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Pubblicazioni recenti - cardiac stem
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Chitosan-Based Biomaterials for Tissue Regeneration.
Pharmaceutics2023 Mar;15(3):. doi: 807.
Kim Yevgeniy, Zharkinbekov Zharylkasyn, Raziyeva Kamila, Tabyldiyeva Laura, Berikova Kamila, Zhumagul Dias, Temirkhanova Kamila, Saparov Arman,
Abstract
Chitosan is a chitin-derived biopolymer that has shown great potential for tissue regeneration and controlled drug delivery. It has numerous qualities that make it attractive for biomedical applications such as biocompatibility, low toxicity, broad-spectrum antimicrobial activity, and many others. Importantly, chitosan can be fabricated into a variety of structures including nanoparticles, scaffolds, hydrogels, and membranes, which can be tailored to deliver a desirable outcome. Composite chitosan-based biomaterials have been demonstrated to stimulate in vivo regeneration and the repair of various tissues and organs, including but not limited to, bone, cartilage, dental, skin, nerve, cardiac, and other tissues. Specifically, de novo tissue formation, resident stem cell differentiation, and extracellular matrix reconstruction were observed in multiple preclinical models of different tissue injuries upon treatment with chitosan-based formulations. Moreover, chitosan structures have been proven to be efficient carriers for medications, genes, and bioactive compounds since they can maintain the sustained release of these therapeutics. In this review, we discuss the most recently published applications of chitosan-based biomaterials for different tissue and organ regeneration as well as the delivery of various therapeutics.
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Safety and Efficacy of Autologous Stem Cell Treatment for Facetogenic Chronic Back Pain.
J Pers Med2023 Feb;13(3):. doi: 436.
Rothoerl Ralf, Tomelden Junee, Alt Eckhard Udo,
Abstract
BACKGROUND:
Chronic back pain due to facet joint syndrome is a common and debilitating condition. Advances in regenerative medicine have shown that autologous unmodified adipose tissue-derived regenerative cells (ADRC) provide several beneficial effects. These regenerative cells can differentiate into various tissues and exhibit a strong anti-inflammatory potential. ADRCs can be obtained from a small amount of fatty tissue derived from the patient's abdominal fat.
METHODS:
We report long-term results of 37 patients (age 31-78 years, mean 62.5) suffering from "Facet Joint Syndrome" The pathology was confirmed by clinical, radiological examinations and fluoroscopically guided test injections. Then, liposuction was performed. An amount of 50-100 cc of fat was harvested. To recover stem cells from adipose tissue, we use the CE-certified Transpose RT? system from InGeneron GmbH. The cells were then injected under fluoroscopic control in the periarticular fat. Follow-up examinations were performed at 1 week, 1 year, and 5 years.
RESULTS:
Every patient reported improved VAS pain at any follow-up (1 week, 1 year, and 5 years) with ADRCs compared to the baseline.
CONCLUSIONS:
Our observational data indicate that facet joint syndrome patients treated with unmodified adipose tissue-derived regenerative cells experience improved the quality of life in the long term.
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Extracellular Vesicles Produced by the Cardiac Microenvironment Carry Functional Enzymes to Produce Lipid Mediators In Situ.
Int J Mol Sci2023 Mar;24(6):. doi: 5866.
Ong-Meang Varravaddheay, Blanzat Muriel, Savchenko Lesia, Perquis Lucie, Guardia Mégane, Pizzinat Nathalie, Poinsot Verena,
Abstract
The impact of the polyunsaturated fatty acids (PUFAs) at physiological concentrations on the composition of eicosanoids transported within the extracellular vesicles (EVs) of rat bone marrow mesenchymal stem cells and cardiomyoblasts was reported by our group in 2020. The aim of this article was to extend this observation to cells from the cardiac microenvironment involved in the processes of inflammation, namely mouse J774 macrophages and rat heart mesenchymal stem cells cMSCs. Moreover, to enhance our capacity to understand the paracrine exchange between these orchestrators of cardiac inflammation, we investigated some machinery involved in the eicosanoid's synthesis transported by the EVs produced by these cells (including the two formerly described cells: bone marrow mesenchymal stem cells BM-MSC and cardiomyoblasts H9c2). We analyzed the oxylipin and the enzymatic content of the EVs collected from cell cultures supplemented (or not) with PUFAs. We prove that large eicosanoid profiles are exported in the EVs by the cardiac microenvironment cells, but also that these EVs carry some critical and functional biosynthetic enzymes, allowing them to synthesize inflammation bioactive compounds by sensing their environment. Moreover, we demonstrate that these are functional. This observation reinforces the hypothesis that EVs are key factors in paracrine signaling, even in the absence of the parent cell. We also reveal a macrophage-specific behavior, as we observed a radical change in the lipid mediator profile when small EVs derived from J774 cells were exposed to PUFAs. To summarize, we prove that the EVs, due to the carried functional enzymes, can alone produce bioactive compounds, in the absence of the parent cell, by sensing their environment. This makes them potential circulating monitoring entities.
