Targeted, programmable, and precise tandem duplication in the mammalian genome.

Tandem duplications are frequent structural variations of the genome and play important roles in genetic disease and cancer. However, interpreting the phenotypic consequences of tandem duplications remains challenging, in part owing to the lack of genetic tools to model such variations. Here, we developed a strategy, tandem duplication via prime editing (TD-PE), to create targeted, programmable, and precise tandem duplication in the mammalian genome. In this strategy, we design a pair of in trans prime editing guide RNAs (pegRNAs) for each targeted tandem duplication, which encode the same edits but prime the single-stranded DNA (ssDNA) extension in opposite directions. The reverse transcriptase (RT) template of each extension is designed homologous to the target region of the other single guide RNA (sgRNA) to promote the reannealing of the edited DNA strands and the duplication of the fragment in between. We showed that TD-PE produced robust and precise in situ tandem duplications of genomic fragments ranging from ∼50 bp to ∼10 kb, with a maximal efficiency up to 28.33%. By fine-tuning the pegRNAs, we achieved simultaneous targeted duplication and fragment insertion. Finally, we successfully produced multiple disease-relevant tandem duplications, showing the general utility of TD-PE in genetic research.

In Situ Fabrication of SnO2 Nanowalls for Robust Acetylene Sensing at Low Temperature.

Acetylene (C2 H2 ) monitoring in real time and online is essential for erasing transformer risks and guaranteeing normal equipment operation and operator safety. This study examines the direct fabrication of ultrathin SnO2 nanowalls on Ag-Pd substrates using a simple solvothermal method that doesn't demand the use of any additional motivators or templates. The thickness and shape of the nanowalls can be controlled by varying the cetyl trimethyl ammonium bromide (CTAB) concentration in the solvent. As observed, the gas sensor (SnO2 -3) fabricated by 2.4 g CTAB exhibits superior gas-sensing features. This is primarily due to the hollow structure constructed by the arrangement of nanowalls, which delivers not only enough gas diffusion pathways but also enough reaction sites during the gas sensing processes. The findings suggest that low-cost SnO2 nanowalls created using a straightforward procedure could be taken into consideration as prospective candidates for use in industrial C2 H2 sensing applications.

Direct cellular reprogramming techniques for cardiovascular regenerative therapeutics.

Cardiovascular diseases remain a leading cause of hospitalization affecting approximately 38 million people worldwide. While pharmacological and revascularization techniques can improve the patient's survival and quality of life, they cannot help reversing myocardial infarction injury and heart failure. Direct reprogramming of somatic cells to cardiomyocyte and cardiac progenitor cells offers a new approach to cellular reprogramming and paves the way for translational regenerative medicine. Direct reprogramming can bypass the pluripotent stage with the potential advantage of non-immunogenic cell products, reduced carcinogenic risk, and no requirement for embryonic tissue. The process of directly reprogramming cardiac cells was first achieved through the overexpression of transcription factors such as GATA4, MEF2C, and TBX5. However, over the past decade, significant work has been focused on enhancing direct reprogramming using a mixture of transcription factors, microRNAs, and small molecules to achieve cardiac cell fate. This review discusses the evolution of direct reprogramming, recent progress in achieving efficient cardiac cell fate conversion, and describes the reprogramming mechanisms at a molecular level. We also explore various viral and non-viral delivery methods currently being used to aid in the delivery of reprogramming factors to improve efficiency. However, further studies will be needed to overcome molecular and epigenetic barriers to successfully achieve translational cardiac regenerative therapeutics.

Cuproptosis related gene PDHB is identified as a biomarker inversely associated with the progression of clear cell renal cell carcinoma.

