intramyocardial-transplantation-msc-loading-injectable-hydrogels

Intramyocardial Transplantation of MSC-Loading Injectable Hydrogels after Myocardial Infarction in a Murine Model

One of the major issues facing current cardiac stem cell therapies for preventing postinfarct heart failure is the low retention and survival rates of ...

a-rabbit-aortic-valve-stenosis-model-induced-by-direct-balloon-injury

A Rabbit Aortic Valve Stenosis Model Induced by Direct Balloon Injury

Animal models are emerging as an important tool to understand the pathologic mechanisms underlying aortic valve stenosis (AVS) because of the lack of ...

The Catholic University of Korea

The Catholic University of korea

Endothelial progenitor cells (EPCs) were transfected with the haptoglobin (Hp) gene to investigate the effect of Hp on cell function. Hp potentiated the gene expression of various pro-angiogenic factors in the EPCs. The Hp-modified EPCs also increased in vitro tube formation on Matrigel compared with control cells. In hindlimb ischaemia models, Hp-EPCs showed a greater ability for improving blood perfusion and recovery from ischaemic injury. These results indicate that Hp improves EPC function in neovasculogenesis, which suggests that ex vivo modification of EPCs with the Hp gene can be applied to the treatment of vascular damage.

Enhancement of angiogenic and vasculogenic potential of endothelial progenitor cells by haptoglobin.

A 56-year-old female was referred to our hospital due to a mass measuring 5 cm in size in the left pelvic cavity, which was found incidentally during a health examination by ultrasonography. Exploratory laparotomy was performed and the mass was located at the left retroperitoneal parametrium without invasion of the uterus and ovary. The pathology report confirmed squamous cell carcinoma. Even after further studies, we did not find any other primary lesion. Human papillomavirus (HPV) DNA chip test (HPV 9G DNA Membrane Kit, Biometrixtechnology Inc.) showed that the surgical specimen was positive for HPV 18. She received adjuvant chemotherapy and would receive radiation therapy for the possibility of occult gynecologic cancer. Retroperitoneal squamous cell carcinoma of unknown primary is extremely rare and little is known about it. It is reported that HPV may be associated with the disease. Hence, the result of HPV test could have an impact on finding a suspicious primary lesion and treatment modality in this case. 

HPV-Related Retroperitoneal Squamous Cell Carcinoma of Unknown Primary: A Case Report.

Rapid and accurate diagnosis is crucial to reduce both the shedding and clinical signs of canine parvovirus (CPV). The quartz crystal microbalance (QCM) is a new tool for measuring frequency changes associated with antigen-antibody interactions. In this study, the QCM biosensor and ProLinker™ B were used to rapidly diagnosis CPV infection. ProLinker™ B enables antibodies to be attached to a gold-coated quartz surface in a regular pattern and in the correct orientation for antigen binding. Receiver operating characteristics (ROC) curves were used to set a cut-off value using reference CPVs (two groups: one CPV-positive and one CPV-negative). The ROC curves overlapped and the point of intersection was used as the cut-off value. A QCM biosensor with a cut-off value of -205 Hz showed 95.4% (104/109) sensitivity and 98.0% (149/152) specificity when used to test 261 field fecal samples compared to PCR. In conclusion, the QCM biosensor described herein is eminently suitable for the rapid diagnosis of CPV infection with high sensitivity and specificity. Therefore, it is a promising analytical tool that will be useful for clinical diagnosis, which requires rapid and reliable analyses.

A novel assay for detecting canine parvovirus using a quartz crystal microbalance biosensor.

We report on a patient with lung adenocarcinoma and a concomitant epithelial growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) translocation who developed a disease flare after discontinuing gefitinib. A 63-year-old woman with lung adenocarcinoma and a concomitant activating EGFR mutation and ALK translocation was treated with first-line gefitinib. After 4 months, she discontinued the gefitinib due to disease progression. She was admitted to the emergency room complaining of severe dyspnea and back pain 22 days after discontinuing gefitinib. A chest image showed numerous hematogenous lung metastases and extensive bone metastasis, which was compatible with a previously reported disease flare after stopping EGFR tyrosine kinase inhibitors (TKIs). Aggravated respiratory failure and progression of multiple organ dysfunction led to death 26 days after discontinuing gefitinib. This was a rare case of a disease flare up in patient with a concomitant EGFR mutation and ALK translocation after discontinuing an EGFR-TKI.

Disease flare after discontinuing gefitinib in a patient with lung adenocarcinoma and concomitant epithelial growth factor receptor mutation and anaplastic lymphoma kinase translocation.

