Single-cell analysis of graft-infiltrating host cells identifies caspase-1 as a potential therapeutic target for heart transplant rejection.

Aims: Understanding the cellular mechanisms underlying early allograft rejection is crucial for the development of effective immunosuppressant strategies. This study aims to investigate the cellular composition of graft-infiltrating cells during the early rejection stage at a single-cell level and identify potential therapeutic targets. Methods: A heterotopic heart transplant model was established using enhanced green fluorescent protein (eGFP)-expressing mice as recipients of allogeneic or syngeneic grafts. At 3 days post-transplant, eGFP-positive cells infiltrating the grafts were sorted and subjected to single-cell RNA-seq analysis. Potential molecular targets were evaluated by assessing graft survival and functions following administration of various pharmacological inhibitors. Results: A total of 27,053 cells recovered from syngrafts and allografts were classified into 20 clusters based on expression profiles and annotated with a reference dataset. Innate immune cells, including monocytes, macrophages, neutrophils, and dendritic cells, constituted the major infiltrating cell types (>90%) in the grafts. Lymphocytes, fibroblasts, and endothelial cells represented a smaller population. Allografts exhibited significantly increased proportions of monocyte-derived cells involved in antigen processing and presentation, as well as activated lymphocytes, as compared to syngrafts. Differential expression analysis revealed upregulation of interferon activation-related genes in the innate immune cells infiltrating allografts. Pro-inflammatory polarization gene signatures were also enriched in these infiltrating cells of allografts. Gene profiling and intercellular communication analysis identified natural killer cells as the primary source of interferon-γ signaling, activating inflammatory monocytes that displayed strong signals of major histocompatibility complexes and co-stimulatory molecules. The inflammatory response was also associated with promoted T cell proliferation and activation in allografts during the early transplant stages. Notably, caspase-1 exhibited specific upregulation in inflammatory monocytes in response to interferon signaling. The regulon analysis also revealed a significant enrichment of interferon-related motifs within the transcriptional regulatory network of downstream inflammatory genes including caspase-1. Remarkably, pharmacological inhibition of caspase-1 was shown to reduce immune infiltration, prevent acute graft rejection, and improve cardiac contractile function. Conclusion: The single-cell transcriptional profile highlighted the crucial role of caspase-1 in interferon-mediated inflammatory monocytes infiltrating heart transplants, suggesting its potential as a therapeutic target for attenuating rejection.

A Novel Quantitative Electrocardiography Strategy Reveals the Electroinhibitory Effect of Tamoxifen on the Mouse Heart.

Tamoxifen, a selective estrogen receptor modulator, was initially used to treat cancer in women and more recently to induce conditional gene editing in rodent hearts. However, little is known about the baseline biological effects of tamoxifen on the myocardium. In order to clarify the short-term effects of tamoxifen on cardiac electrophysiology of myocardium, we applied a single-chest-lead quantitative method and analyzed the short-term electrocardiographic phenotypes induced by tamoxifen in the heart of adult female mice. We found that tamoxifen prolonged the PP interval and caused a decreased heartbeat, and further induced atrioventricular block by gradually prolonging the PR interval. Further correlation analysis suggested that tamoxifen had a synergistic and dose-independent inhibition on the time course of the PP interval and PR interval. This prolongation of the critical time course may represent a tamoxifen-specific ECG excitatory-inhibitory mechanism, leading to a reduction in the number of supraventricular action potentials and thus bradycardia. Segmental reconstructions showed that tamoxifen induced a decrease in the conduction velocity of action potentials throughout the atria and parts of the ventricles, resulting in a flattening of the P wave and R wave. In addition, we detected the previously reported prolongation of the QT interval, which may be due to a prolonged duration of the ventricular repolarizing T wave rather than the depolarizing QRS complex. Our study highlights that tamoxifen can produce patterning alternations in the cardiac conduction system, including the formation of inhibitory electrical signals with reduced conduction velocity, implying its involvement in the regulation of myocardial ion transport and the mediation of arrhythmias. A Novel Quantitative Electrocardiography Strategy Reveals the Electroinhibitory Effect of Tamoxifen on the Mouse Heart（Figure 9）. A working model of tamoxifen producing acute electrical disturbances in the myocardium. SN, sinus node; AVN, atrioventricular node; RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle.