BACKGROUND: Cuproptosis is a newly discovered programmed cell death dependent on mitochondrial respiratory disorder induced by copper overload. Pyruvate dehydrogenase E1 subunit beta (PDHB) is one of the cuproptosis genesand is a nuclear-encoded pyruvate dehydrogenase, which catalyzes the conversion of pyruvate to acetyl coenzyme A. However, the mechanism of PDHB in clear cell renal cell carcinoma (ccRCC) remains unclear. METHODS: We used data from TCGA and GEO to assess the expression of PDHB in normal and tumor tissues. We further analyzed the relationship between PDHB and somatic mutations and immune infiltration. Finally, we preliminarily explored the impact of PDHB on ccRCC. RESULTS: The expression level of PDHB was lower in tumor tissue compared with normal tissue. Meanwhile, the expression level of PDHB was also lower in high-grade tumors than low-grade tumors. PDHB is positively correlated with prognosis in ccRCC. Furthermore, PDHB may be associated with decreased risk of VHL, PBRM1 and KDM5C mutations. In 786-O cells, copper chloride could promote the expression of cuproptosis genes (DLAT, PDHB and FDX1) and inhibit cell growth. Last but not least, we found that PDHB could inhibit the proliferation and migration of ccRCC cells. CONCLUSION: Our results demonstrated that PDHB could inhibit the proliferation, migration and invasion in ccRCC cells, which might be a prognostic predictor of ccRCC. Targeting this molecular might provide a new therapeutic strategy for patients with advanced ccRCC.

A new multimodality fusion classification approach to explore the uniqueness of schizophrenia and autism spectrum disorder.

Schizophrenia (SZ) and autism spectrum disorder (ASD) sharing overlapping symptoms have a long history of diagnostic confusion. It is unclear what their differences at a brain level are. Here, we propose a multimodality fusion classification approach to investigate their divergence in brain function and structure. Using brain functional network connectivity (FNC) calculated from resting-state fMRI data and gray matter volume (GMV) estimated from sMRI data, we classify the two disorders using the main data (335 SZ and 380 ASD patients) via an unbiased 10-fold cross-validation pipeline, and also validate the classification generalization ability on an independent cohort (120 SZ and 349 ASD patients). The classification accuracy reached up to 83.08% for the testing data and 72.10% for the independent data, significantly better than the results from using the single-modality features. The discriminative FNCs that were automatically selected primarily involved the sub-cortical, default mode, and visual domains. Interestingly, all discriminative FNCs relating to the default mode network showed an intermediate strength in healthy controls (HCs) between SZ and ASD patients. Their GMV differences were mainly driven by the frontal gyrus, temporal gyrus, and insula. Regarding these regions, the mean GMV of HC fell intermediate between that of SZ and ASD, and ASD showed the highest GMV. The middle frontal gyrus was associated with both functional and structural differences. In summary, our work reveals the unique neuroimaging characteristics of SZ and ASD that can achieve high and generalizable classification accuracy, supporting their potential as disorder-specific neural substrates of the two entwined disorders.

A Hierarchical Blockchain-Assisted Conditional Privacy-Preserving Authentication Scheme for Vehicular Ad Hoc Networks.

Through information sharing, vehicles can know the surrounding road condition information timely in Vehicular Adhoc Networks. To ensure the validity of these messages and the security of vehicles, the message authentication, privacy-preserving, and delay problems are three important issues. Although many conditional privacy-preserving authentication schemes have been proposed to ensure secure communication, there still exist some imperfections such as frequent interactions or unlinkability. From this, our paper proposes a novel hierarchical blockchain-assisted authentication scheme to solve these existing issues comprehensively. First, unlinkability is achieved by a dynamic key derivation algorithm. Second, the proposed scheme can reduce correlation processing delay, queuing delay, and deployment costs by adopting hierarchical Vehicle Fog Computing. Third, cross-region authentication is achieved by taking advantage of the properties of blockchain. In addition, we demonstrate our scheme can fulfill the security criteria of the Vehicular Adhoc Network by security analysis. Furthermore, the simulations are carried out to show its availability by using JAVA and NS-3. The findings reveal that the suggested method outperforms earlier schemes in terms of computation cost and communication cost. All in all, making the authentication scheme more efficient and concise is the focus of our future research.

