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The Impact of mRNA Technology in Regenerative Therapy: Lessons for Oral Tissue Regeneration

Terapia celular - Mié, 03/23/2022 - 10:00

J Dent Res. 2022 Mar 23:220345221084205. doi: 10.1177/00220345221084205. Online ahead of print.

ABSTRACT

Oral tissue regeneration following chronic diseases and injuries is limited by the natural endogenous wound-healing process. Current regenerative approaches implement exogenous systems, including stem cells, scaffolds, growth factors, and plasmid DNA/viral vectors, that induce variable clinical outcomes. An innovative approach that is safe, effective, and inexpensive is needed. The lipid nanoparticle-encapsulated nucleoside-modified messenger RNA (mRNA) platform has proven to be a successful vaccine modality against coronavirus disease 2019, demonstrating safety and high efficacy in humans. The same fundamental technology platform could be applied to facilitate the development of mRNA-based regenerative therapy. While the platform has not yet been studied in the field of oral tissue regeneration, mRNA therapeutics encoding growth factors have been evaluated and demonstrated promising findings in various models of soft and hard tissue regeneration such as myocardial infarction, diabetic wound healing, and calvarial and femoral bone defects. Because restoration of both soft and hard tissues is crucial to oral tissue physiology, this new therapeutic modality may help to overcome challenges associated with the reconstruction of the unique and complex architecture of oral tissues. This review discusses mRNA therapeutics with an emphasis on findings and lessons in different regenerative animal models, and it speculates how we can apply mRNA-based platforms for oral tissue regeneration.

PMID:35319289 | DOI:10.1177/00220345221084205

Categorías: Terapia celular

Human Growth Factor/Immunoglobulin Complexes for Treatment of Myocardial Ischemia-Reperfusion Injury

Terapia celular - Jue, 03/17/2022 - 10:00

Front Bioeng Biotechnol. 2022 Feb 28;10:749787. doi: 10.3389/fbioe.2022.749787. eCollection 2022.

ABSTRACT

Hepatocyte Growth Factor (HGF) and Fibroblast Growth Factor 2 (FGF2) are receptor tyrosine kinase agonists that promote cell survival after tissue injury and angiogenesis, cell proliferation and migration during tissue repair and regeneration. Both ligands have potential as systemic treatments for ischemia-reperfusion injury, however clinical use of HGF and FGF2 has been limited by poor pharmacokinetic profiles, i.e., their susceptibility to serum proteases, rapid clearance and short half-lives. Previously, we reported vaso- and cardioprotective protein complexes formed between HGF and polyclonal, non-specific immunoglobulin (IgG) with therapeutic efficacy in a rat model of myocardial ischemia with reperfusion (MI/R). Here, using a pre-clinical porcine MI/R model, we demonstrate human HGF/IgG complexes provide significant myocardial salvage, reduce infarct size, and are detectable in myocardial tissue 24 h after intracoronary injection. Furthermore, we show that multiple daily infusions of HGF/IgG complexes after MI do not lead to production of HGF-specific auto-antibodies, an important concern for administered biologic drugs. In experiments to identify other growth factors that non-covalently interact with IgG, we found that human FGF2 associates with IgG. Similar to human HGF/IgG complexes, FGF2/IgG complexes protected primary human cardiac endothelial cells under simulated ischemia (1% oxygen and nutrient deprivation) for 48-72 h. Molecular modeling studies suggested that FGF2 and HGF both interact with the Fc domain of IgG. Also, we tested whether an Fc-fusion protein would bind FGF2 to form complexes. By native gel electrophoretic assays and biochemical pulldowns, we found that Jagged1, a Notch1 ligand that controls stem cell self-renewal and tissue regeneration, bound FGF2 when presented as a Jagged1- Fc fusion protein. Our results suggest that human growth factor/IgG and FGF2/Fc- fusion complexes have potential to provide a biologics platform to treat myocardial ischemia-reperfusion and other forms of tissue injury.

PMID:35295649 | PMC:PMC8918831 | DOI:10.3389/fbioe.2022.749787

Categorías: Terapia celular

Cardiac Cell Therapy with Pluripotent Stem Cell-Derived Cardiomyocytes: What Has Been Done and What Remains to Do?

Terapia celular - Vie, 03/11/2022 - 11:00

Curr Cardiol Rep. 2022 Mar 11. doi: 10.1007/s11886-022-01666-9. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Exciting pre-clinical data presents pluripotent stem cell-derived cardiomyocytes (PSC-CM) as a novel therapeutic prospect following myocardial infarction, and worldwide clinical trials are imminent. However, despite notable advances, several challenges remain. Here, we review PSC-CM pre-clinical studies, identifying key translational hurdles. We further discuss cell production and characterization strategies, identifying markers that may help generate cells which overcome these barriers.

