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Adult Stem Cell Therapy for Injured Solid-Organ Tissue (with Emphasis on Cardiac Tissue Repair)
Martin K rbling
The Open Conference Proceedings Journal , 2010, DOI: 10.2174/2210289201001010183]
Abstract: Adult hematopoietic tissue-derived stem cells are primarily used for hematopoietic reconstitution in patients with malignant lympho-hematopoietic disorders undergoing stem cell transplantation. Their therapeutic use for solidorgan tissue repair such as cardiac tissue is a novel treatment strategy. Besides hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs) and even solid-organ tissue resident stem cells (e.g. cardiac stem cells [CSC]) are known to contribute to solid-organ tissue repair. Stem cell delivery for cardiac tissue repair is by transvascular or intramyocardial injection. Myocardial tissue engineering takes advantage of biocompatible materials as stem cell carriers (scaffolds). Stem cell concentration at the site of tissue injury and engineering the stem cell microenvironment are additional components that determine treatment outcome. Mechanisms that explain how stem cells generate solid-organ specific cells include nuclear re-programming (transdifferentiation), cell fusion, and paracrine secretion of transplanted cells (e.g., MSCs). One preferred therapeutic concept is the stepwise induction of neovascularization followed by activation of the solid-organ resident stem cell pool. Cardiac tissue repair in patients with acute myocardial infarction is currently at the forefront of clinical stem cell treatment research. The outcome of major clinical trials will be discussed.
The Role of Antioxidation and Immunomodulation in Postnatal Multipotent Stem Cell-Mediated Cardiac Repair  [PDF]
Arman Saparov,Chien-Wen Chen,Sarah A. Beckman,Yadong Wang,Johnny Huard
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms140816258
Abstract: Oxidative stress and inflammation play major roles in the pathogenesis of coronary heart disease including myocardial infarction (MI). The pathological progression following MI is very complex and involves a number of cell populations including cells localized within the heart, as well as cells recruited from the circulation and other tissues that participate in inflammatory and reparative processes. These cells, with their secretory factors, have pleiotropic effects that depend on the stage of inflammation and regeneration. Excessive inflammation leads to enlargement of the infarction site, pathological remodeling and eventually, heart dysfunction. Stem cell therapy represents a unique and innovative approach to ameliorate oxidative stress and inflammation caused by ischemic heart disease. Consequently, it is crucial to understand the crosstalk between stem cells and other cells involved in post-MI cardiac tissue repair, especially immune cells, in order to harness the beneficial effects of the immune response following MI and further improve stem cell-mediated cardiac regeneration. This paper reviews the recent findings on the role of antioxidation and immunomodulation in postnatal multipotent stem cell-mediated cardiac repair following ischemic heart disease, particularly acute MI and focuses specifically on mesenchymal, muscle and blood-vessel-derived stem cells due to their antioxidant and immunomodulatory properties.
Role of paracrine factors in stem and progenitor cell mediated cardiac repair and tissue fibrosis
Jana S Burchfield, Stefanie Dimmeler
Fibrogenesis & Tissue Repair , 2008, DOI: 10.1186/1755-1536-1-4
Abstract: Although coronary artery disease accounts for two-thirds of heart failure cases in the United States [1], other causes leading to heart failure are due to non-ischemic events and include myocarditis, hypertension, diabetes, arrhythmias, valvular disease, hypothyroidism, and drug-induced cardiotoxicity. The molecular and cellular mechanisms mediating heart failure have been the focus of numerous research efforts, and include cardiac myocyte apoptosis and necrosis, cardiac myocyte hypertrophy, interstitial fibrosis, decreased contractility, inflammation, oxidative stress, and impaired neovascularization. Pharmacological therapies for the treatment of heart failure have traditionally targeted pump function and quality of life for end-stage heart failure patients, and although several medications are available to limit the progression of the disease, the current therapies or interventional procedures do not lead to replacement of tissue and, thus, do not stop or reverse progression of adverse left ventricular (LV) remodeling in all patients [2,3]. The use of stem cell-based therapy is becoming increasingly recognized as having the potential to salvage damaged myocardium and to promote endogenous repair of cardiac tissue [4-6]. Although the available data in this area are highly debatable, the potential of stem cell-based therapy for the treatment of heart failure remains an alternative option.Stem cells are defined as cells that have the capacity to self renew, multipotency/pluriopotency, and clonality, and are divided into embryonic stem cells and adult stem cells. Although embryonic stem cells may have more potential for cardiac differentiation and thus replacement of damaged myocardium, few studies have focused on paracrine factors released from these cells that may be involved in mediating cardiac repair. Therefore, this review will focus on adult stem or adult progenitor cells, since numerous studies suggest that paracrine factors released from these cells may comp
Cardiac Differentiation of Pluripotent Stem Cells  [PDF]
Kristiina Rajala,Mari Pekkanen-Mattila,Katriina Aalto-Set?l?