Data Collection Based on Opportunistic Node Connections in Wireless Sensor Networks.

The working⁻sleeping cycle strategy used for sensor nodes with limited power supply in wireless sensor networks can effectively save their energy, but also causes opportunistic node connections due to the intermittent communication mode, which can affect the reliability of data transmission. To address this problem, a data collection scheme based on opportunistic node connections is proposed to achieve efficient data collection in a network with a mobile sink. In this scheme, the mobile sink first broadcasts a tag message to start a data collection period, and all nodes that receive this message will use the probe message to forward their own source information to the mobile sink. On receiving these probe messages, the mobile sink then constructs an opportunistic connection random graph by analyzing the source information included in them, and calculates the optimal path from itself to each node in this random graph, therefore a spanning tree could be generated with the mobile sink play as the root node, finally, it broadcasts this spanning tree so that each node could obtain an optimal path from itself to the mobile sink to forward the sensing data. In addition, a routing protocol that adapts to different nodes operating statuses is proposed to improve the reliability of data transmission. Simulation results show that the proposed scheme works better concerning the packet delivery rate, energy consumption and network lifetime.

Adjustable Trajectory Design Based on Node Density for Mobile Sink in WSNs.

The design of movement trajectories for mobile sink plays an important role in data gathering for Wireless Sensor Networks (WSNs), as it affects the network coverage, and packet delivery ratio, as well as the network lifetime. In some scenarios, the whole network can be divided into subareas where the nodes are randomly deployed. The node densities of these subareas are quite different, which may result in a decreased packet delivery ratio and network lifetime if the movement trajectory of the mobile sink cannot adapt to these differences. To address these problems, we propose an adjustable trajectory design method based on node density for mobile sink in WSNs. The movement trajectory of the mobile sink in each subarea follows the Hilbert space-filling curve. Firstly, the trajectory is constructed based on network size. Secondly, the adjustable trajectory is established based on node density in specific subareas. Finally, the trajectories in each subarea are combined to acquire the whole network's movement trajectory for the mobile sink. In addition, an adaptable power control scheme is designed to adjust nodes' transmitting range dynamically according to the movement trajectory of the mobile sink in each subarea. The simulation results demonstrate that the proposed trajectories can adapt to network changes flexibly, thus outperform both in packet delivery ratio and in energy consumption the trajectories designed only based on the network size and the whole network node density.

Tracking Mobile Sinks via Analysis of Movement Angle Changes in WSNs.

Existing methods for tracking mobile sinks in Wireless Sensor Networks (WSNs) often incur considerable energy consumption and overhead. To address this issue, we propose a Detour-Aware Mobile Sink Tracking (DAMST) method via analysis of movement angle changes of mobile sinks, for collecting data in a low-overhead and energy efficient way. In the proposed method, while a mobile sink passes through a region, it appoints a specific node as a region agent to collect information of the whole region, and records nodes near or on its trajectory as footprints. If it needs information from the region agent in a future time it will construct an energy efficient path from the region agent to itself by calculating its own movement angles according to the footprints, as well as getting rid of detours by analyzing these movement angles. Finally, the performance of the tracking method is evaluated systematically under different trajectory patterns and footprint appointment intervals. The simulation results consolidate that DAMST has advantages in reducing energy consumption and data overhead.

A survey of brain functional network extraction methods using fMRI data.

Functional network (FN) analyses play a pivotal role in uncovering insights into brain function and understanding the pathophysiology of various brain disorders. This paper focuses on classical and advanced methods for deriving brain FNs from functional magnetic resonance imaging (fMRI) data. We systematically review their foundational principles, advantages, shortcomings, and interrelations, encompassing both static and dynamic FN extraction approaches. In the context of static FN extraction, we present hypothesis-driven methods such as region of interest (ROI)-based approaches as well as data-driven methods including matrix decomposition, clustering, and deep learning. For dynamic FN extraction, both window-based and windowless methods are surveyed with respect to the estimation of time-varying FN and the subsequent computation of FN states. We also discuss the scope of application of the various methods and avenues for future improvements.