RECENT FINDINGS: PSC-CMs can robustly repopulate infarcted myocardium with functional, force generating cardiomyocytes. However, current differentiation protocols produce immature and heterogenous cardiomyocytes, creating related issues such as arrhythmogenicity, immunogenicity and poor engraftment. Recent efforts have enhanced our understanding of cardiovascular developmental biology. This knowledge may help implement novel differentiation or gene editing strategies that could overcome these limitations. PSC-CMs are an exciting therapeutic prospect. Despite substantial recent advances, limitations of the technology remain. However, with our continued and increasing biological understanding, these issues are addressable, with several worldwide clinical trials anticipated in the coming years.

PMID:35275365 | DOI:10.1007/s11886-022-01666-9

Categorías: Terapia celular

Moderate heart rate reduction promotes cardiac regeneration through stimulation of the metabolic pattern switch

Terapia celular - Mié, 03/09/2022 - 11:00

Cell Rep. 2022 Mar 8;38(10):110468. doi: 10.1016/j.celrep.2022.110468.

ABSTRACT

As a biological pump, the heart needs to consume a substantial amount of energy to maintain sustained beating. Myocardial energy metabolism was recently reported to be related to the loss of proliferative capacity in cardiomyocytes (CMs). However, the intrinsic relationship between beating rate and proliferation in CMs and whether energy metabolism can regulate this relationship remains unclear. In this study, we find that moderate heart rate reduction (HRR) induces CM proliferation under physiological conditions and promotes cardiac regenerative repair after myocardial injury. Mechanistically, moderate HRR induces G1/S transition and increases the expression of glycolytic enzymes in CMs. Furthermore, moderate HRR induces a metabolic pattern switch, activating glucose metabolism and increasing the relative proportion of ATP production by the glycolytic pathway for biosynthesis of substrates needed for proliferative CMs. These results highlight the potential therapeutic role of HRR in not only acute myocardial protection but also long-term CM restoration.

PMID:35263588 | DOI:10.1016/j.celrep.2022.110468

Categorías: Terapia celular

CTGF-D4 Amplifies LRP6 Signaling to Promote Grafts of Adult Epicardial-derived Cells That Improve Cardiac Function After Myocardial Infarction

Terapia celular - Mar, 03/08/2022 - 11:00

Stem Cells. 2022 Mar 16;40(2):204-214. doi: 10.1093/stmcls/sxab016.

ABSTRACT

Transplantation of stem/progenitor cells holds promise for cardiac regeneration in patients with myocardial infarction (MI). Currently, however, low cell survival and engraftment after transplantation present a major barrier to many forms of cell therapy. One issue is that ligands, receptors, and signaling pathways that promote graft success remain poorly understood. Here, we prospectively isolate uncommitted epicardial cells from the adult heart surface by CD104 (β-4 integrin) and demonstrate that C-terminal peptide from connective tissue growth factor (CTGF-D4), when combined with insulin, effectively primes epicardial-derived cells (EPDC) for cardiac engraftment after MI. Similar to native epicardial derivatives that arise from epicardial EMT at the heart surface, the grafted cells migrated into injured myocardial tissue in a rat model of MI with reperfusion. By echocardiography, at 1 month after MI, we observed significant improvement in cardiac function for animals that received epicardial cells primed with CTGF-D4/insulin compared with those that received vehicle-primed (control) cells. In the presence of insulin, CTGF-D4 treatment significantly increased the phosphorylation of Wnt co-receptor LRP6 on EPDC. Competitive engraftment assays and neutralizing/blocking studies showed that LRP6 was required for EPDC engraftment after transplantation. Our results identify LRP6 as a key target for increasing EPDC engraftment after MI and suggest amplification of LRP6 signaling with CTGF-D4/insulin, or by other means, may provide an effective approach for achieving successful cellular grafts in regenerative medicine.

PMID:35257185 | DOI:10.1093/stmcls/sxab016

Categorías: Terapia celular

Heart regeneration: 20 years of progress and renewed optimism

Terapia celular - Mar, 03/01/2022 - 11:00

Dev Cell. 2022 Feb 28;57(4):424-439. doi: 10.1016/j.devcel.2022.01.012.