Stem Cells International , 2011, DOI: 10.4061/2011/383709
Abstract: The ability of human pluripotent stem cells to differentiate towards the cardiac lineage has attracted significant interest, initially with a strong focus on regenerative medicine. The ultimate goal to repair the heart by cardiomyocyte replacement has, however, proven challenging. Human cardiac differentiation has been difficult to control, but methods are improving, and the process, to a certain extent, can be manipulated and directed. The stem cell-derived cardiomyocytes described to date exhibit rather immature functional and structural characteristics compared to adult cardiomyocytes. Thus, a future challenge will be to develop strategies to reach a higher degree of cardiomyocyte maturation in vitro, to isolate cardiomyocytes from the heterogeneous pool of differentiating cells, as well as to guide the differentiation into the desired subtype, that is, ventricular, atrial, and pacemaker cells. In this paper, we will discuss the strategies for the generation of cardiomyocytes from pluripotent stem cells and their characteristics, as well as highlight some applications for the cells. 1. Introduction Human cardiomyocytes can be isolated from heart biopsies, but the access to human heart tissue is very limited, and the procedure is complicated; it is difficult to obtain viable cell preparations in large quantities, and the cells obtained do not beat spontaneously. Thus, physiologically relevant in vitro models for human cardiomyocytes are currently limited. This has led in the creation of alternative models, such as isolation of cardiomyocytes from various newborn animals or production of genetically engineered cell lines overexpressing certain target proteins (e.g., ion channels) [1]. All of these models, however, share significant limitations with respect to their basic physiological differences compared to human cardiomyocytes as well as high costs and ethical questions. A number of different human tissues have been proposed as the source of stem cells able to generate new cardiomyocytes (e.g., fetal cardiomyocytes, adult cardiac progenitor cells, skeletal myoblasts, bone marrow-derived stem cells, adipose-derived stem cells, umbilical cord-derived stem cells, and pluripotent stem cells) [2]. The cardiac differentiation potential of adult, multipotent, stem cells found in fetal and adult tissues, however, is controversial [3, 4]. This has been attributed to the limited plasticity of adult stem cells, which precludes their differentiation into functional cardiomyocytes. The only adult stem cells that clearly have the potential to differentiate into
The Relative Contribution of Paracine Effect versus Direct Differentiation on Adipose-Derived Stem Cell Transplantation Mediated Cardiac Repair  [PDF]
Dezhong Yang, Wei Wang, Liangpeng Li, Yulan Peng, Peng Chen, Haiyun Huang, Yanli Guo, Xuewei Xia, Yuanyuan Wang, Hongyong Wang, Wei Eric Wang, Chunyu Zeng
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0059020
Abstract: Background Recent studies have demonstrated that transplantation of adipose-derived stem cell (ADSC) can improve cardiac function in animal models of myocardial infarction (MI). However, the mechanisms underlying the beneficial effect are not fully understood. In this study, we characterized the paracrine effect of transplanted ADSC and investigated its relative importance versus direct differentiation in ADSC transplantation mediated cardiac repair. Methodology/Principal Findings MI was experimentally induced in mice by ligation of the left anterior descending coronary artery. Either human ADSC, conditioned medium (CM) collected from the same amount of ADSC or control medium was injected into the peri-infarct region immediately after MI. Compared with the control group, both ADSC and ADSC-CM significantly reduced myocardial infarct size and improved cardiac function. The therapeutic efficacy of ADSC was moderately superior to ADSC-CM. ADSC-CM significantly reduced cardiomyocyte apoptosis in the infarct border zone, to a similar degree with ADSC treatment. ADSC enhanced angiogenesis in the infarct border zone, but to a stronger degree than that seen in the ADSC-CM treatment. ADSC was able to differentiate to endothelial cell and smooth muscle cell in post-MI heart; these ADSC-derived vascular cells amount to about 9% of the enhanced angiogenesis. No cardiomyocyte differentiated from ADSC was found. Conclusions ADSC-CM is sufficient to improve cardiac function of infarcted hearts. The therapeutic function of ADSC transplantation is mainly induced by paracrine-mediated cardioprotection and angiogenesis, while ADSC differentiation contributes a minor benefit by being involved in angiogenesis. Highlights 1 ADSC-CM is sufficient to exert a therapeutic potential. 2. ADSC was able to differentiate to vascular cells but not cardiomyocyte. 3. ADSC derived vascular cells amount to about 9% of the enhanced angiogenesis. 4. Paracrine effect is the major mechanism of ADSC therapeutic function for MI.