SMART (Splitting-Merging Assisted Reliable) Independent Component Analysis for Extracting Accurate Brain Functional Networks.

Functional networks (FNs) hold significant promise in understanding brain function. Independent component analysis (ICA) has been applied in estimating FNs from functional magnetic resonance imaging (fMRI). However, determining an optimal model order for ICA remains challenging, leading to criticism about the reliability of FN estimation. Here, we propose a SMART (splitting-merging assisted reliable) ICA method that automatically extracts reliable FNs by clustering independent components (ICs) obtained from multi-model-order ICA using a simplified graph while providing linkages among FNs deduced from different-model orders. We extend SMART ICA to multi-subject fMRI analysis, validating its effectiveness using simulated and real fMRI data. Based on simulated data, the method accurately estimates both group-common and group-unique components and demonstrates robustness to parameters. Using two age-matched cohorts of resting fMRI data comprising 1,950 healthy subjects, the resulting reliable group-level FNs are greatly similar between the two cohorts, and interestingly the subject-specific FNs show progressive changes while age increases. Furthermore, both small-scale and large-scale brain FN templates are provided as benchmarks for future studies. Taken together, SMART ICA can automatically obtain reliable FNs in analyzing multi-subject fMRI data, while also providing linkages between different FNs.

HAX1-Overexpression Augments Cardioprotective Efficacy of Stem Cell-Based Therapy Through Mediating Hippo-Yap Signaling.

Although stem/progenitor cell therapy shows potential for myocardial infarction repair, enhancing the therapeutic efficacy could be achieved through additional genetic modifications. HCLS1-associated protein X-1 (HAX1) has been identified as a versatile modulator responsible for cardio-protective signaling, while its role in regulating stem cell survival and functionality remains unknown. In this study, we investigated whether HAX1 can augment the protective potential of Sca1+ cardiac stromal cells (CSCs) for myocardial injury. The overexpression of HAX1 significantly increased cell proliferation and conferred enhanced resistance to hypoxia-induced cell death in CSCs. Mechanistically, HAX1 can interact with Mst1 (a prominent conductor of Hippo signal transduction) and inhibit its kinase activity for protein phosphorylation. This inhibition led to enhanced nuclear translocation of Yes-associated protein (YAP) and activation of downstream therapeutic-related genes. Notably, HAX1 overexpression significantly increased the pro-angiogenic potential of CSCs, as demonstrated by elevated expression of vascular endothelial growth factors. Importantly, implantation of HAX1-overexpressing CSCs promoted neovascularization, protected against functional deterioration, and ameliorated cardiac fibrosis in ischemic mouse hearts. In conclusion, HAX1 emerges as a valuable and efficient inducer for enhancing the effectiveness of cardiac stem or progenitor cell therapeutics.

IABC: A Toolbox for Intelligent Analysis of Brain Connectivity.

Brain functional networks and connectivity have played an important role in exploring brain function for understanding the brain and disclosing the mechanisms of brain disorders. Independent component analysis (ICA) is one of the most widely applied data-driven methods to extract brain functional networks/connectivity. However, it is hard to guarantee the reliability of networks/connectivity due to the randomness of component order and the difficulty in selecting an optimal component number in ICA. To facilitate the analysis of brain functional networks and connectivity using ICA, we developed a MATLAB toolbox called Intelligent Analysis of Brain Connectivity (IABC). IABC incorporates our previously proposed group information guided independent component analysis (GIG-ICA), NeuroMark, and splitting-merging assisted reliable ICA (SMART ICA) methods, which can estimate reliable individual-subject neuroimaging measures for further analysis. After user inputs functional magnetic resonance imaging (fMRI) data of multiple subjects that are regularly organized (e.g., in Brain Imaging Data Structure (BIDS)) and clicks a few buttons to set parameters, IABC automatically outputs brain functional networks, their related time courses, and functional network connectivity of each subject. All these neuroimaging measures are promising for providing clues in understanding brain function and differentiating brain disorders.