ABSTRACT

Cardiovascular disease is a leading cause of death worldwide, and thus there remains great interest in regenerative approaches to treat heart failure. In the past 20 years, the field of heart regeneration has entered a renaissance period with remarkable progress in the understanding of endogenous heart regeneration, stem cell differentiation for exogenous cell therapy, and cell-delivery methods. In this review, we highlight how this new understanding can lead to viable strategies for human therapy. For the near term, drugs, electrical and mechanical devices, and heart transplantation will remain mainstays of cardiac therapies, but eventually regenerative therapies based on fundamental regenerative biology may offer more permanent solutions for patients with heart failure.

PMID:35231426 | PMC:PMC8896288 | DOI:10.1016/j.devcel.2022.01.012

Categorías: Terapia celular

Tunable biomaterials for myocardial tissue regeneration: promising new strategies for advanced biointerface control and improved therapeutic outcomes

Terapia celular - Mar, 03/01/2022 - 11:00

Biomater Sci. 2022 Mar 1. doi: 10.1039/d1bm01641e. Online ahead of print.

ABSTRACT

Following myocardial infarction (MI) and the natural healing process, the cardiac mechanostructure changes significantly leading to reduced contractile ability and resulting in additional pressure on the heart muscle thereby increasing the risk of heart failure (HF). The application of cardiac scaffolds in the form of epicardial patches or injectable hydrogels at the infarcted region of the myocardium helps to mechanically reinforce the ventricular walls and allows control over the various stages of the healing process, reducing pathological remodeling and fibrosis and eventually restoring cardiac function. Recent progress in the field of biomaterials engineering allows tuning of cardiac scaffold properties for more effective tissue-biomaterial interaction leading to improved therapeutic outcomes. Nanoscaffold characteristics required for myocardial tissue engineering (TE) including mechanical property, pore size/porosity, immunomodulation, bioactivity, electroconductivity, injectability (for hydrogels) and thickness (for cardiac patches) are herewith reviewed. Strategies for controlling each of these properties via blending, scaffold fabrication, degree of crosslinking, and incorporation of bioactive molecules, amongst others are also discussed. The mechanism of myocardial restoration via enhanced angiogenesis, stem cell homing and mechanical support is further detailed. Finally, key novel innovative strategies with high promise for clinical translation are presented; in particular, the use of extracellular vesicle-loaded scaffolds, integration of electronics within scaffolds for real time monitoring of the engineered tissue performance as well as the possibility of refilling scaffolds with drugs/cells/proteins via a subcutaneous port are highlighted.

PMID:35230359 | DOI:10.1039/d1bm01641e

Categorías: Terapia celular

Role of platelet rich plasma mediated repair and regeneration of cell in early stage of cardiac injury

Terapia celular - Mar, 03/01/2022 - 11:00

Regen Ther. 2022 Feb 15;19:144-153. doi: 10.1016/j.reth.2022.01.006. eCollection 2022 Mar.

ABSTRACT

Platelet-rich plasma (PRP) is a widely accepted treatment approach and has heightened the quality of care among physicians. PRP has been used over the last decade to boost clinical results of plastic therapies, periodontal surgery and intra-bony defects. According to certain research, elevated levels of PRP growth factors that could promote tissue repair and have the potential for PRP to be beneficial in regenerating processes that Maxillofacial and Oral Surgeons, Veterinary Officers, Athletic medicine specialists and Dermatologists have long admired. PRP is an autologous whole blood fraction that has a heavy amount of a variety of growth factors such as epidermal growth factor (EGF), Vascular Endothelial Growth Factor (VEGF), hepatocyte growth factor (HGF), fibroblast growth factors (FGFs), transforming growth factor beta-1 (TGF-b), insulin-like growth factor-I (IGF-I) and platelet-derived growth factor (PDGF) which can facilitate repair and regeneration. Moreover, a clinical trial of PRP in severe angina patients has shown its excellent safety profile. However, PRP is a very complex biological substance with an array of active biomolecules, its functions are yet to be fully clarified. In-addition, there was insufficient work assessing possible cardiovascular tissue benefits from PRP. Thus, it still remains necessary to identify the most clinically important cardiovascular applications and further research in clinical scenario need to be validated.

PMID:35229012 | PMC:PMC8856949 | DOI:10.1016/j.reth.2022.01.006

Categorías: Terapia celular

Restoring Ravaged Heart: Molecular Mechanisms and Clinical Application of miRNA in Heart Regeneration

Terapia celular - Lun, 02/28/2022 - 11:00

Front Cardiovasc Med. 2022 Feb 10;9:835138. doi: 10.3389/fcvm.2022.835138. eCollection 2022.