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An Adjuvant Stem Cell Patch with Coronary Artery Bypass Graft Surgery Improves Diastolic Recovery in Porcine Hibernating Myocardium.
Int J Mol Sci2023 Mar;24(6):. doi: 5475.
Aggarwal Rishav, Potel Koray N, Shao Annie, So Simon W, Swingen Cory, Reyes Christina P, Rose Rebecca, Wright Christin, Hocum Stone Laura L, McFalls Edward O, Butterick Tammy A, Kelly Rosemary F,
Abstract
Diastolic dysfunction persists despite coronary artery bypass graft surgery (CABG) in patients with hibernating myocardium (HIB). We studied whether the adjunctive use of a mesenchymal stem cells (MSCs) patch during CABG improves diastolic function by reducing inflammation and fibrosis. HIB was induced in juvenile swine by placing a constrictor on the left anterior descending (LAD) artery, causing myocardial ischemia without infarction. At 12 weeks, CABG was performed using the left-internal-mammary-artery (LIMA)-to-LAD graft with or without placement of an epicardial vicryl patch embedded with MSCs, followed by four weeks of recovery. The animals underwent cardiac magnetic resonance imaging (MRI) prior to sacrifice, and tissue from septal and LAD regions were collected to assess for fibrosis and analyze mitochondrial and nuclear isolates. During low-dose dobutamine infusion, diastolic function was significantly reduced in HIB compared to the control, with significant improvement after CABG + MSC treatment. In HIB, we observed increased inflammation and fibrosis without transmural scarring, along with decreased peroxisome proliferator-activated receptor-gamma coactivator (PGC1?), which could be a possible mechanism underlying diastolic dysfunction. Improvement in PGC1? and diastolic function was noted with revascularization and MSCs, along with decreased inflammatory signaling and fibrosis. These findings suggest that adjuvant cell-based therapy during CABG may recover diastolic function by reducing oxidant stress-inflammatory signaling and myofibroblast presence in the myocardial tissue.
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Pro-Arrhythmic Potential of Accumulated Uremic Toxins Is Mediated via Vulnerability of Action Potential Repolarization.
Int J Mol Sci2023 Mar;24(6):. doi: 5373.
van Ham Willem B, Cornelissen Carlijn M, Polyakova Elizaveta, van der Voorn Stephanie M, Ligtermoet Merel L, Monshouwer-Kloots Jantine, Vos Marc A, Bossu Alexandre, van Rooij Eva, van der Heyden Marcel A G, van Veen Toon A B,
Abstract
Chronic kidney disease (CKD) is represented by a diminished filtration capacity of the kidneys. End-stage renal disease patients need dialysis treatment to remove waste and toxins from the circulation. However, endogenously produced uremic toxins (UTs) cannot always be filtered during dialysis. UTs are among the CKD-related factors that have been linked to maladaptive and pathophysiological remodeling of the heart. Importantly, 50% of the deaths in dialysis patients are cardiovascular related, with sudden cardiac death predominating. However, the mechanisms responsible remain poorly understood. The current study aimed to assess the vulnerability of action potential repolarization caused by exposure to pre-identified UTs at clinically relevant concentrations. We exposed human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and HEK293 chronically (48 h) to the UTs indoxyl sulfate, kynurenine, or kynurenic acid. We used optical and manual electrophysiological techniques to assess action potential duration (APD) in the hiPSC-CMs and recorded I currents in stably transfected HEK293 cells (HEK-hERG). Molecular analysis of K11.1, the ion channel responsible for I, was performed to further understand the potential mechanism underlying the effects of the UTs. Chronic exposure to the UTs resulted in significant APD prolongation. Subsequent assessment of the repolarization current I, often most sensitive and responsible for APD alterations, showed decreased current densities after chronic exposure to the UTs. This outcome was supported by lowered protein levels of K11.1. Finally, treatment with an activator of the I current, LUF7244, could reverse the APD prolongation, indicating the potential modulation of electrophysiological effects caused by these UTs. This study highlights the pro-arrhythmogenic potential of UTs and reveals a mode of action by which they affect cardiac repolarization.
