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Fibroblast and Immune Cell Cross Talk in Cardiac Repair
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Stelios Psarras, Georgina Xanthou
In accordance with the pronounced heterogeneity and plasticity observed in fibro-blasts, ECM is also dynamically changing following cardiac injury. Collagens I and III are deposited to maintain cardiac tissue homeostasis, protecting from rupture post-MI but sustaining detrimental fibrosis in the long term. Other components, such as the proteoglycan agrin, support cardiac regeneration by promoting cardiomyocyte proliferation in the neonatal murine heart. Indeed, local agrin administration post-MI suppressed inflammation and fibrosis and improved cardiac function in preclinical models (47). Paradoxically, collagen V, a minor collagen species of the basement membrane upregulated upon MI injury, diminishes the infarct size by regulating fibroblast mechanosensing signaling in an integrin-dependent manner (48). The importance of ECM was clearly demonstrated in experiments in which decellularized ECM derived from regeneration-prone neonatal mouse hearts and injected into adult hearts alleviated cardiac dysfunction and scar expansion post-MI (49).
The circulatory system and hormones
Published in Frank J. Dye, Human Life Before Birth, 2019
Cardiac organoids: During an ischemic (oxygen-deprived) event, although the adult human heart exhibits limited regenerative potential, it undergoes pathological changes in response to such injury. However, it is unknown if the immature human heart can undergo complete regeneration, even though cardiac regeneration has been documented in zebrafish and neonatal mouse hearts. Recently, researchers at the University of Queensland and the University of Melbourne, in Australia, using advances in pluripotent stem cell differentiation and tissue engineering, developed human cardiac organoids (hCOs). These organoids resemble fetal heart tissue and were used to ascertain the regenerative capacity of immature human heart tissue in response to injury, specifically cryoinjury with a dry ice probe. They discovered that the hCOs exhibited a regenerative response, with full recovery 2 weeks after such injury. This recovery occurred without pathological fibrosis or cardiomyocyte hypertrophy. It was noted that cardiomyocyte proliferation may have been responsible for the regenerative capacity of the hCOs. The researchers suggested that immature human heart tissue has an intrinsic capacity to regenerate.
Nanoparticles for Cardiovascular Medicine: Trends in Myocardial Infarction Therapy
Published in Harishkumar Madhyastha, Durgesh Nandini Chauhan, Nanopharmaceuticals in Regenerative Medicine, 2022
Gelatin (Gel) is a natural, versatile, polypeptide biopolymer; it is an appealing carrier material due to its low production cost, abundant supply, biodegradability, biocompatibility, and ease of modification through its many active groups (Elzoghby 2013; Azarmi et al. 2006). Gel is obtained from the hydrolysis of collagen and has shown strong potential as a drug carrier for controlled release (Bajpai and Choubey 2006). The different mechanical properties (thermal range, swelling) of Gel rely on its amphoteric interactions and degree of cross-linking density (Saxena et al. 2005). Fang et al. loaded gel nanoparticles with mollusc-derived 6-bromoindirubin-3-oxime (BIO) (Fang et al. 2015). BIO was shown to inhibit glycogen synthase kinase-3, induce cardiomyocyte and endothelial cell dedifferentiation, and lead to the promotion of mature cardiomyocyte proliferation (Tseng et al. 2006; Leri et al. 2014). In addition, Gel nanoparticles loaded with insulin-like growth factor 1 (IGF-1), a cytokine involved in cardiomyocyte growth and survival (Torella et al. 2004; Shafiq et al. 2018), were also synthesised. Codelivery by daily intramyocardial injection of BIO and IGF-1 to the MI area maintained nondetrimental levels of therapeutic agents and increased resident cardiac cells in rat MI models. BIO also promoted dedifferentiation and proliferation of terminally differentiated cardiomyocytes, as evidenced through cytoskeletal rearrangement and inhibited cardiac troponin-T expression (Tseng et al. 2006). Local delivery and sustained expression of IGF-1 increased angiogenesis and rescued cardiac function. Codelivery of BIO and IGF-1 significantly improved revascularisation, heart functional recovery, and supported the proliferation of resident cardiomyocytes (Fang et al. 2015). He et al. took advantage of the facile adaptability of gel by loading polypyrrole, a conductive and electrically stable polymer, into methyl acrylic anhydride-modified gel (GelMA) nanoparticles (He et al. 2018). This modification enabled the facile dopamine cross-linking of nanoparticles into a mussel-inspired GelMA/polycaprolactone hydrogel delivery scaffolds or heart patches. GelMA nanoparticles shaped and neutralised toxicity of polypyrrole during oxidative polymerisation, thus conveying preferable biocompatibility at high concentrations. The high conductivity of heart patches promoted cardiomyocyte function, enhanced revascularisation, and reduced inflammatory infiltration into the MI area – both in the presence and absence of exogenous cardiomyocytes.