Retraction: Wang et al. Cardiovascular Disease and Exercise: From Molecular Mechanisms to Clinical Applications. J. Clin. Med. 2022, 11, 7511.

The Journal of Clinical Medicine retracts the article entitled "Cardiovascular Disease and Exercise: From Molecular Mechanisms to Clinical Applications" [...].

An injectable gelatin/sericin hydrogel loaded with human umbilical cord mesenchymal stem cells for the treatment of uterine injury.

Abnormal endometrial receptivity is a major cause of the failure of embryo transplantation, which may lead to infertility, adverse pregnancy, and neonatal outcomes. While hormonal treatment has dramatically improved the fertility outcomes in women with endometriosis, a substantial unmet need persists in the treatment. In this study, methacrylate gelatin (GelMA) and methacrylate sericin (SerMA) hydrogel with human umbilical cord mesenchymal stem cells (HUMSC) encapsulation was designed for facilitating endometrial regeneration and fertility restoration through in situ injection. The presented GelMA/10%SerMA hydrogel showed appropriate swelling ratio, good mechanical properties, and degradation stability. In vitro cell experiments showed that the prepared hydrogels had excellent biocompatibility and cell encapsulation ability of HUMSC. Further in vivo experiments demonstrated that GelMA/SerMA@HUMSC hydrogel could increase the thickness of endometrium and improve the endometrial interstitial fibrosis. Moreover, regenerated endometrial tissue was more receptive to transfer embryos. Summary, we believed that GelMA/SerMA@HUMSC hydrogel will hold tremendous promise to repair or regenerate damaged endometrium.

Construction of multifunctional hydrogel with metal-polyphenol capsules for infected full-thickness skin wound healing.

Damaged skin cannot prevent harmful bacteria from invading tissues, causing infected wounds or even severe tissue damage. In this study, we developed a controlled-release antibacterial composite hydrogel system that can promote wound angiogenesis and inhibit inflammation by sustained releasing Cu-Epigallocatechin-3-gallate (Cu-EGCG) nano-capsules. The prepared SilMA/HAMA/Cu-EGCG hydrogel showed an obvious inhibitory effect on Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). It could also promote the proliferation and migration of L929 fibroblasts. In vivo full-thickness infected wound healing experiments confirmed the angiogenesis and inflammation regulating effect. Accelerate collagen deposition and wound healing speed were also observed in the SilMA/HAMA/Cu-EGCG hydrogel treated group. The findings of this study show the great potential of this controlled-release antibacterial composite hydrogel in the application of chronic wound healing.

Genetic lineage tracing identifies cardiac mesenchymal-to-adipose transition in an arrhythmogenic cardiomyopathy model.

Arrhythmogenic cardiomyopathy (ACM) is one of the most common inherited cardiomyopathies, characterized by progressive fibrofatty replacement in the myocardium. However, the cellular origin of cardiac adipocytes in ACM remains largely unknown. Unraveling the cellular source of cardiac adipocytes in ACM would elucidate the underlying pathological process and provide a potential target for therapy. Herein, we generated an ACM mouse model by inactivating desmosomal gene desmoplakin in cardiomyocytes; and examined the adipogenic fates of several cell types in the disease model. The results showed that SOX9+, PDGFRa+, and PDGFRb+ mesenchymal cells, but not cardiomyocytes or smooth muscle cells, contribute to the intramyocardial adipocytes in the ACM model. Mechanistically, Bmp4 was highly expressed in the ACM mouse heart and functionally promoted cardiac mesenchymal-to-adipose transition in vitro.

Maturation of induced pluripotent stem cell-derived cardiomyocytes and its therapeutic effect on myocardial infarction in mouse.