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Advances in 3D Organoid Models for Stem Cell-Based Cardiac Regeneration.
Int J Mol Sci2023 Mar;24(6):. doi: 5188.
Martin Marcy, Gähwiler Eric K N, Generali Melanie, Hoerstrup Simon P, Emmert Maximilian Y,
Abstract
The adult human heart cannot regain complete cardiac function following tissue injury, making cardiac regeneration a current clinical unmet need. There are a number of clinical procedures aimed at reducing ischemic damage following injury; however, it has not yet been possible to stimulate adult cardiomyocytes to recover and proliferate. The emergence of pluripotent stem cell technologies and 3D culture systems has revolutionized the field. Specifically, 3D culture systems have enhanced precision medicine through obtaining a more accurate human microenvironmental condition to model disease and/or drug interactions in vitro. In this study, we cover current advances and limitations in stem cell-based cardiac regenerative medicine. Specifically, we discuss the clinical implementation and limitations of stem cell-based technologies and ongoing clinical trials. We then address the advent of 3D culture systems to produce cardiac organoids that may better represent the human heart microenvironment for disease modeling and genetic screening. Finally, we delve into the insights gained from cardiac organoids in relation to cardiac regeneration and further discuss the implications for clinical translation.
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Electrical Stimulation Increases the Secretion of Cardioprotective Extracellular Vesicles from Cardiac Mesenchymal Stem Cells.
Cells2023 Mar;12(6):. doi: 875.
Zhang Haitao, Shen Yan, Kim Il-Man, Liu Yutao, Cai Jingwen, Berman Adam E, Nilsson Kent R, Weintraub Neal L, Tang Yaoliang,
Abstract
Clinical trials have shown that electric stimulation (ELSM) using either cardiac resynchronization therapy (CRT) or cardiac contractility modulation (CCM) approaches is an effective treatment for patients with moderate to severe heart failure, but the mechanisms are incompletely understood. Extracellular vesicles (EV) produced by cardiac mesenchymal stem cells (C-MSC) have been reported to be cardioprotective through cell-to-cell communication. In this study, we investigated the effects of ELSM stimulation on EV secretion from C-MSCs (C-MSC). We observed enhanced EV-dependent cardioprotection conferred by conditioned medium (CM) from C-MSC compared to that from non-stimulated control C-MSC (C-MSC). To investigate the mechanisms of ELSM-stimulated EV secretion, we examined the protein levels of neutral sphingomyelinase 2 (nSMase2), a key enzyme of the endosomal sorting complex required for EV biosynthesis. We detected a time-dependent increase in nSMase2 protein levels in C-MSC compared to C-MSC. Knockdown of nSMase2 in C-MSC by siRNA significantly reduced EV secretion in C-MSC and attenuated the cardioprotective effect of CM from C-MSC in HL-1 cells. Taken together, our results suggest that ELSM-mediated increases in EV secretion from C-MSC enhance the cardioprotective effects of C-MSC through an EV-dependent mechanism involving nSMase2.
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Randomized Trial of 21% versus 100% Oxygen during Chest Compressions Followed by Gradual versus Abrupt Oxygen Titration after Return of Spontaneous Circulation in Neonatal Lambs.
Children (Basel)2023 Mar;10(3):. doi: 575.