Macroporous honeycomb-like magnesium oxide fabricated as long-life and outstanding Pb(II) adsorbents combined with mechanism insight.

The macroporous honeycomb-like MgO (MHM) had been successfully prepared by hard template method using polystyrene (PS) spheres with different particle sizes of about 400, 600, and 800 nm, respectively. The adsorption performance (3700, 3470, and 3087 mg/g) and specific surface areas (64.0, 51.4, and 34.4 m2/g) of MHM materials were inversely proportional to their pore diameters. Among the prepared MHM materials, MHM-400 exhibited the most excellent adsorption performance of 3700 mg/g towards Pb(II) at 25 °C. In this study, the macropore size in MHM played a major role in the adsorption process; Dubinin-Radushkevich (D-R) model further indicated that Pb(II) removal by MHM-400 was dominated by chemical adsorption. The thermodynamic analysis (ΔG0 < 0, ΔH0 > 0, and ΔS0 > 0) revealed that the Pb(II) adsorption was spontaneous and endothermic. After storing for 360 days, the Pb(II) removal efficiency of MHM-400 was still higher than 98.2%, exhibiting ultra-long life for Pb(II) capture. MHM-400 also exhibited high anti-interference ability towards typically coexisting ions (Na+ and K+). According to the density functional theory (DFT) calculation, the Pb could be adsorbed on the top site of the oxygen atom at the surface of the cubic MgO (200) plane; the adsorption energy (Ead) was 0.159 eV. The XRD and FTIR analyses revealed the further formation of Pb3(CO3)2(OH)2 and PbO after Pb(II) adsorption. Furthermore, MHM-400 could effectively remove both Cd(II) and Pb(II) ions from wastewater within 20 min, and the adsorption efficiency achieved > 99%, suggesting that MHM-400 was a potential material for effective Pb(II) removal.

Activation of MG53 Enhances Cell Survival and Engraftment of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Injured Hearts.

BACKGROUND AND OBJECTIVE: Our previous studies demonstrated that MG53 protein can protect the myocardium, but its use as a therapeutic is challenging due to its short half-life in blood circulation. This study aimed to investigate the cardioprotective role of MG53 on human induced pluripotent stem cell-derived cardiomyocytes (HiPSC-CMs) in the context of myocardial ischemia/reperfusion (I/R). METHODS: In vitro: HiPSC-CMs were transfected with adenoviral MG53 (HiPSC-CMsMG53), in which the expression of MG53 can be controlled by doxycycline (Dox), and the cells were then exposed to H2O2 to mimic ischemia/reperfusion injury. In vivo: HiPSC-CMsMG53 were transplanted into the peri-infarct region in NSG™ mice after I/R. After surgery, mice were treated with Dox (+ Dox) to activate MG53 expression (sucrose as a control of -Dox) and then assessed by echocardiography and immunohistochemistry. RESULTS: MG53 can be expressed in HiPSC-CMMG53 and released into the culture medium after adding Dox. The cell survival rate of HiPSC-CMMG53 was improved by Dox under the H2O2 condition. After 14 and 28 days of ischemia/reperfusion (I/R), transplanted HiPSC-CMsMG53 + Dox significantly improved heart function, including ejection fraction (EF) and fractional shortening (FS) in mice, compared to HiPSC-CMsMG53-Dox, and reduced the size of the infarction. Additionally, HiPSC-CMMG53 + Dox mice demonstrated significant engraftment in the myocardium as shown by staining human nuclei-positive cells. In addition, the cell survival-related AKT signaling was found to be more active in HiPSC-CMMG53 + Dox transplanted mice's myocardium compared to the HiPSC-CMMG53-Dox group. Notably, the Dox treatment did not cause harm to other organs. CONCLUSION: Inducible MG53 expression is a promising approach to enhance cell survival and engraftment of HiPSC-CMs for cardiac repair.