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have an irreplaceable role in the treatment of myocardial infarction (MI), which can be injected into the transplanted area with new cardiomyocytes (Cardiomyocytes, CMs), and improve myocardial function. However, the immaturity of the structure and function of iPSC-CMs is the main bottleneck at present. Since collagen participates in the formation of extracellular matrix (ECM), we synthesized nano colloidal gelatin (Gel) with collagen as the main component, and confirmed that the biomaterial has good biocompatibility and is suitable for cellular in vitro growth. Subsequently, we combined the PI3K/AKT/mTOR pathway inhibitor BEZ-235 with Gel and found that the two combined increased the sarcomere length and action potential amplitude (APA) of iPSC-CMs, and improved the Ca2+ processing ability, the maturation of mitochondrial morphological structure and metabolic function. Not only that, Gel can also prolong the retention rate of iPSC-CMs in the myocardium and increase the expression of Cx43 and angiogenesis in the transplanted area of mature iPSC-CMs, which also provides a reliable basis for the subsequent treatment of mature iPSC-CMs.

Cardiovascular Disease and Exercise: From Molecular Mechanisms to Clinical Applications.

Inactivity is a significant risk factor for cardiovascular disease. Exercise may greatly enhance the metabolism and function of the cardiovascular system, lower several risk factors, and prevent the development and treatment of cardiovascular disease while delivering easy, physical, and emotional enjoyment. Exercise regulates the cardiovascular system by reducing oxidative stress and chronic inflammation, regulating cardiovascular insulin sensitivity and the body's metabolism, promoting stem cell mobilization, strengthening autophagy and myocardial mitochondrial function, and enhancing cardiovascular damage resistance, among other effects. Appropriate exercise intervention has become an essential adjuvant therapy in clinical practice for treating and rehabilitating various cardiovascular diseases. However, the prescription of exercise for preventing and treating cardiovascular diseases, particularly the precise selection of individual exercise techniques and their volume, remains controversial. Using multiomics to explain further the molecular process underlying the positive effects of exercise on cardiovascular health will not only improve our understanding of the effects of exercise on health but also establish a scientific basis and supply new ideas for preventing and treating cardiovascular diseases by activating the endogenous protective mechanisms of the body and suggesting more specific exercise prescriptions for cardiovascular rehabilitation.

Essential role of MESP1-RING1A complex in cardiac differentiation.

Heart development is controlled by a complex transcriptional network composed of transcription factors and epigenetic regulators. Mutations in key developmental transcription factor MESP1 and chromatin factors, such as PRC1 and cohesin components, have been found in human congenital heart diseases (CHDs), although their functional mechanism during heart development remains elusive. Here, we find that MESP1 interacts with RING1A/RING1, the core component of PRC1. RING1A depletion impairs human cardiomyocyte differentiation, and cardiac abnormalities similar to those in patients with MESP1 mutations were observed in Ring1A knockout mice. Mechanistically, MESP1 associates with RING1A to activate cardiogenic genes through promoter-enhancer interactions regulated by cohesin and CTCF and histone acetylation mediated by p300. Importantly, CHD mutations of MESP1 significantly affect such mechanisms and impair target gene activation. Together, our results demonstrate the importance of MESP1-RING1A complex in heart development and provide insights into the pathogenic mechanisms of CHDs caused by mutations in MESP1, PRC1, and cohesin components.

Effect of modified esophagectomy perioperative technique resection for patients with locally advanced esophageal cancer (tumor length > 8 cm): initial experience in 45 cases.