Sankaran Deepika, Giusto Evan M, Lesneski Amy L, Hardie Morgan E, Joudi Houssam M, Lane Emily C A, Hammitt Victoria L, Tully Kirstie C, Vali Payam, Lakshminrusimha Satyan,
Abstract
The combination of perinatal acidemia with postnatal hyperoxia is associated with a higher incidence of hypoxic-ischemic encephalopathy (HIE) in newborn infants. In neonatal cardiac arrest, current International Liaison Committee on Resuscitation (ILCOR) and Neonatal Resuscitation Program (NRP) guidelines recommend increasing inspired O to 100% during chest compressions (CC). Following the return of spontaneous circulation (ROSC), gradual weaning from 100% O based on pulse oximetry (SpO) can be associated with hyperoxia and risk for cerebral tissue injury owing to oxidative stress. We hypothesize that compared to gradual weaning from 100% O with titration based on preductal SpO, abrupt or rapid weaning of inspired O to 21% after ROSC or use of 21% O during CC followed by upward titration of inspired O to achieve target SpO after ROSC will limit hyperoxia after ROSC. Nineteen lambs were randomized before delivery and asphyxial arrest was induced by umbilical cord occlusion. There was no difference in oxygenation during chest compressions between the three groups. Gradual weaning of inspired O from 100% O after ROSC resulted in supraphysiological PaO and higher cerebral oxygen delivery compared to 21% O during CC or 100% O during CC followed by abrupt weaning to 21% O after ROSC. The use of 21% O during CC was associated with very low PaO after ROSC and higher brain tissue lactic acid compared to other groups. Our findings support the current recommendations to use 100% O during CC and additionally suggest the benefit of abrupt decrease in inspired oxygen to 21% O after ROSC. Clinical studies are warranted to investigate optimal oxygen titration after chest compressions and ROSC during neonatal resuscitation.
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Unlocking the Pragmatic Potential of Regenerative Therapies in Heart Failure with Next-Generation Treatments.
Biomedicines2023 Mar;11(3):. doi: 915.
Kishino Yoshikazu, Fukuda Keiichi,
Abstract
Patients with chronic heart failure (HF) have a poor prognosis due to irreversible impairment of left ventricular function, with 5-year survival rates
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Tissue Engineering and Targeted Drug Delivery in Cardiovascular Disease: The Role of Polymer Nanocarrier for Statin Therapy.
Biomedicines2023 Mar;11(3):. doi: 798.
Montelione Nunzio, Loreni Francesco, Nenna Antonio, Catanese Vincenzo, Scurto Lucia, Ferrisi Chiara, Jawabra Mohamad, Gabellini Teresa, Codispoti Francesco Alberto, Spinelli Francesco, Chello Massimo, Stilo Francesco,
Abstract
Atherosclerosis-related coronary artery disease (CAD) is the leading cause of mortality and morbidity worldwide. This requires effective primary and secondary prevention in reducing the complications related to CAD; the regression or stabilization of the pathology remains the mainstay of treatment. Statins have proved to be the most effective treatment in reducing adverse effects, but there are limitations related to the administration and achievement of effective doses as well as side effects due to the lack of target-related molecular specificity. The implemented technological steps are polymers and nanoparticles for the administration of statins, as it has been seen how the conjugation of drug delivery systems (DDSs) with statins increases bioavailability by circumventing the hepatic-renal filter and increases the related target specificity, enhancing their action and decreasing side effects. Reduction of endothelial dysfunction, reduced intimal hyperplasia, reduced ischemia-reperfusion injury, cardiac regeneration, positive remodeling in the extracellular matrix, reduced neointimal growth, and increased reendothelialization are all drug-related effects of statins enhanced by binding with DDSs. Recent preclinical studies demonstrate how the effect of statins stimulates the differentiation of endogenous cardiac stem cells. Poly-lactic-co-glycolic acid (PLGA) seems to be the most promising DDS as it succeeds more than the others in enhancing the effect of the bound drug. This review intends to summarize the current evidence on polymers and nanoparticles for statin delivery in the field of cardiovascular disease, trying to shed light on this topic and identify new avenues for future studies.
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A Simplified and Effective Approach for the Isolation of Small Pluripotent Stem Cells Derived from Human Peripheral Blood.
Biomedicines2023 Mar;11(3):. doi: 787.