Emergence of rationally designed therapeutic strategies for breast cancer targeting DNA repair mechanisms
Bryan P Rowe, Peter M Glazer
Breast Cancer Research , 2010, DOI: 10.1186/bcr2566
Abstract: Mammalian cells exist under constant genotoxic stress from both endogenous and exogenous sources. Replication errors, chemical decay of bases, and reactive oxygen species generated during metabolism all contribute to DNA damage from within the cell while UV light, ionizing radiation (IR), and chemical exposures assault the cell's DNA from outside [1]. To mitigate damage to DNA, a number of mechanisms have evolved to repair a variety of lesions.Several processes repair single-stranded DNA damage by using the undamaged strand as a template. Base excision repair (BER) uses DNA glycosylases to recognize and remove non-bulky damaged bases [2]. BER has been reviewed in detail previously [3]. Nucleotide excision repair (NER) removes bulky distortion in the DNA helix and is crucial for the processing of UV-induced damage and chemical adducts [4]. The mismatch repair system (MMR) removes base-base mismatches and small insertion or deletion mismatches that can occur during replication [5].Double-strand breaks (DSBs) are repaired by either non-homologous end joining (NHEJ) or homologous recombination (HR). NHEJ is more prone to deletions and other alterations since the fragmented ends are processed and re-ligated with no available template to ensure accuracy. HR is essentially an error-proof mechanism that occurs during the S or G2 phases of the cell cycle, when the sister chromatid can provide a template for accurate repair [1]. HR is also involved in repairing lesions that disrupt the replication fork. A more complete review of DSB repair is available elsewhere [6].Translesion synthesis (TLS) is a DNA tolerance process that allows DNA replication to bypass certain lesions (for example, thymine dimers and abasic sites) by substituting specialized translesion polymerases that function in the presence of damaged nucleotides. TLS is involved in the removal of interstrand crosslinks (ICLs) [7].All of the above processes are crucial for a cell's ability to maintain genomic fidelit
New directions in cardiac stem cell therapy: An update for clinicians  [PDF]
Sarabjeet Singh, Mohammad Kashif, Neil Bhambi, Rajendra R. Makkar, James S. Forrester
World Journal of Cardiovascular Diseases (WJCD) , 2012, DOI: 10.4236/wjcd.2012.23032
Abstract: The emergence of cardiac stem cell therapy can be traced to late 2001, when studies in small animal models of myocardial infarction suggested that stem cells could engraft, proliferate, and regenerate myo-cardium. Subsequent animal laboratory studies showed improved cardiac function, perfusion and survival compared to controls (Figure 1). Within two years, the first clinical trials of stem cell therapy began to appear, and we now have several trials of intracoronary infusion of bone marrow cells with more than one year follow-up. Although this clinical therapy has proven to be safe, the magnitude of improvement in objective measures like ejection fraction has been modest, and the therapy has not entered clinical practice. In the absence of a large prospective randomized trial, the field has moved back to the laboratory. This manuscript aims to provide clinicians with a broad overview of this complex field by briefly reviewing the existing status of clinical myocardial regeneration therapy, then describing selected examples from the laboratory research approaches that may provide a platform for new and potentially increasingly effective clinical strategies.