BACKGROUND: Patients with locally advanced esophageal cancer with a lesion length greater than 8 cm (LCWEC) are prone to high mortality in a short time due to esophagotracheal fistula (ETF) and esophagoaortic fistula (EAF). We tried to explore a safe salvage surgical method during the perioperative period to maximize the resection of the tumor on the premise of safety and reconstruction of the alimentary tract to avoid early death due to ETF and EAF. METHODS: From December 2007 to November 2018, forty-five LCWEC patients were treated using the modified Wu's esophagectomy. Patient features, surgical techniques, postoperative complications, and pathology outcomes were analyzed. RESULTS: The average length of the tumors was 12.5 cm (range 8.1-22.5 cm), and the average transverse tumor diameter was 5.8 cm (range 4.5-7.8 cm). No complications like anastomotic leakage, anastomotic stenosis, chylothorax, delayed gastric emptying, vocal cord paralysis, dumping syndrome, and reflux were detected. The 30-day and in-hospital mortality rates were 0%. Complete (R0) resection was achieved in 38 (84.4%) cases. The resection margin rate of positive anastomosis was 0%. Until the death of the patients, no feeding failure due to gastrointestinal obstruction and early death due to ETF or EAF occurrence. During follow-up, the median time to death was 17.2 months for patients treated with surgery alone and 32 months for patients treated with postoperative multimodal treatment. CONCLUSION: The modified Wu's esophagectomy is a safe and feasible salvage surgical method for LCWEC resection.

Regulation of cohesin-mediated chromosome folding by PDS5 in mammals.

Cohesin regulates sister chromatid cohesion but also contributes to chromosome folding by promoting the formation of chromatin loops, a process mediated by loop extrusion. Although PDS5 regulates cohesin dynamics on chromatin, the exact function of PDS5 in cohesin-mediated chromatin looping remains unclear. Two paralogs of PDS5 exist in vertebrates, PDS5A and PDS5B. Here we show that PDS5A and PDS5B co-localize with RAD21 and CTCF at loop anchors. Rapid PDS5A or PDS5B degradation in liver cancer cells using an inducible degron system reduces chromatin loops and increases loop size. RAD21 enrichment at loop anchors is decreased upon depletion of PDS5A or PDS5B. PDS5B loss also reduces CTCF signals at loop anchors and has a stronger effect on loop enlargement compared with PDS5A. Co-depletion of PDS5A and PDS5B reduces RAD21 levels at loop anchors although the amount of cohesin on chromatin is increased. Our study provides insight into how PDS5 proteins regulate cohesin-mediated chromatin looping.

Nanocomposite hydrogels for biomedical applications.

Nanomaterials' unique structures at the nanometer level determine their incredible functions, and based on this, they can be widely used in the field of nanomedicine. However, nanomaterials do possess disadvantages that cannot be ignored, such as burst release, rapid elimination, and poor bioadhesion. Hydrogels are scaffolds with three-dimensional structures, and they exhibit good biocompatibility and drug release capacity. Hydrogels are also associated with disadvantages for biomedical applications such as poor anti-tumor capability, weak bioimaging capability, limited responsiveness, and so on. Incorporating nanomaterials into the 3D hydrogel network through physical or chemical covalent action may be an effective method to avoid their disadvantages. In nanocomposite hydrogel systems, multifunctional nanomaterials often work as the function core, giving the hydrogels a variety of properties (such as photo-thermal conversion, magnetothermal conversion, conductivity, targeting tumor, etc.). While, hydrogels can effectively improve the retention effect of nanomaterials and make the nanoparticles have good plasticity to adapt to various biomedical applications (such as various biosensors). Nanocomposite hydrogel systems have broad application prospects in biomedicine. In this review, we comprehensively summarize and discuss the most recent advances of nanomaterials composite hydrogels in biomedicine, including drug and cell delivery, cancer treatment, tissue regeneration, biosensing, and bioimaging, and we also briefly discussed the current situation of their commoditization in biomedicine.

Multifunctional electrospun asymmetric wettable membrane containing black phosphorus/Rg1 for enhancing infected wound healing.