Filidou Eirini, Kandilogiannakis Leonidas, Tarapatzi Gesthimani, Spathakis Michail, Su Colin, Rai Alin, Greening David W, Arvanitidis Konstantinos, Paspaliaris Vasilis, Kolios George,
Abstract
Pluripotent stem cells are key players in regenerative medicine. Embryonic pluripotent stem cells, despite their significant advantages, are associated with limitations such as their inadequate availability and the ethical dilemmas in their isolation and clinical use. The discovery of very small embryonic-like (VSEL) stem cells addressed the aforementioned limitations, but their isolation technique remains a challenge due to their small cell size and their efficiency in isolation. Here, we report a simplified and effective approach for the isolation of small pluripotent stem cells derived from human peripheral blood. Our approach results in a high yield of small blood stem cell (SBSC) population, which expresses pluripotent embryonic markers (e.g., Nanog, SSEA-3) and the Yamanaka factors. Further, a fraction of SBSCs also co-express hematopoietic markers (e.g., CD45 and CD90) and/or mesenchymal markers (e.g., CD29, CD105 and PTH1R), suggesting a mixed stem cell population. Finally, quantitative proteomic profiling reveals that SBSCs contain various stem cell markers (CD9, ITGA6, MAPK1, MTHFD1, STAT3, HSPB1, HSPA4), and Transcription reg complex factors (e.g., STAT5B, PDLIM1, ANXA2, ATF6, CAMK1). In conclusion, we present a novel, simplified and effective isolating process that yields an abundant population of small-sized cells with characteristics of pluripotency from human peripheral blood.
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Animal Disease Models and Patient-iPS-Cell-Derived In Vitro Disease Models for Cardiovascular Biology-How Close to Disease?
Biology (Basel)2023 Mar;12(3):. doi: 468.
Kawaguchi Nanako, Nakanishi Toshio,
Abstract
Currently, zebrafish, rodents, canines, and pigs are the primary disease models used in cardiovascular research. In general, larger animals have more physiological similarities to humans, making better disease models. However, they can have restricted or limited use because they are difficult to handle and maintain. Moreover, animal welfare laws regulate the use of experimental animals. Different species have different mechanisms of disease onset. Organs in each animal species have different characteristics depending on their evolutionary history and living environment. For example, mice have higher heart rates than humans. Nonetheless, preclinical studies have used animals to evaluate the safety and efficacy of human drugs because no other complementary method exists. Hence, we need to evaluate the similarities and differences in disease mechanisms between humans and experimental animals. The translation of animal data to humans contributes to eliminating the gap between these two. In vitro disease models have been used as another alternative for human disease models since the discovery of induced pluripotent stem cells (iPSCs). Human cardiomyocytes have been generated from patient-derived iPSCs, which are genetically identical to the derived patients. Researchers have attempted to develop in vivo mimicking 3D culture systems. In this review, we explore the possible uses of animal disease models, iPSC-derived in vitro disease models, humanized animals, and the recent challenges of machine learning. The combination of these methods will make disease models more similar to human disease.
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[Chinese expert consensus on autologous stem cell transplantation for the treatment of heart failure].
Zhonghua Yi Xue Za Zhi2023 Mar;103():1-10. doi: 10.3760/cma.j.cn112137-20230217-00224.
,
Abstract
Cardiovascular diseases have been the leading cause of death in both urban and rural residents. Among them, heart failure, which develops from various heart diseases to the end stage, is the main cause of death. With the development of regenerative medicine, stem cell transplantation is expected to be a potential and promising treatment for heart failure. In recent years, basic research and clinical application research related to stem cells have been vigorously developed in China, and many latest achievements and progress have been obtained. However, relevant guidance documents are still needed to standardize and scale up clinical applications of stem cell transplantation. Therefore, experts from the Tissue Repair and Regeneration Branch of the Chinese Medical Association, by referring to the latest research results, discussed the treatment of heart failure by autologous stem cell transplantation and reached the following consensus. The key technical issues related to autologous stem cell transplantation were mainly expounded, and scientific suggestions were proposed to standardize and promote the clinical research and application of stem cells.
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Plant-derived Biomaterials and their Potential in Cardiac Tissue Repair.
Adv Healthc Mater2023 Mar;():e2202827. doi: 10.1002/adhm.202202827.