We evaluated the relationship between myocardial infarct size and inflammatory response using cardiac magnetic resonance imaging (CMR) in an acute myocardial infarction (AMI) mouse model. Myocardial infarction (MI) was induced in 14 mice by permanent ligation of the left anterior descending artery. Late gadolinium enhancement (LGE), manganese-enhanced MRI (MEMRI), and magnetofluorescent nanoparticle MRI (MNP-MRI) were performed 1, 2, and 3 days after MI, respectively. The size of the enhanced lesion was quantitatively determined using Otsu's thresholding method in area-based and sector-based approaches and was compared statistically. Linear correlation between the enhanced lesion sizes was evaluated by Pearson's correlation coefficients. Differences were compared using Bland-Altman analysis. The size of the inflammatory area determined by MNP-MRI (57.1 ± 10.1%) was significantly larger than that of the infarct area measured by LGE (40.8 ± 11.7%,  < 0.0001) and MEMRI (44.1 ± 14.9%,  < 0.0001). There were significant correlations between the sizes of the infarct and inflammatory lesions (MNP-MRI versus LGE:  = 0.3418,  = 0.0099; MNP-MRI versus MEMRI:  = 0.4764,  = 0.0002). MNP-MRI provides information about inflammatory responses in a mouse model of AMI. Thus, MNP-MRI associated with LGE and MEMRI may play an important role in monitoring the disease progression in MI.

MR Assessment of Acute Pathologic Process after Myocardial Infarction in a Permanent Ligation Mouse Model: Role of Magnetic Nanoparticle-Contrasted MRI.

Background The immune and inflammatory responses play a considerable role in left ventricular remodeling after myocardial infarction (MI). Binding of AhR (aryl hydrocarbon receptor) to its ligands modulates immune and inflammatory responses; however, the effects of AhR in the context of MI are unknown. Therefore, we evaluated the potential association between AhR and MI by treating mice with a nontoxic endogenous AhR ligand, ITE (2-[1'H-indole-3'-carbonyl]-thiazole-4-carboxylic acid methyl ester). We hypothesized that activation of AhR by ITE in MI mice would boost regulatory T-cell differentiation, modulate macrophage activity, and facilitate infarct healing. Methods and Results Acute MI was induced in C57BL/6 mice by ligation of the left anterior descending coronary artery. Then, the mice were randomized to daily intraperitoneal injection of ITE (200 µg/mouse, n=19) or vehicle (n=16) to examine the therapeutic effects of ITE during the postinfarct healing process. Echocardiographic and histopathological analyses revealed that ITE-treated mice exhibited significantly improved systolic function (<0.001) and reduced infarct size compared with control mice (<0.001). In addition, we found that ITE increased regulatory T cells in the mediastinal lymph node, spleen, and infarcted myocardium, and shifted the M1/M2 macrophage balance toward the M2 phenotype in vivo, which plays vital roles in the induction and resolution of inflammation after acute MI. In vitro, ITE expanded the Foxp3 (forkhead box protein P3-positive) regulatory T cells and tolerogenic dendritic cell populations. Conclusions Activation of AhR by a nontoxic endogenous ligand, ITE, improves cardiac function after MI. Post-MI mice treated with ITE have a significantly lower risk of developing advanced left ventricular systolic dysfunction than nontreated mice. Thus, the results imply that ITE has a potential as a stimulator of cardiac repair after MI to prevent heart failure.

Activation of Aryl Hydrocarbon Receptor by ITE Improves Cardiac Function in Mice After Myocardial Infarction.

Severe cardiac damage following myocardial infarction (MI) causes excessive inflammation, which sustains tissue damage and often induces adverse cardiac remodeling toward cardiac function impairment and heart failure. Timely resolution of post-MI inflammation may prevent cardiac remodeling and development of heart failure. Cell therapy approaches for MI are time-consuming and costly, and have shown marginal efficacy in clinical trials. Here, nanoparticles targeting the immune system to attenuate excessive inflammation in infarcted myocardium are presented. Liposomal nanoparticles loaded with MI antigens and rapamycin (L-Ag/R) enable effective induction of tolerogenic dendritic cells presenting the antigens and subsequent induction of antigen-specific regulatory T cells (Tregs). Impressively, intradermal injection of L-Ag/R into acute MI mice attenuates inflammation in the myocardium by inducing Tregs and an inflammatory-to-reparative macrophage polarization, inhibits adverse cardiac remodeling, and improves cardiac function. Nanoparticle-mediated blocking of excessive inflammation in infarcted myocardium may be an effective intervention to prevent the development of post-MI heart failure.

Nanoparticle-Mediated Blocking of Excessive Inflammation for Prevention of Heart Failure Following Myocardial Infarction.