ABSTRACT

Human heart development is a complex and tightly regulated process, conserving proliferation, and multipotency of embryonic cardiovascular progenitors. At terminal stage, progenitor cell type gets suppressed for terminal differentiation and maturation. In the human heart, most cardiomyocytes are terminally differentiated and so have limited proliferation capacity. MicroRNAs (miRNAs) are non-coding single-stranded RNA that regulate gene expression and mRNA silencing at the post-transcriptional level. These miRNAs play a crucial role in numerous biological events, including cardiac development, and cardiomyocyte proliferation. Several cardiac cells specific miRNAs have been discovered. Inhibition or overexpression of these miRNAs could induce cardiac regeneration, cardiac stem cell proliferation and cardiomyocyte proliferation. Clinical application of miRNAs extends to heart failure, wherein the cell cycle arrest of terminally differentiated cardiac cells inhibits the heart regeneration. The regenerative capacity of the myocardium can be enhanced by cardiomyocyte specific miRNAs controlling the cell cycle. In this review, we focus on cardiac-specific miRNAs involved in cardiac regeneration and cardiomyocyte proliferation, and their potential as a new clinical therapy for heart regeneration.

PMID:35224063 | PMC:PMC8866653 | DOI:10.3389/fcvm.2022.835138

Categorías: Terapia celular

Mapping the developing human cardiac endothelium at single cell resolution identifies MECOM as a regulator of arteriovenous gene expression

Terapia celular - Vie, 02/25/2022 - 11:00

Cardiovasc Res. 2022 Feb 25:cvac023. doi: 10.1093/cvr/cvac023. Online ahead of print.

ABSTRACT

AIMS: Coronary vasculature formation is a critical event during cardiac development, essential for heart function throughout perinatal and adult life. However, current understanding of coronary vascular development has largely been derived from transgenic mouse models. The aim of this study was to characterise the transcriptome of the human fetal cardiac endothelium using single-cell RNA sequencing (scRNA-seq) to provide critical new insights into the cellular heterogeneity and transcriptional dynamics that underpin endothelial specification within the vasculature of the developing heart.

METHODS AND RESULTS: We acquired scRNA-seq data of over 10,000 fetal cardiac endothelial cells (EC), revealing divergent EC subtypes including endocardial, capillary, venous, arterial, and lymphatic populations. Gene regulatory network analyses predicted roles for SMAD1 and MECOM in determining the identity of capillary and arterial populations, respectively. Trajectory inference analysis suggested an endocardial contribution to the coronary vasculature and subsequent arterialisation of capillary endothelium accompanied by increasing MECOM expression. Comparative analysis of equivalent data from murine cardiac development demonstrated that transcriptional signatures defining endothelial subpopulations are largely conserved between human and mouse. Comprehensive characterisation of the transcriptional response to MECOM knockdown in human embryonic stem cell-derived EC (hESC-EC) demonstrated an increase in the expression of non-arterial markers, including those enriched in venous EC.

CONCLUSIONS: scRNA-seq of the human fetal cardiac endothelium identified distinct EC populations. A predicted endocardial contribution to the developing coronary vasculature was identified, as well as subsequent arterial specification of capillary EC. Loss of MECOM in hESC-EC increased expression of non-arterial markers, suggesting a role in maintaining arterial EC identity.

TRANSLATIONAL PERSPECTIVE: Endogenous blood vessel formation in the adult heart following myocardial infarction is insufficient to support adequate survival of the remaining myocardium, often ultimately leading to heart failure. Improved understanding of the mechanisms regulating human coronary vessel formation is required to inform therapeutic strategies to reactivate developmental pathways promoting therapeutic angiogenesis in patients. We applied scRNA-seq to map the transcriptome of the endothelium of the developing human heart. We identified novel transcriptional signatures underlying the cellular heterogeneity and dynamic changes occurring within the developing cardiac endothelium. This included identifying and validating MECOM as a novel regulator of arterial EC identity which may serve as a target for therapeutic neovascularization.

PMID:35212715 | DOI:10.1093/cvr/cvac023

Categorías: Terapia celular

Unraveling and Targeting Myocardial Regeneration Deficit in Diabetes

Terapia celular - Vie, 02/25/2022 - 11:00

Antioxidants (Basel). 2022 Jan 22;11(2):208. doi: 10.3390/antiox11020208.