Dai Yichen, Qiao Kai, Li Demin, Isingizwe Phocas, Liu Haohao, Liu Yu, Lim Khoon, Woodfield Tim, Liu Guozhen, Hu Jinming, Yuan Jie, Tang Junnan, Cui Xiaolin,
Abstract
Cardiovascular disease remains the leading cause of mortality worldwide. The inability of cardiac tissue to regenerate after an infarction results in scar tissue formation, leading to cardiac dysfunction. Therefore, cardiac repair has always been a popular research topic. Recent advances in tissue engineering and regenerative medicine offer promising solutions combining stem cells and biomaterials to construct tissue substitutes that could have functions similar to healthy cardiac tissue. Among these biomaterials, plant-derived biomaterials show great promise in supporting cell growth due to their inherent biocompatibility, biodegradability, and mechanical stability. More importantly, plant-derived materials have reduced immunogenic properties compared to popular animal-derived materials (e.g., collagen and gelatin). In addition, they also offer improved wettability on scaffolds compared to synthetic materials. To date, limited literature is available to systemically summarize the progression of plant-derived biomaterials in cardiac tissue repair. Herein, this paper highlights the most common plant-derived biomaterials from both land and marine plants. The beneficial properties of these materials for tissue repair are further discussed. More importantly, the applications of plant-derived biomaterials in cardiac tissue engineering, including tissue-engineered scaffolds, bioink in three-dimensional biofabrication, delivery vehicles, and bioactive molecules, are also summarized using the latest preclinical and clinical examples. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
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Preliminary In Vitro Assessment of Decellularized Porcine Descending Aorta for Clinical Purposes.
J Funct Biomater2023 Mar;14(3):. doi: 141.
Casarin Martina, Fortunato Tiago Moderno, Imran Saima Jalil, Todesco Martina, Sandrin Deborah, Marchesan Massimo, Gerosa Gino, Romanato Filippo, Bagno Andrea, Dal Moro Fabrizio, Morlacco Alessandro,
Abstract
Conduit substitutes are increasingly in demand for cardiovascular and urological applications. In cases of bladder cancer, radical cystectomy is the preferred technique: after removing the bladder, a urinary diversion has to be created using autologous bowel, but several complications are associated with intestinal resection. Thus, alternative urinary substitutes are required to avoid autologous intestinal use, preventing complications and facilitating surgical procedures. In the present paper, we are proposing the exploitation of the decellularized porcine descending aorta as a novel and original conduit substitute. After being decellularized with the use of two alternative detergents (Tergitol and Ecosurf) and sterilized, the porcine descending aorta has been investigated to assess its permeability to detergents through methylene blue dye penetration analysis and to study its composition and structure by means of histomorphometric analyses, including DNA quantification, histology, two-photon microscopy, and hydroxyproline quantification. Biomechanical tests and cytocompatibility assays with human mesenchymal stem cells have been also performed. The results obtained demonstrated that the decellularized porcine descending aorta preserves its major features to be further evaluated as a candidate material for urological applications, even though further studies have to be carried out to demonstrate its suitability for the specific application, by performing in vivo tests in the animal model.
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Electrical Stimulation Promotes the Vascularization and Functionalization of an Engineered Biomimetic Human Cardiac Tissue.
Adv Healthc Mater2023 Mar;():e2300607. doi: 10.1002/adhm.202300607.
Lu Bingchuan, Ye Min, Xia Jingjing, Zhang Zhenrui, Xiong Zhuo, Zhang Ting,
Abstract
The formation of multiscale vascular networks is essential for the in vitro construction of large-scale biomimetic cardiac tissues/organs. Although a variety of bioprinting processes have been developed to achieve the construction of mesoscale and large-scale blood vessels, the formation of microvascular networks still mainly depends on the self-assembly behavior of endothelial cells, which is inefficient and demanding without appropriate stimulus. To address this problem, We seek to promote the elongation and connection of endothelial cells in engineered cardiac tissue (ECT) by electrical stimulation (ES) to achieve vascularization. As proof of the concept, bio-inks are composed of GelMA / fibrin hydrogel, human pluripotent stem cells induced cardiomyocytes (iPSC-CM), and human umbilical vein endothelial cells (HUVEC) are used for the bioprinting of ECTs. We demonstrate that electrical stimulation significantly promotes the elongation, migration, and interconnection of HUVECs in ECT and increases the expression of related genes. Moreover, ES also enhances the secretion of signal factors interacting between CMs and HUVECs. It seems that the HUVECs further strengthen the contractility of cardiac tissue. Taken together, electrical stimulation promotes vascularization and CMs functionalization in ECT, which has important application potential in the fabrication of vascularized ECT and its clinical transplantation. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
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Lifting the cloche: Jeroen Bakkers interviews Didier Stainier.