Failing heart; remodel, replace or repair?  [cached]
Ahmet Ruchan Akar,Serkan Durdu,Gunseli Cubukcuoglu Deniz,Alp Aslan
Anadolu Kardiyoloji Dergisi , 2008,
Abstract: In the era of proton-antiproton collisions, stem cell field has emerged as the newly recognized protons of regenerative medicine. Great interest and enthusiasm were depending on their behavioral difference such as self-renewal, clonogenicity and differentiation into functional progeny that may become vehicles for regenerative medicine. Although progress has evolved dramatically strategies using stem-cell-driven cardiac regeneration involve extremely complex and dynamic molecular mechanisms. Cell death in transplanted heart continues to be a significant issue. Every step from stem cell homing, and migration to retention, engraftment, survival and differentiation in cardiac cytotherapy deserves intense research for optimum results. Furthermore, regeneration of contractile tissue remains controversial for human studies and careful interpretation is warranted for modest benefit in clinical trials. Currently, the only realistic approach to replace the damaged cardiomyocytes is cardiac transplantation for patients with end-stage heart failure. Ultimately, the giant footsteps in cell-based cardiac repair can only be achieved by an enthusiastic but also skeptical teams adhering to good manufacturing practices. Better understanding of cell-fate decisions and functional properties in cardiac cytotherapy may change the erosion of initial enthusiasm and may open new prospects for cardiovascular medicine.
Current strategies for articular cartilage repair  [cached]
Redman S. N.,Oldfield S. F.,Archer C. W.
European Cells and Materials (ECM) , 2005,
Abstract: Defects of articular cartilage that do not penetrate to the subchondral bone fail to heal spontaneously. Defects that penetrate to the subchondral bone elicit an intrinsic repair response that yields a fibrocartilaginous repair tissue which is a poor substitute for hyaline articular cartilage. Many arthroscopic repair strategies employed utilise this intrinsic repair response to induce the formation of a repair tissue within the defect. The goal, however, is to produce a repair tissue that has the same functional and mechanical properties of hyaline articular cartilage. To this end, autologous osteochondral transfer can provide symptomatic relief. This technique involves the excision of healthy cartilage plugs from "non-load bearing" regions of the joint for implantation into the defect. Cell based transplantation methods currently involve the transplantation of expanded autologous chondrocytes to the defects to form a repair tissue. This technique again involves the excision of healthy cartilage from the joint for expansion. Current research is exploring the potential use of mesenchymal stem cells as a source for tissue engineering, as well as the combination of cells with biodegradable scaffolds. Although current repair strategies improve joint function, further research is required to prevent future degeneration of repair tissue.
Disrupted Signaling through the Fanconi Anemia Pathway Leads to Dysfunctional Hematopoietic Stem Cell Biology: Underlying Mechanisms and Potential Therapeutic Strategies  [PDF]
Anja Geiselhart,Amelie Lier,Dagmar Walter,Michael D. Milsom
Anemia , 2012, DOI: 10.1155/2012/265790
Abstract: Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. FA patients suffer to varying degrees from a heterogeneous range of developmental defects and, in addition, have an increased likelihood of developing cancer. Almost all FA patients develop a severe, progressive bone marrow failure syndrome, which impacts upon the production of all hematopoietic lineages and, hence, is thought to be driven by a defect at the level of the hematopoietic stem cell (HSC). This hypothesis would also correlate with the very high incidence of MDS and AML that is observed in FA patients. In this paper, we discuss the evidence that supports the role of dysfunctional HSC biology in driving the etiology of the disease. Furthermore, we consider the different model systems currently available to study the biology of cells defective in the FA signaling pathway and how they are informative in terms of identifying the physiologic mediators of HSC depletion and dissecting their putative mechanism of action. Finally, we ask whether the insights gained using such disease models can be translated into potential novel therapeutic strategies for the treatment of the hematologic disorders in FA patients. 1. Introduction Fanconi anemia (FA) is a rare, autosomal recessive and X-linked hereditary disorder, which is characterized by progressive bone marrow failure (BMF), congenital developmental defects, and an early onset of cancers such as leukemia and some solid tumors [1]. In general, the hematologic manifestations of FA remain the primary cause of morbidity and mortality, with patients suffering from a markedly increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In addition, FA patients are also predisposed towards various forms of solid tumor such as squamous cell carcinoma of the head and neck, esophagus, and gynecologic area [2, 3]. FA is a genetically heterogeneous disorder caused by inactivating mutations in genes that are thought to function in an epistatic signaling pathway. Loss of function of any of the FA family members results in inefficient repair of DNA damage and deregulation of signaling pathways controlling cell proliferation and apoptosis. To date, 15 genes associated with FA in patients have been identified and cloned: FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ/BACH1/BRIP1, FANCL/PHF9/POG, FANCM, FANCN/PALB2, FANCO/Rad51C [4], and FANCP/SLX4/BTBD12 (Table 1) [5–7]. The FA proteins appear to function in a common biochemical ubiquitin-phosphorylation network, the FA signaling pathway,
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