Bacterial infection is one of the most frequent complications in the burn and chronic wounds. Inspired by natural existing superhydrophobic surface structures, a novel asymmetric wettable membrane was prepared using the electrospinning technique for facilitating the bacteria-infected wound healing. Herein, the prepared membrane consists of two layers: The hydrophobic outer layer was composed of poly (lactic-co-glycolic) acid (PLGA) and black phosphorus-grafted chitosan (HACC-BP), while the hydrophilic inner layer was composed by using a mixture of gelatin (Gel) with ginsenoside Rg1 (Rg1). Biological studies in vitro showed BP@PLGA/Gel (BP@BM) membrane with excellent antibacterial activity could significantly inhibit the adhesion of bacteria, and Rg1 could facilitate the migration and tube formation of human umbilical vein endothelial cells (HUVECs). Compared to Aquacel Ag dressing, the result in vivo revealed that the Rg1/BP@BM could facilitate better wound healing by triggering phosphoinositide 3-kinase (P-PI3K/PI3K) and phosphorylation of protein kinase B (P-AKT/AKT) signaling pathways, upregulating Ki67, CD31, α-SMA, and TGF-ß1, and downregulating TNF-α, IL-1ß, and IL-6, promoting M2 polarization (IL-10, CD206, and Arg-1) of macrophages, inhibiting M1 polarization (iNOS) of macrophages. These findings suggested that the asymmetric wettable membrane have the huge potential for wound healing.

Engineered Schwann Cell-Based Therapies for Injury Peripheral Nerve Reconstruction.

Compared with the central nervous system, the adult peripheral nervous system possesses a remarkable regenerative capacity, which is due to the strong plasticity of Schwann cells (SCs) in peripheral nerves. After peripheral nervous injury, SCs de-differentiate and transform into repair phenotypes, and play a critical role in axonal regeneration, myelin formation, and clearance of axonal and myelin debris. In view of the limited self-repair capability of SCs for long segment defects of peripheral nerve defects, it is of great clinical value to supplement SCs in necrotic areas through gene modification or stem cell transplantation or to construct tissue-engineered nerve combined with bioactive scaffolds to repair such tissue defects. Based on the developmental lineage of SCs and the gene regulation network after peripheral nerve injury (PNI), this review summarizes the possibility of using SCs constructed by the latest gene modification technology to repair PNI. The therapeutic effects of tissue-engineered nerve constructed by materials combined with Schwann cells resembles autologous transplantation, which is the gold standard for PNI repair. Therefore, this review generalizes the research progress of biomaterials combined with Schwann cells for PNI repair. Based on the difficulty of donor sources, this review also discusses the potential of "unlimited" provision of pluripotent stem cells capable of directing differentiation or transforming existing somatic cells into induced SCs. The summary of these concepts and therapeutic strategies makes it possible for SCs to be used more effectively in the repair of PNI.

Downregulated ALKBH5 contributes to myocardial ischemia/reperfusion injury by increasing m6A modification of Trio mRNA.

Background: The modification of N6-methyladenosine (m6A) is a dynamic and reversible course that might play a role in cardiovascular disease. However, the mechanisms of m6A modification in myocardial ischemia/reperfusion injury (MIRI) remain unclear. Methods: A mouse model of MIRI and a cell model of oxygen-glucose deprivation/reperfusion (OGD/R) HL-1 cells were employed. In an in vivo study, the total RNA m6A modification levels were determined by dot blot, and the key genes related to m6A modification were screened by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. In an in vitro study, the effects of AlkB homolog 5 (ALKBH5), an RNA demethylase, on cell proliferation, cell injury, and apoptosis were detected by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, lactate dehydrogenase (LDH) and cardiac troponin-I (cTnI) levels, and flow cytometry. Besides, the m6A modification-changed and differentially expressed messenger RNA (mRNA) were determined by methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) in ALKBH5-overexpressed HL-1 cells. Finally, the mRNA levels of the promising targeted gene were examined by RT-qPCR and its m6A modification levels were examined by MeRIP-qPCR. Results: Our results showed that RNA m6A modification was involved in MIRI, in which ALKBH5 was downregulated. Functionally, by overexpressing or silencing ALKBH5 in experimental cells, we verified its protective properties on cell proliferation, cell injury, and apoptosis in the process of MIRI. Besides, we provided a mass of latent different mRNAs with m6A modification variation in ALKBH5-overexpressed HL-1 cells. Mechanistically, we further screened the most potential targeted mRNAs and suggested that triple functional domain (Trio) mRNA could be upregulated by ALKBH5 by reducing m6A level of Trio. Conclusions: This study demonstrated that the downregulated ALKBH5 might contribute to MIRI process by increasing the m6A modification of Trio mRNA and downregulating Trio.