Aminoacyl-tRNA synthetase-interacting multifunctional protein 3 (AIMP3), a tumor suppressor, mediates a progeroid phenotype in mice by downregulating lamin A. We investigated whether AIMP3 induces laminopathy and senescence of human aortic smooth muscle cells (HASMCs) and is associated with vascular aging in mice and humans in line with decreased lamin A expression. Cellular senescence was evaluated after transfecting HASMCs with AIMP3. Molecular analyses of genes encoding AIMP3, lamin A, chemokine (C-C motif) ligand 2 (CCL2), and C-C chemokine receptor type 2 (CCR2) and histological comparisons of aortas were performed with mice at various ages (7 weeks, 5 months, 12 months, 24 months, and 32 months), AIMP3-transgenic mice, and human femoral arteries of cadavers. AIMP3-transfected HASMCs exhibited increased AIMP3 and senescence marker p16 protein expression and decreased lamin A protein expression in accordance with their disrupted nuclear morphology in histological analyses. AIMP3-transgenic mice displayed increased AIMP3 protein expression and decreased lamin A protein expression in aortas together with typical aging pathologies. Similar changes were observed in wild-type aging (24-month-old) mice but not in wild-type young (7-week-old) mice. In humans, AIMP3 and lamin A protein expression was higher and lower, respectively, in femoral arteries of elderly individuals than in those of their younger counterparts. This study found that AIMP3 overexpression in vitro decreased lamin A expression and induced nuclear laminopathy and cellular senescence. Similar findings were made in the vasculature of aging mice and elderly humans.

AIMP3 induces laminopathy and senescence of vascular smooth muscle cells by reducing lamin A expression and leads to vascular aging in vivo.

Identification of a vulnerable atherosclerotic plaque before rupture is an unmet clinical need. Integrating nanomedicine with multimodal imaging has the potential to precisely detect biological processes in atherosclerosis. We synthesized silica-coated iron oxide nanoparticles (SIONs) coated with rhodamine B isothiocyanate and polyethylene glycol and investigated their feasibility in the detection of macrophages in inflamed atherosclerotic plaques of apolipoprotein E-deficient (ApoE) mice via magnetic resonance (MR) and fluorescence reflectance (FR) imaging. In vitro cellular uptake of SIONs was assessed in macrophages using confocal laser scanning microscopy (CLSM). In vivo MR imaging was performed 24 h after SION injection via the tail vein in 26-week-old ApoE mice fed a high-cholesterol diet (HCD). We also performed FR imaging of the extracted aortas from four different mice: two normal-diet-fed C57BL/6 mice injected with saline or 10 mg/kg SIONs and two HCD-fed ApoE mice injected with 5 or 10 mg/kg SIONs. The harvested aortas were cryosectioned and stained with immunohistochemical staining. The CLSM images at 24 h after incubation showed efficient uptake of SIONs by macrophages, with no evidence of cytotoxicity. The in vivo and ex vivo MR and FR images demonstrated SION deposition in the atheroma. Upon immunohistochemical staining of the aorta, CLSM images revealed colocalization of macrophages and SIONs in the atherosclerotic plaque. These results demonstrate that polyethylene glycosylated SIONs could be a highly effective method to identify macrophage activity in atherosclerotic plaques as a multimodal imaging agent.

In vivo MRI detection of intraplaque macrophages with biocompatible silica-coated iron oxide nanoparticles in murine atherosclerosis.

 extract (LOE), a traditional herbal medicine used to enhance blood circulation and to reduce inflammation, induced NO-mediated endothelium-dependent relaxation, and reduced the formation of reactive oxygen species (ROS). The study investigated whether LOE improves endothelial dysfunction and reduces plaque inflammation and progression by inhibiting ROS generation in a mouse model of atherosclerosis. Eight-week-old apolipoprotein E-deficient (apoE) mice fed with a western diet (WD) were randomized into different groups by administering vehicle (0.5% carboxymethylcellulose (CMC)), LOE (100 mg/kg/day), or losartan (30 mg/kg/day) by gavage until the age of 28 weeks. Fourteen male C57BL/6 mice that were fed normal chow and treated with CMC were used as negative controls. Similar to losartan treatment, LOE treatment induced the concentration-dependent relaxation of aorta rings in WD-fed apoE mice. LOE treatment significantly reduced the vascular ROS formation and expression of NADPH oxidase subunits, including p22phox and p47phox. Compared with WD-fed apoE mice, mice exposed to chronic LOE treatment exhibited reductions in plaque inflammation-related fluorescence signals and atherosclerotic lesions. These effects were greater than those of losartan treatment. In conclusion, LOE treatment improves endothelial dysfunction and reduces plaque inflammation as well as lesion areas by reducing vascular NADPH oxidase-induced ROS generation in a mouse model of atherosclerosis.