ABSTRACT

Cardiomyopathy is a common complication in diabetic patients. Ventricular dysfunction without coronary atherosclerosis and hypertension is driven by hyperglycemia, hyperinsulinemia and impaired insulin signaling. Cardiomyocyte death, hypertrophy, fibrosis, and cell signaling defects underlie cardiomyopathy. Notably, detrimental effects of the diabetic milieu are not limited to cardiomyocytes and vascular cells. The diabetic heart acquires a senescent phenotype and also suffers from altered cellular homeostasis and the insufficient replacement of dying cells. Chronic inflammation, oxidative stress, and metabolic dysregulation damage the population of endogenous cardiac stem cells, which contribute to myocardial cell turnover and repair after injury. Therefore, deficient myocardial repair and the progressive senescence and dysfunction of stem cells in the diabetic heart can represent potential therapeutic targets. While our knowledge of the effects of diabetes on stem cells is growing, several strategies to preserve, activate or restore cardiac stem cell compartments await to be tested in diabetic cardiomyopathy.

PMID:35204091 | PMC:PMC8868283 | DOI:10.3390/antiox11020208

Categorías: Terapia celular

Novel oral edaravone attenuates diastolic dysfunction of diabetic cardiomyopathy by activating the Nrf2 signaling pathway

Terapia celular - Jue, 02/24/2022 - 11:00

Eur J Pharmacol. 2022 Apr 5;920:174846. doi: 10.1016/j.ejphar.2022.174846. Epub 2022 Feb 22.

ABSTRACT

Oxidative stress plays a crucial role in the pathophysiology of diastolic dysfunction associated with diabetic cardiomyopathy. Novel oral edaravone (OED) alleviates oxidative stress by scavenging free radicals and may be suitable for the treatment of chronic diseases such as diabetic cardiomyopathy. Oral administration of OED to type 2 diabetic rats (induced by high-sugar/high-fat diet and intraperitoneal injection of streptozotocin) for 4 w decreased malondialdehyde and increased superoxide dismutase. Moreover, it significantly improved ratios of early to late diastolic peak velocity, myocardium hypertrophy accompanied by decreased cross-sectional areas of cardiomyocytes, the proportion of apoptotic cells, collagen volume fractions, and deposition of collagen I/III. In H9c2 cells, OED reduced reactive oxygen species, cell surface area, and numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling-positive cells induced by glucolipotoxicity. OED remarkably upregulated expression of the nuclear factor E2-related factor (Nrf2) signaling pathway both in vivo and in vitro. In addition, OED promoted Nrf2 nuclear translocation and upregulated nicotinamide adenine dinucleotide phosphate quinone oxidoreductase and heme oxygenase. Silencing of Nrf2 abolished the protective effect of OED in H9c2 cells. Our findings demonstrate that OED has the therapeutic potential to ameliorate diastolic dysfunction associated with diabetic cardiomyopathy. Its effect was mainly achieved by attenuating hyperglycemia and hyperlipidemia-induced cardiomyocyte hypertrophy, apoptosis, and fibrosis by activating the Nrf2 signaling pathway.

PMID:35202676 | DOI:10.1016/j.ejphar.2022.174846

Categorías: Terapia celular

Enhanced Generation of Human Induced Pluripotent Stem Cells from Peripheral Blood and Using Their Mesoderm Differentiation Ability to Regenerate Infarcted Myocardium

Terapia celular - Lun, 02/21/2022 - 11:00

Stem Cells Int. 2022 Feb 11;2022:4104622. doi: 10.1155/2022/4104622. eCollection 2022.

ABSTRACT

Тhe most pressing issue in generating induced pluripotent stem cells (iPSCs) in clinical practice is the cell source. Compared to human dermal fibroblasts (HDFs), which have been widely used, human peripheral blood could be a more easily obtainable alternative. However, iPSCs generated from fresh peripheral blood require inconvenient specific methods including isolation. Recently, we succeeded in isolating and culturing human heart-derived circulating cells called circulating multipotent stem (CiMS) cells. Here, we investigated the generation efficiency of CiMS-derived iPSCs (CiMS-iPSCs) and tested their differentiation potential into mesodermal lineages and cardiovascular cells. We isolated and cultured CiMS cells from peripheral mononuclear cells with a high efficiency. Moreover, our method succeeded in reprogramming the CiMS cells and generating iPSCs with higher efficiency compared to when HDFs were used. Compared to HDF-iPSCs or human embryonic stem cells (hESCs), CiMS-iPSCs showed high differentiation potential into mesodermal lineage cells and subsequently into endothelial cells, vascular smooth muscle cells, and cardiomyocytes. Further, we checked the epigenetic status of each cell type. While methylation of the CpG site of the brachyury T promoter did not differ between cell types, the histone H3 lysine 4 trimethylation level in the brachyury T promoter region was enhanced in CiMS-iPSCs, compared to that in other cell types. In contrast, histone H3 lysine 9 acetylation was downregulated during the differentiation process of the CiMS-iPSCs. In the myocardial infarction model, the CiMS-iPSCs group showed more therapeutic potential in regenerating the myocardium than other cell types. Our study showed a new method to isolate human heart-derived stem cells from human peripheral blood and to generate iPSCs efficiently. Due to epigenetic memory, these CiMS-iPSCs easily differentiated into cardiovascular lineage cells, resulting in improved efficiency in vivo. These results suggest that our new method using CiMS cells has therapeutic potential in regenerative medicine using cell therapy.