Histatin-1 loaded multifunctional, adhesive and conductive biomolecular hydrogel to treat diabetic wound.

Micro-/macroangiopathy, neuropathy and prolonged inflammation are common in diabetic wound, however, traditional wound dressing cannot treat these problems in the same time. Herein, we developed a multifunctional hydrogel with promoted angiogenesis, cell proliferation and anti-inflammation ability to treat diabetic wound. The hydrogel was composed of natural polymers, including gelatin and chitosan, which have excellent biocompatibility. Histatin-1 (His-1) was added into the hydrogel to improve the cell adhesion, proliferation and angiogenesis. Besides, polypyrrole based conductive nanoparticles (G-Ppy) were introduced in the hydrogel to enhance the electrical signal conduction between skin and promote the mechanical strength of the hydrogel. The polypyrrole nanoparticles were growth in the chain of methacryloyl grafted gelatin (Gel-MA), leading to a better biocompatibility and water dispersibility. In vivo wound healing experiment proved that the hydrogel accelerated the wound healing rate, down regulation the expression of pro-inflammation factor TNF-α and upregulation the expression of CD31 and α-SMA, indicating the prospects in the application of diabetic wound healing.

Ce doped polyaniline nanoparticles for absorption and photoacoustic imaging response to GSH in vitro and in vivo.

Glutathione (GSH) is an important biological thiol in cells, which is involved in many physiological processes in the organism and regulates pathological processes of cells. Rapid and accurate monitoring of GSH in vitro and in vivo is quite needed in investigating important biochemical events. In this contribution, innovative cerium (Ce) doped polyaniline (Ce-Fe@PANI NPs) were prepared via Fe(III) induced oxidization polymerization method. Upon addition of GSH, the absorption of Ce-Fe@PANI NPs red shifted from the visible to the NIR region, confirming the excellent absorption response to GSH. Moreover, Ce-Fe@PANI NPs exhibited excellent photoacoustic (PA) imaging enhancement in tube and shifted the PA intensity peak from 680 nm to 820 nm upon addition of GSH. In vitro and in vivo experiment verified that Ce-Fe@PANI NPs can monitor GSH in deep tissues via PA imaging technology. Collectively, this research provides Ce-Fe@PANI NPs would serve as a powerful nanoplatform to realize PA imaging detection of GSH in vitro and in vivo.

[Clinical application of arthroscopic automatic reverse guide wire passer in posterior meniscus root reconstruction].

Objective: To explore the application value and operation skills of arthroscopic automatic reverse guide wire passer (hereinafter referred to as wire passer) in the posterior meniscus root reconstruction. Methods: Between August 2015 and December 2020, 36 patients with posterior meniscus root tears were admitted. There were 16 males and 20 females, with an average age of 46 years (range, 26-66 years). There were 15 cases of sports injury and 21 cases of degenerative injury. The disease duration was 3-180 days, with a median of 28 days. The posterior root of the medial meniscus was injured in 29 cases, and the posterior root of the lateral meniscus was injured in 7 cases. The preoperative Lysholm score of the knee joint was 47.6±3.9, and the International Knee Score Committee (IKDC) score was 39.3±3.0. The meniscus was sutured by using wire passer under arthroscopy. During operation, the suture operation was evaluated according to the self-defined evaluation standard. Lysholm score and IKDC score were used to evaluate knee joint function. Results: All meniscuses were sutured successfully by using wire passer. The operation time of suture was 5-15 minutes, with an average of 10 minutes. According to the self-defined evaluation standard, the suture operation was scored as 0-10, with an average of 5. After operation, except for 2 cases of incision fat liquefaction, the incisions of the other patients healed by first intention. All patients were followed up 1-3 years, with an average of 1.5 years. The Lysholm score was 88.2±2.1 and the IKDC score was 51.7±2.3 at 1 year after operation, showing significant difference when compared with preoperative ones ( P<0.001). Fifteen cases underwent MRI re-examination, the results showed that the continuity and integrity of the posterior root had been restored. Conclusion: Under arthroscopy, the wire passer for the posterior meniscus root reconstruction has the advantages of simple operation, reliable suture quality, and shorter operation time.