Improving the adsorption performance of urea by using polyhydroxy groups to modify two-dimensional Ti3C2Tx.

Wearable artificial kidney can provide continuous dynamic dialysis for uremia patients. For the sake of practical application, the critical step is to find an adsorbent that can effectively remove urea and have excellent biological compatibility. The layered Ti3C2Tx (DL-Ti3C2Tx) with high specific surface area and good dispersion was prepared by a two-step etching method. From the first principles calculation, urea can be adsorbed by different groups (-F, -O, -OH) on the surface of Ti3C2Tx, among which -OH has the greatest binding energy to urea. Therefore, DL-Ti3C2Tx was modified with different alkali solutions (KOH, NaOH, LiOH) to introduce -OH on the surface, which can increase the adsorption capacity of urea. The experimental results showed that DL-Ti3C2Tx (LiOH-Ti3C2Tx) after treated by LiOH had the highest urea adsorption efficiency, and the urea removal rate of LiOH-Ti3C2Tx was still higher than 92% when the urea concentration was 500 mg/L. In the Simulated dialysate, Ti3C2Tx treated with three kinds of alkali solutions still maintained a good adsorption efficiency for urea, and still had a certain adsorption capacity after recycling for four times. Biocompatibility experiments showed that Ti3C2Tx in different concentrations did not cause hemolysis of erythrocyte, and had no obvious damage to vascular endothelial cells. This study greatly improves the urea adsorption efficiency of MXene, which has a broad application prospect in the selection of adsorbent for wearable artificial kidney.

Myocardial IGF2R is a critical mediator of inflammation and fibrosis after ischemia-reperfusion injury.

Ischemia-reperfusion (I/R) injury is a common occurrence in various surgical procedures used to treat heart diseases. However, the role of insulin-like growth factor 2 receptor (IGF2R) during the process of myocardial I/R remains unclear. Therefore, this study aims to investigate the expression, distribution, and functionality of IGF2R in various I/R-associated models (such as reoxygenation, revascularization, and heart transplant). Loss-of-function studies (including myocardial conditional knockout and CRISPR interference) were performed to clarify the role of IGF2R in I/R injuries. Following hypoxia, IGF2R expression increased, but this effect was reversed upon restoration of oxygen levels. Loss of myocardial IGF2R was found to enhance the cardiac contractile functions, and reduced cell infiltration or cardiac fibrosis of I/R mouse models compared to the genotype control. CRISPR-inhibition of IGF2R decreased cell apoptotic death under hypoxia. RNA sequencing analysis indicated that myocardial IGF2R played a critical role in regulating the inflammatory response, innate immune response, and apoptotic process following I/R. Integrated analysis of the mRNA profiling, pulldown assays, and mass spectrometry identified granulocyte-specific factors as potential targets of myocardial IGF2R in the injured heart. In conclusion, myocardial IGF2R emerges as a promising therapeutic target to ameliorate inflammation or fibrosis following I/R injuries.

Global burden and inequality of autism spectrum disorders: Based on data from the 2019 Global Burden of Disease study.