PMID:35186091 | PMC:PMC8856835 | DOI:10.1155/2022/4104622

Categorías: Terapia celular

Ruvbl2 Suppresses Cardiomyocyte Proliferation During Zebrafish Heart Development and Regeneration

Terapia celular - Vie, 02/18/2022 - 11:00

Front Cell Dev Biol. 2022 Feb 1;10:800594. doi: 10.3389/fcell.2022.800594. eCollection 2022.

ABSTRACT

Cardiomyocyte proliferation is an important source of new myocardium during heart development and regeneration. Consequently, mutations in drivers of cardiomyocyte proliferation cause congenital heart disease, and infarcted human hearts scar because cardiomyocytes exit the cell cycle postnatally. To boost cardiomyocyte proliferation in either setting, critical regulators must be identified. Through an ENU screen in zebrafish, the liebeskummer (lik) mutant was isolated and described as having elevated cardiomyocyte numbers during embryogenesis. The lik mutation results in a three amino acid insertion into Ruvbl2, a highly conserved ATPase. Because both gain- and loss-of-function properties have been described for ruvbl2 lik , it remains unclear whether Ruvbl2 positively or negatively regulates cardiomyocyte proliferation. Here, we demonstrate that Ruvbl2 is a suppressor of cardiomyocyte proliferation during zebrafish heart development and regeneration. First, we confirmed speculation that augmented cardiomyocyte numbers in ruvbl2 lik/lik hearts arise by hyperproliferation. To characterize bona fide ruvbl2 null animals, we created a ruvbl2 locus deletion allele (ruvbl2 Δ ). Like ruvbl2 lik/lik mutants, ruvbl2 Δ/Δ and compound heterozygote ruvbl2 lik/Δ animals display ventricular hyperplasia, demonstrating that lik is a loss of function allele and that ruvbl2 represses cardiomyocyte proliferation. This activity is autonomous because constitutive myocardial overexpression of Ruvbl2 is sufficient to suppress cardiomyocyte proliferation in control hearts and rescue the hyperproliferation observed in ruvbl2 Δ/Δ mutant hearts. Lastly, heat-shock inducible overexpression of Ruvbl2 suppresses cardiomyocyte proliferation during heart regeneration and leads to scarring. Together, our data demonstrate that Ruvbl2 functions autonomously as a suppressor of cardiomyocyte proliferation during both zebrafish heart development and adult heart regeneration.

PMID:35178388 | PMC:PMC8844374 | DOI:10.3389/fcell.2022.800594

Categorías: Terapia celular

Transcription Factors are the Heart of Heart Regeneration; A Potential Novel Therapeutic Strategy

Terapia celular - Mié, 02/16/2022 - 11:00

Curr Mol Med. 2022 Feb 16. doi: 10.2174/1566524022666220216123650. Online ahead of print.

ABSTRACT

Myocardial cell injury and following sequelae are the primary reason of death globally. Unfortunately, cardiomyocytes in adults have limited regeneration capacity. Therefore, the generation of neo cardiomyocytes from non-myocardial cells is a surrogate strategy. Transcription factors (TFs) can be recruited to achieve this tremendous goal. Transcriptomic analyses have suggested that GATA, Mef2c, and Tbx5 (GMT cocktail) are master TFs to transdifferentiate/reprogram cell linage of fibroblasts, somatic cells, mesodermal cells into cardiomyocytes. However, adding MESP1, MYOCD, ESRRG, and ZFPM2 TFs induces the generation of more efficient and physiomorphological features for induced cardiomyocytes. Moreover, the same cocktail of transcription factors can induce the proliferation and differentiation of induced/pluripotent stem cells into myocardial cells. The amelioration of impaired myocardial cells involved activation of healing transcription factors, which are induced by inflammation mediators; IL6, tumor growth factor β, and IL22. Transcription factors regulate the cellular and subcellular physiology of cardiomyocytes to include mitotic cell cycling regulation, karyokinesis and cytokinesis, hypertrophic growth, adult sarcomeric contractile protein gene expression, fatty acid metabolism, and mitochondrial biogenesis and maturation. Cell therapy of transcription factors can be applied to cardiogenesis and improve impaired cardiocytes.