Dis Model Mech2023 May;16(5):. doi: dmm050147.
Stainier Didier Y R, Bakkers Jeroen,
Abstract
Didier Stainier is Director of the Department of Developmental Genetics at the Max Planck Institute for Heart and Lung Research in Bad Nauheim, Germany. He became acquainted with the zebrafish model as a PhD student in Walter Gilbert's lab at Harvard, which motivated him to champion the use of this powerful model organism to study heart development as a postdoctoral fellow with Mark Fishman at Massachusetts General Hospital. Although his scientific focus has expanded significantly since then, zebrafish modelling and heart development and regeneration remain key topics in his research. The developmental biology and zebrafish modelling communities have embraced him as an inspiring mentor and advocate for basic research. Jeroen Bakkers is a group leader at the Hubrecht Institute for Developmental Biology and Stem Cell Research and Professor of Molecular Cardiogenetics at the University Medical Center Utrecht, The Netherlands. Jeroen did hid PhD with Herman Spaink at Leiden University, The Netherlands. A short visit to Massachusetts Institute of Technology during his doctoral training introduced him to the zebrafish model, which he applied to his PhD project. Zebrafish development remained the focus of his career, including during his postdoctoral training in the lab of Matthias Hammerschmidt at the Max Planck Institute of Immunology and Epigenetics in Freiburg and in his own lab at the Hubrecht Institute, where his group uses this powerful model organism to investigate cardiac development, disease and regeneration. Jeroen and Didier met up at a recent conference to talk about their shared interest in cardiac regeneration, a zebrafish mutant with a curious name and Didier's commitment to mentorship.
© 2023. Published by The Company of Biologists Ltd.
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Thymidine Phosphorylase Deficiency or Inhibition Preserves Cardiac Function in Mice With Acute Myocardial Infarction.
J Am Heart Assoc2023 Mar;():e028023. doi: 10.1161/JAHA.122.028023.
Du Lili, Yue Hong, Rorabaugh Boyd R, Li Oliver Q Y, DeHart Autumn R, Toloza-Alvarez Gretel, Hong Liang, Denvir James, Thompson Ellen, Li Wei,
Abstract
Background Ischemic cardiovascular disease is the leading cause of death worldwide. Current pharmacologic therapy has multiple limitations, and patients remain symptomatic despite maximal medical therapies. Deficiency or inhibition of thymidine phosphorylase (TYMP) in mice reduces thrombosis, suggesting that TYMP could be a novel therapeutic target for patients with acute myocardial infarction (AMI). Methods and Results A mouse AMI model was established by ligation of the left anterior descending coronary artery in C57BL/6J wild-type and TYMP-deficient () mice. Cardiac function was monitored by echocardiography or Langendorff assay. TYMP-deficient hearts had lower baseline contractility. However, cardiac function, systolic left ventricle anterior wall thickness, and diastolic wall strain were significantly greater 4?weeks after AMI compared with wild-type hearts. TYMP deficiency reduced microthrombus formation after AMI. TYMP deficiency did not affect angiogenesis in either normal or infarcted myocardium but increased arteriogenesis post-AMI. TYMP deficiency enhanced the mobilization of bone marrow stem cells and promoted mesenchymal stem cell (MSC) proliferation, migration, and resistance to inflammation and hypoxia. TYMP deficiency increased the number of larger MSCs and decreased matrix metalloproteinase-2 expression, resulting in a high homing capability. TYMP deficiency induced constitutive AKT phosphorylation in MSCs but reduced expression of genes associated with retinoid-interferon-induced mortality-19, a molecule that enhances cell death. Inhibition of TYMP with its selective inhibitor, tipiracil, phenocopied TYMP deficiency, improved post-AMI cardiac function and systolic left ventricle anterior wall thickness, attenuated diastolic stiffness, and reduced infarct size. Conclusions This study demonstrated that TYMP plays an adverse role after AMI. Targeting TYMP may be a novel therapy for patients with AMI.
