC as well as exogenously administered MSC have also been suggested to migrate and participate in cardiac repair. On the basis of information obtained from basic and translational research, several clinical trials have recently been started to evaluate the safety and efficacy of autologous MSC for heart failure.

PMID: 17675261 [PubMed – indexed for MEDLINE]

Prepare cells to repair the heart: mesenchymal stem cells for the treatment of heart failure

Am J Nephrol. 2007;27(3):301-7
Authors: Ohnishi S, Nagaya N

Heart failure is one of the most important cardiovascular diseases, with high mortality, and invasive treatment such as mechanical circulatory support and cardiac transplantation is sometimes required for severe heart failure. Therefore, the development of less invasive and more effective therapeutic strategies is desired. Cell therapy is attracting growing interest as a new approach for the treatment of heart failure. As a cell source, various kinds of stem/progenitor cells such as bone marrow cells, endothelial progenitor cells, mesenchymal stem cells (MSC) and cardiac stem cells have been investigated for their efficacy and safety. Especially, bone marrow-derived MSC possess multipotency and can be easily expanded in culture, and are thus an attractive therapeutic tool for heart failure. Recent studies have revealed the underlying mechanisms of MSC in cardiac repair: MSC not only differentiate into specific cell types such as cardiomyocytes and vascular endothelial cells, but also secrete a variety of paracrine angiogenic and cytoprotective factors. It has also been suggested that endogenous MSC as well as exogenously transplanted MSC migrate and participate in cardiac repair. Based on these findings, several clinical trials have just been started to evaluate the safety and efficacy of MSC for the treatment of heart failure.

PMID: 17460394 [PubMed – indexed for MEDLINE]

Effects of autologous stem cell transplantation on ventricular electrophysiology in doxorubicin-induced heart failure

Cell Biol Int. 2006 Jul;30(7):576-82
Authors: Chen M, Fan ZC, Liu XJ, Deng JL, Zhang L, Rao L, Yang Q, Huang DJ

To investigate whether stem cell transplantation affects ventricular electrophysiology in vivo, either autologous bone marrow mesenchymal stem cells or skeletal myoblast cells were transplanted via a catheter into a doxorubicin-treated failing heart. Four weeks after transplantation, electrophysiological investigation showed that transplantation of either cell type prolonged the local activation time and increased the activation time dispersion. In the stem cell transplantation groups, a positive correlation was demonstrated between activation time dispersion and the number of stem cell-derived cells in the pacing site. It is concluded that transplantation of either mesenchymal stem cells or skeletal myoblast cells might exacerbate abnormalities of local ventricular conduction in the doxorubicin-treated failing heart.

PMID: 16731012 [PubMed – indexed for MEDLINE]

New era of cardiac stem cell therapy in heart failure

Rinsho Byori. 2005 Jan;53(1):61-9
Authors: Oh H

Despite of plethora of reports on stem cell transplantation leading to neovascularization in infarct models, whether sustaining clinical benefit in post-myocardial infarction patients is manifested by myocyte repair remains unclear. Cardiac muscle regeneration in adult heart is thought to occur through the mobilization and differentiation of mesenchymal stem cells in bone marrow origin, however, recent studies have suggested that substantial cardiac stem cells may exist in the heart itself, repopulating the damaged cardiac muscle during injury or aging processes. The implications of cardiac stem cells-based myocyte plasticity have recently begun to define in human heart, neither arisen from bone marrow nor circulating precursors. Introduction of cardiac stem cells may improve myocardial function, but several hurdles exist and should be coaxed far beyond the clinical application of cardiac regenerative therapies. On-going investigations may lead to the discovery of mediators of cardiac stem cells migration, proliferation and differentiation that, in turn, might result in the mending of the broken heart after injury.

PMID: 15724492 [PubMed – indexed for MEDLINE]