PMID:35170408 | DOI:10.2174/1566524022666220216123650

Categorías: Terapia celular

Exosomal-ribosomal proteins-driven heterogeneity of epicardial adipose tissue derived stem cells under ischemia for cardiac regeneration

Terapia celular - Jue, 02/10/2022 - 11:00

J Tissue Eng Regen Med. 2022 Feb 10. doi: 10.1002/term.3289. Online ahead of print.

ABSTRACT

Extracellular ribosomal proteins secreted in exosomes elicit biological/regenerative responses; however, ribosomal proteins contained in the exosomes of ischemia-challenged epicardial adipose tissue-derived stem cells (EATDS) remain unexplored. This study focuses on the identification of ribosomal proteins in the exosomes of ischemia-challenged EATDS and their sub-populations based on the key ribosomal proteins using single-cell genomics. Exosomes were isolated from control, ischemic (ISC), and reperfused (ISC/R) EATDS harvested from hyperlipidemic microswine, and the proteins were detected using Liquid chromatography with tandem mass spectrometry (LC-MS/MS). One hundred ninety-nine proteins and 177 proteins were detected in ISC and ISC/R groups, respectively with significant fold-change compared to controls. Five ribosomal proteins, RPL10A, 40SRPS18, 40SRPS30, 60SRPL14, and 40SRPSA, were significant owing to their abundance based on LC-MS/MS data. Expression of these proteins, except RPL10A, at transcript and protein levels were lower in ISC group compared to the control. scRNAseq analysis revealed EATDS heterogeneity based on the upregulation of 40SRPSA, 40SRPL18, and 40SRPS18. Pro-inflammatory sub-populations upregulated CCL5, anti-inflammatory sub-population upregulated IL-11, proliferative sub-population upregulated cell cycle and DNA replication mediators, and non-proliferative population downregulated the cell cycle and DNA replication mediators. Overall, the functional role of extracellular ribosomal proteins in driving unique phenotypes of EATDS population offers promise for designing effective translational approaches for myocardial regeneration.

PMID:35142442 | DOI:10.1002/term.3289

Categorías: Terapia celular

Epicardium-Derived Tbx18<sup>+</sup> CDCs Transplantation Improve Heart Function in Infarcted Mice

Terapia celular - Jue, 02/10/2022 - 11:00

Front Cardiovasc Med. 2022 Jan 24;8:744353. doi: 10.3389/fcvm.2021.744353. eCollection 2021.

ABSTRACT

Cardiosphere-derived cells (CDCs) constitute a cardiac stem cell pool, a promising therapeutics in treating myocardial infarction (MI). However, the cell source of CDCs remains unclear. In this study, we isolated CDCs directly from adult mouse heart epicardium named primary epicardium-derived CDCs (pECDCs), which showed a different expression profile compared with primary epicardial cells (pEpiCs). Interestingly, pECDCs highly expressed T-box transcription factor 18 (Tbx18) and showed multipotent differentiation ability in vitro. Human telomerase reverse transcriptase (hTERT) transduction could inhibit aging-induced pECDCs apoptosis and differentiation, thus keeping a better proliferation capacity. Furthermore, immortalized epicardium CDCs (iECDCs) transplantation extensively promote cardiogenesis in the infracted mouse heart. This study demonstrated epicardium-derived CDCs that may derive from Tbx18+ EpiCs, which possess the therapeutic potential to be applied to cardiac repair and regeneration and suggest a new kind of CDCs with identified origination that may be followed in the developing and injured heart.

PMID:35141286 | PMC:PMC8820322 | DOI:10.3389/fcvm.2021.744353

Categorías: Terapia celular

Emerging Trends in Mesenchymal Stem Cells Applications for Cardiac Regenerative Therapy: Current Status and Advances

Terapia celular - Sáb, 02/05/2022 - 11:00

Stem Cell Rev Rep. 2022 Feb 4. doi: 10.1007/s12015-021-10314-8. Online ahead of print.