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Conserved transcription factors promote cell fate stability and restrict reprogramming potential in differentiated cells.
Nat Commun2023 Mar;14(1):1709. doi: 1709.
Missinato Maria A, Murphy Sean, Lynott Michaela, Yu Michael S, Kervadec Anaïs, Chang Yu-Ling, Kannan Suraj, Loreti Mafalda, Lee Christopher, Amatya Prashila, Tanaka Hiroshi, Huang Chun-Teng, Puri Pier Lorenzo, Kwon Chulan, Adams Peter D, Qian Li, Sacco Alessandra, Andersen Peter, Colas Alexandre R,
Abstract
Defining the mechanisms safeguarding cell fate identity in differentiated cells is crucial to improve 1) - our understanding of how differentiation is maintained in healthy tissues or altered in a disease state, and 2) - our ability to use cell fate reprogramming for regenerative purposes. Here, using a genome-wide transcription factor screen followed by validation steps in a variety of reprogramming assays (cardiac, neural and iPSC in fibroblasts and endothelial cells), we identified a set of four transcription factors (ATF7IP, JUNB, SP7, and ZNF207 [AJSZ]) that robustly opposes cell fate reprogramming in both lineage and cell type independent manners. Mechanistically, our integrated multi-omics approach (ChIP, ATAC and RNA-seq) revealed that AJSZ oppose cell fate reprogramming by 1) - maintaining chromatin enriched for reprogramming TF motifs in a closed state and 2) - downregulating genes required for reprogramming. Finally, KD of AJSZ in combination with MGT overexpression, significantly reduced scar size and improved heart function by 50%, as compared to MGT alone post-myocardial infarction. Collectively, our study suggests that inhibition of barrier to reprogramming mechanisms represents a promising therapeutic avenue to improve adult organ function post-injury.
© 2023. The Author(s).
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Berberine attenuates sunitinib-induced cardiac dysfunction by normalizing calcium regulation disorder via SGK1 activation.
Food Chem Toxicol2023 Mar;():113743. doi: 10.1016/j.fct.2023.113743.
Li Congxin, Wu Wenting, Xing Jiahui, Yan Wei, Zhang Jiali, Sun Jinglei, Zhang Zhihan, Qiu Suhua, Xu Yanfang, Wang Xianying,
Abstract
Sunitinib (SNT)-induced cardiotoxicity is associated with abnormal calcium regulation caused by phosphoinositide 3 kinase inhibition in the heart. Berberine (BBR) is a natural compound that exhibits cardioprotective effects and regulates calcium homeostasis. We hypothesized that BBR ameliorates SNT-induced cardiotoxicity by normalizing the calcium regulation disorder via serum and glucocorticoid-regulated kinase 1 (SGK1) activation. Mice, neonatal rat cardiomyocytes (NRVMs), and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used to study the effects of BBR-mediated SGK1 activity on the calcium regulation disorder caused by SNT as well as the underlying mechanism. BBR offered prevention against SNT-induced cardiac systolic dysfunction, QT interval prolongation, and histopathological changes in mice. After the oral administration of SNT, the Ca transient and contraction of cardiomyocytes was significantly inhibited, whereas BBR exhibited an antagonistic effect. In NRVMs, BBR was significantly preventive against the SNT-induced reduction of calcium transient amplitude, prolongation of calcium transient recovery, and decrease in SERCA2a protein expression; however, SGK1 inhibitors resisted the preventive effects of BBR. In hiPSC-CMs, BBR pretreatment significantly prevented SNT from inhibiting the contraction, whereas coincubation with SGK1 inhibitors antagonized the effects of BBR. These findings indicate that BBR attenuates SNT-induced cardiac dysfunction by normalizing the calcium regulation disorder via SGK1 activation.
Copyright © 2023. Published by Elsevier Ltd.
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