Injectable conductive gelatin methacrylate / oxidized dextran hydrogel encapsulating umbilical cord mesenchymal stem cells for myocardial infarction treatment.

Umbilical cord mesenchymal stem cells (UCMSCs) transplantation has been proposed as a promising treatment modality for myocardial infarction (MI), but the low retention rate remains a considerable challenge. Injectable natural polymer hydrogels with conductivity ability are highly desirable as cell delivery vehicles to repair infarct myocardium and restore the cardiac function. In this work, we developed a hydrogel system based on gelatin methacrylate (GelMA) and oxidized dextran (ODEX) as cell delivery vehicles for MI. And dopamine could be used as a reductant of graphene oxide (GO) to form reductive GO (rGO). By adjusting the amount of rGO, the conductivity of hydrogels with 0.5 mg/mL rGO concentration (≈10-4 S/cm) was similar to that of natural heart tissue. In vitro cell experiments showed that the prepared hydrogels had excellent biocompatibility and cell delivery ability of UCMSCs. More importantly, GelMA-O5/rGO hydrogel could promote UCMSCs growth and proliferation, improve the myocardial differentiation ability of UCMSCs, and up-regulate the expression of cTnI and Cx43. Further in vivo experiments demonstrated that GelMA-O5/rGO/UCMSCs Hydrogel could significantly improve the ejection fraction (EF) of rats and significantly reduce myocardial infarct area compared to PBS group, promote the survival of UCMSCs, enhance the expression level of cTnI and Cx43, and decrease the expression level of caspase-3. The findings of this study suggested that the injectable conductive GelMA-O5/rGO hydrogel encapsulating UCMSCs could improve damaged myocardial tissue and reconstruct myocardial function, which will be a promising therapeutic strategy for cardiac repair.

An MMP-degradable and conductive hydrogel to stabilize HIF-1α for recovering cardiac functions.

Rationale: Although a few injectable hydrogels have shown a reliable biosafety and a moderate promise in treating myocardial infarction (MI), the updated hydrogel systems with an on-demand biodegradation and multi-biofunctions to deliver therapeutic drug would achieve more prominent efficacy in the future applications. In this report, a conductive and injectable hydrogel crosslinked by matrix metalloproteinase-sensitive peptides (MMP-SP) was rationally constructed to stabilize hypoxia-inducible factor-1α (HIF-1α) to recover heart functions after MI. Methods: Firstly, tetraaniline (TA) was incorporated into partially oxidized alginate (ALG-CHO) to endow the hydrogels with conductivity. The 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (DPCA) nanodrug was manufactured with high drug loading capacity and decorated with polymerized dopamine (PDA) to achieve a stable release of the drug. Both ALG-CHO and DPCA@PDA can be cross-linked by thiolated hyaluronic acid (HA-SH) and thiolated MMP-SP to construct a MMP-degradable and conductive hydrogel. After administration in the infarcted heart of rats, echocardiographic assessments, histological evaluation, and RT-PCR were used to evaluate therapeutic effects of hydrogels. Results: The cell viability and the results of subcutaneous implantation verify a good cytocompatibility and biocompatibility of the resulting hydrogels. The hydrogel shows remarkable strength in decreasing the expression of inflammatory factors, maintaining a high level of HIF-1α to promote the vascularization, and promoting the expression of junctional protein connexin 43. Meanwhile, the multifunctional hydrogels greatly reduce the infarcted area (by 33.8%) and improve cardiac functions dramatically with ejection fraction (EF) and fractional shortening (FS) being increased by 31.3% and 19.0%, respectively. Conclusion: The as-prepared hydrogels in this report achieve a favorable therapeutic effect, offering a promising therapeutic strategy for treating heart injury.