ABSTRACT

Irreversible myocardium infarction is one of the leading causes of cardiovascular disease (CVD) related death and its quantum is expected to grow in coming years. Pharmacological intervention has been at the forefront to ameliorate injury-related morbidity and mortality. However, its outcomes are highly skewed. As an alternative, stem cell-based tissue engineering/regenerative medicine has been explored quite extensively to regenerate the damaged myocardium. The therapeutic modality that has been most widely studied both preclinically and clinically is based on adult multipotent mesenchymal stem cells (MSC) delivered to the injured heart. However, there is debate over the mechanistic therapeutic role of MSC in generating functional beating cardiomyocytes. This review intends to emphasize the role and use of MSC in cardiac regenerative therapy (CRT). We have elucidated in detail, the various aspects related to the history and progress of MSC use in cardiac tissue engineering and its multiple strategies to drive cardiomyogenesis. We have further discussed with a focus on the various therapeutic mechanism uncovered in recent times that has a significant role in ameliorating heart-related problems. We reviewed recent and advanced technologies using MSC to develop/create tissue construct for use in cardiac regenerative therapy. Finally, we have provided the latest update on the usage of MSC in clinical trials and discussed the outcome of such studies in realizing the full potential of MSC use in clinical management of cardiac injury as a cellular therapy module.

PMID:35122226 | DOI:10.1007/s12015-021-10314-8

Categorías: Terapia celular

CDH18 is a fetal epicardial biomarker regulating differentiation towards vascular smooth muscle cells

Terapia celular - Jue, 02/03/2022 - 11:00

NPJ Regen Med. 2022 Feb 2;7(1):14. doi: 10.1038/s41536-022-00207-w.

ABSTRACT

The epicardium is a mesothelial layer covering the myocardium serving as a progenitor source during cardiac development. The epicardium reactivates upon cardiac injury supporting cardiac repair and regeneration. Fine-tuned balanced signaling regulates cell plasticity and cell-fate decisions of epicardial-derived cells (EPCDs) via epicardial-to-mesenchymal transition (EMT). However, powerful tools to investigate epicardial function, including markers with pivotal roles in developmental signaling, are still lacking. Here, we recapitulated epicardiogenesis using human induced pluripotent stem cells (hiPSCs) and identified type II classical cadherin CDH18 as a biomarker defining lineage specification in human active epicardium. The loss of CDH18 led to the onset of EMT and specific differentiation towards cardiac smooth muscle cells. Furthermore, GATA4 regulated epicardial CDH18 expression. These results highlight the importance of tracing CDH18 expression in hiPSC-derived epicardial cells, providing a model for investigating epicardial function in human development and disease and enabling new possibilities for regenerative medicine.

PMID:35110584 | PMC:PMC8810917 | DOI:10.1038/s41536-022-00207-w

Categorías: Terapia celular

Diabetes-Induced Cellular Senescence and Senescence-Associated Secretory Phenotype Impair Cardiac Regeneration and Function Independently of Age

Terapia celular - Mié, 02/02/2022 - 11:00

Diabetes. 2022 Feb 2:db210536. doi: 10.2337/db21-0536. Online ahead of print.

ABSTRACT

Diabetes Mellitus (DM) affects the biology of multipotent cardiac stem/progenitor cells (CSCs) and adult myocardial regeneration. We assessed the hypothesis that senescence and senescence-associated secretory phenotype (SASP) are a main mechanism of cardiac degenerative defect in DM. Accordingly, we tested whether that ablation of senescent CSCs would rescue the cardiac regenerative/reparative defect imposed by DM. We obtained cardiac tissue from non-aged (50-64 years old) DM type 2 (T2DM) and non-diabetic (NDM) patients with post-infarct cardiomyopathy undergoing cardiac surgery. A higher ROS production in T2DM associated with an increased number of senescent/dysfunctional T2DM-human(h)CSCs with reduced proliferation, clonogenesis/spherogenesis and myogenic differentiation vs. NDM-hCSCs in vitro. T2DM-hCSCs show a defined pathologic SASP. A combination of two senolytics, Dasatinib (D) and Quercetin (Q), clears senescent T2DM-hCSCs in vitro restoring their expansion and myogenic differentiation capacities. In a T2DM model in young mice, diabetic status per se (independently of ischemia and age) causes CSC senescence coupled with myocardial pathologic remodeling and cardiac dysfunction. D+Q treatment efficiently eliminates senescent cells, rescuing CSC function, which results in functional myocardial repair/regeneration improving cardiac function in murine DM. In conclusions, DM hampers CSC biology inhibiting their regenerative potential through the induction of cellular senescence and SASP independently from aging. Senolytics clear senescence abrogating the SASP restoring a fully proliferative-/differentiation- competent hCSC pool in T2DM with normalization of cardiac function.

PMID:35108360 | DOI:10.2337/db21-0536

Categorías: Terapia celular
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