It is unclear whether the health equity of autism spectrum disorders (ASDs) has changed in different years, regions, and gender. The aims of this study were to provide a comprehensive description of the ASDs burden and provide evidence for improvement in health policies regarding ASDs inequality. This study is a population-based cross-sectional study based on the Global Burden of Disease datasets 1990-2019. We collected detailed information on ASDs between 1990 and 2019 in 204 countries worldwide, derived from the Global Burden of Disease study in 2019. Burden was calculated in terms of the incidence, prevalence and years lived with disability (YLDs). Concentration curves and concentration indices were used to summarize the degree of income-related inequality in the burden of ASDs. The overall age-standardized incidence rate (ASIR), age-standardized prevalence rate (ASPR) and age-standardized YLDs rate (ASYR) of ASDs was 9.3 (95 %UI 7.7-11.1), 369.4 (95 %UI 305.9-441.2), 56.3 (95 %UI 36.8-81.5) per 100,000 people, respectively. The ASIR, ASPR and ASYR of ASDs affected three times as many males as females. The changing trends of age-standardized rates of ASDs showed that the ASIR of ASDs a slow growing trend globally. However, the ASPR and ASYR of ASDs showed a slow decreasing trend globally. All the concentration curves were below the line of equality and statistically significant. There was no significant difference in the age-standardized rate for different years in socio-demographic index-related inequality happened over 29 years (p > 0.05). The global burden of ASDs has remained higher in males and pro-rich, the income-related inequality tended not to change between 1990 and 2019.

Repetitive drug delivery using Light-Activated liposomes for potential antimicrobial therapies.

Overuse or misuse of antibiotics and their residues in the environment results in the emergence and prevalence of drug-resistant bacteria and leads to serious health problems. Notable progress in liposome research has been made in drug delivery and several liposomal drugs have been approved for clinical use owing to its biocompatibility and improved efficacy. Recently, liposomes have been engineered further to release encapsulated drugs on the target of interest in a dose-controlled fashion in response to external stimuli such as light, pH, and heat. Among those, light-activated liposomal drug delivery gained a lot of attention because drug release at the targeted sites can be precisely controlled by varying laser/light duration, energy and beam area. We envision potential applications of the light-activated liposomal delivery systems for effective drug-resistant antimicrobial therapies. The use of light-activated liposomes will be widely spread in antimicrobial therapies if the amount of drug is precisely controlled for a prolonged time at a target location. In this review, we discussed the breadth and depth of various light-activated liposomal drug delivery technology. Emphasis was given to repetitive release mechanism and applications of light-activated liposomes because the repeatability provides stability and precise control of the drug delivery system to prevent overdose of antimicrobials and treat with minimal doses. We described limitations on translation from pre-clinical to clinical settings and strategies to overcome the limitations. Careful consideration of light-responsive materials, lipid composition, laser parameters and laser safety is important when selecting and designing the drug delivery system for successful applications.

Advances in Cellular Reprogramming-Based Approaches for Heart Regenerative Repair.

Continuous loss of cardiomyocytes (CMs) is one of the fundamental characteristics of many heart diseases, which eventually can lead to heart failure. Due to the limited proliferation ability of human adult CMs, treatment efficacy has been limited in terms of fully repairing damaged hearts. It has been shown that cell lineage conversion can be achieved by using cell reprogramming approaches, including human induced pluripotent stem cells (hiPSCs), providing a promising therapeutic for regenerative heart medicine. Recent studies using advanced cellular reprogramming-based techniques have also contributed some new strategies for regenerative heart repair. In this review, hiPSC-derived cell therapeutic methods are introduced, and the clinical setting challenges (maturation, engraftment, immune response, scalability, and tumorigenicity), with potential solutions, are discussed. Inspired by the iPSC reprogramming, the approaches of direct cell lineage conversion are merging, such as induced cardiomyocyte-like cells (iCMs) and induced cardiac progenitor cells (iCPCs) derived from fibroblasts, without induction of pluripotency. The studies of cellular and molecular pathways also reveal that epigenetic resetting is the essential mechanism of reprogramming and lineage conversion. Therefore, CRISPR techniques that can be repurposed for genomic or epigenetic editing become attractive approaches for cellular reprogramming. In addition, viral and non-viral delivery strategies that are utilized to achieve CM reprogramming will be introduced, and the therapeutic effects of iCMs or iCPCs on myocardial infarction will be compared. After the improvement of reprogramming efficiency by developing new techniques, reprogrammed iCPCs or iCMs will provide an alternative to hiPSC-based approaches for regenerative heart therapies, heart disease modeling, and new drug screening.