NRG1 PLGA MP locally induce macrophage polarisation toward a regenerative phenotype in the heart after acute myocardial infarction
Published in Journal of Drug Targeting, 2019
S. Pascual-Gil, G. Abizanda, E. Iglesias, E. Garbayo, F. Prósper, M. J. Blanco-Prieto
Another factor that is mandatory to consider regarding MP administration is when to administer the treatment. On one hand, piMac are predominant during the first days after AMI and aiMac exert their role afterwards [26]. On the other hand, each type of macrophage may respond in a different way to NRG1 PLGA MP. Moreover, one of the main NRG1 therapeutic actions is the promotion of cardiomyocyte proliferation [33]. After AMI, although the majority of the cardiomyocytes’ death occurs during ischaemia, necrosis and apoptosis processes can continue for up to 3 days [34]. This creates a therapeutic window for arresting cell death using NRG1. In addition, patients promptly treated after the onset of symptoms of AMI will have the best outcomes [35]. In this study we evaluated how NRG1 PLGA MP administration could diversely affect heart inflammatory response depending on the time of treatment administration (15 min, 24, 72 and 168 h after AMI induction). We selected these time points because they are clinically relevant and cover the therapeutic window of NRG1. Surprisingly, we demonstrated that inflammatory response was not modified by the time at which the treatment was administered (Figure 4(B)), and NRG1 PLGA MP treated animals showed a similar macrophage polarisation to control animals regardless of the time of treatment administration. Clinically, this means that PLGA MP could be administered whenever needed in order to meet the therapeutic window of the encapsulated GF, without undesired inflammatory issues.
Bone marrow- and adipose tissue-derived mesenchymal stem cells from donors with coronary artery disease; growth, yield, gene expression and the effect of oxygen concentration
Published in Scandinavian Journal of Clinical and Laboratory Investigation, 2020
Emma Adolfsson, Gisela Helenius, Örjan Friberg, Ninos Samano, Ole Frøbert, Karin Johansson
Cell therapy aiming at myocardial regeneration and repair has potential to counteract loss of function after coronary artery disease and improve quality of life. One strategy for cardiovascular cell therapy is to stimulate the endogenous regenerative mechanisms using mesenchymal stem cells (MSCs). These heterogeneous adult stem cells are located in almost all tissues in the body and can be derived from peripheral blood, adipose tissue or bone marrow in adults and umbilical cord, amnion, cord blood or placenta from neonatal tissues [2]. Administration of MSCs into myocardium results in release of paracrine growth factors. These growth factors promote angiogenesis, inhibit apoptosis, ameliorate fibrosis through remodelling of the extracellular matrix, reduce inflammatory responses and enhance cardiomyocyte proliferation and/or differentiation [3]. Although, the exact mode of action has not been determined, administering MSCs into the myocardium is a safe treatment for chronic heart failure [4,5]. However, one of the challenges for cardiovascular cell therapy is to select the optimal subtype of MSCs. MSCs are a heterogeneous population of cells, and although, they share the characteristics that define them as MSCs [6], MSCs from different locations differ in other aspects [7,8]. In vivo, MSCs are located in perivascular niches where oxygen tension is low. In bone marrow, oxygen concentration is 1–6% and in adipose tissue concentration is 2–8% [9]. Low oxygen tension, i.e. O2 concentration below ambient O2, is crucial for proliferation, plasticity, genetic stability and maintaining the undifferentiated state of MSCs [10–12].
Newt cells secrete extracellular vesicles with therapeutic bioactivity in mammalian cardiomyocytes
Published in Journal of Extracellular Vesicles, 2018
Ryan C. Middleton, Russell G. Rogers, Geoffrey De Couto, Eleni Tseliou, Kristin Luther, Ronald Holewinski, Daniel Soetkamp, Jennifer E. Van Eyk, Travis J. Antes, Eduardo Marbán
To investigate the signalling pathways underlying cytoprotection conferred by A1-CM, we performed RNA-Seq whole cell transcriptomic analysis on NRVMs treated with A1-CM and controls. IPA (Qiagen), focused on pathways involved in cardiomyocyte proliferation and cardioprotection, revealed a significant increase in the PI3K/AKT signalling pathway (Z = +2.12). The Fisher exact test statistical approach (z-score) was employed to determine likely activation states of upstream regulators based on comparison with a model that assigns random regulation directions. A significance threshold was set at the commonly used values of ±1.3. Activation of the PI3K/AKT pathway, which is known to promote both cardiomyocyte proliferation and survival (Figure 3(a)) [38], peaked at 12 h and subsided 24 h after A1-CM exposure (Figure 3(b)). Conversely, there was a significant reduction in the expression of genes associated with cellular differentiation, including bone morphogenetic protein (BMP) signalling (Z = −1.13) and TGF-β signalling (Z = −1.89) pathways [39]. Also shown are the p-values for each of the identified signalling pathways as well as the ratio of genes significantly up- or down-regulated relative to all genes associated with that pathway. P-values in this context indicate the probability of random overlap between our gene data set and genes that are known to be regulated by specific transcriptional regulators. From the table in Figure 3(c), we observed that the PI3K/AKT and VEGF signalling pathways reach significance for up- or down-regulation. Based on this analysis, we chose to further evaluate the expression of genes involved in AKT signalling.