A Standardized  Extract Improves Endothelial Dysfunction and Attenuates Plaque Development in Hyperlipidemic ApoE-Knockout Mice.

Current stem cell-based therapy for cardiac repair and regeneration after myocardial infarction (MI) is not readily translatable into clinical scenarios due to the low retention and survival of the transplanted cells. Here, we evaluated a simple and feasible design of gelatin-hydroxyphenyl propionic acid (GH) hydrogel as an in situ cross-linkable and injectable cell delivery platform for cardiac tissue regeneration. The GH hydrogel exhibited improved cell retention and survival in vitro and in vivo when encapsulating mouse bone marrow-derived mesenchymal stem cells (MSCs) that were used as promising therapeutic candidates for stem cell therapy. Moreover, we demonstrated that MSC-encapsulating GH hydrogels led to a significant improvement in cardiac functional metrics, such as the fractional shortening (FS), ejection fraction (EF), and end-systolic volume (ESV). Similarly, MSC-encapsulating GH hydrogels induced favorable effects in the cardiac structures of the infarcted heart, producing less fibrosis and thicker infarcted walls. These results suggest that GH hydrogels can be used as an instructive cell delivery platform to provide a suitable microenvironment for transplanted cells; therefore, their in vivo applications combined with MSCs may provide great potential for repair and regeneration of injured cardiac tissues after MI.

MSC-Encapsulating in Situ Cross-Linkable Gelatin Hydrogels To Promote Myocardial Repair.

Heart failure (HF) is a frequent consequence of myocardial infarction (MI). Identification of the precise, time-dependent composition of inflammatory cells may provide clues for the establishment of new biomarkers and therapeutic approaches targeting post-MI HF. Here, we investigate the spatiotemporal dynamics of MI-associated immune cells in a mouse model of MI using spatial transcriptomics and single-cell RNA-sequencing (scRNA-seq). We identify twelve major immune cell populations; their proportions dynamically change after MI. Macrophages are the most abundant population at all-time points (>60%), except for day 1 post-MI. Trajectory inference analysis shows upregulation of Trem2 expression in macrophages during the late phase post-MI. In vivo injection of soluble Trem2 leads to significant functional and structural improvements in infarcted hearts. Our data contribute to a better understanding of MI-driven immune responses and further investigation to determine the regulatory factors of the Trem2 signaling pathway will aid the development of novel therapeutic strategies for post-MI HF.

ArticleTotal : 2	Year
Publication title Cited by 1	2020
Publication title Cited by 2	2023

Article	Year
Enhancement of angiogenic and vasculogenic potential of endothelial progenitor cells by haptoglobin. FEBS letters\| PubMed ID: 19751729	2009
HPV-Related Retroperitoneal Squamous Cell Carcinoma of Unknown Primary: A Case Report. Cancer research and treatment : official journal of Korean Cancer Association\| PubMed ID: 25687847	2015
A novel assay for detecting canine parvovirus using a quartz crystal microbalance biosensor. Journal of virological methods\| PubMed ID: 25813597	2015
Disease flare after discontinuing gefitinib in a patient with lung adenocarcinoma and concomitant epithelial growth factor receptor mutation and anaplastic lymphoma kinase translocation. Journal of thoracic disease\| PubMed ID: 28740693	2017
MR Assessment of Acute Pathologic Process after Myocardial Infarction in a Permanent Ligation Mouse Model: Role of Magnetic Nanoparticle-Contrasted MRI. Contrast media & molecular imaging\| PubMed ID: 29114174	2017
Activation of Aryl Hydrocarbon Receptor by ITE Improves Cardiac Function in Mice After Myocardial Infarction. Journal of the American Heart Association\| PubMed ID: 34157850	2021
Nanoparticle-Mediated Blocking of Excessive Inflammation for Prevention of Heart Failure Following Myocardial Infarction. Small (Weinheim an der Bergstrasse, Germany)\| PubMed ID: 34216428	2021
AIMP3 induces laminopathy and senescence of vascular smooth muscle cells by reducing lamin A expression and leads to vascular aging in vivo. Experimental gerontology\| PubMed ID: 34274427	2021
In vivo MRI detection of intraplaque macrophages with biocompatible silica-coated iron oxide nanoparticles in murine atherosclerosis. Journal of applied biomaterials & functional materials\| PubMed ID: 34520279	2021
A Standardized Extract Improves Endothelial Dysfunction and Attenuates Plaque Development in Hyperlipidemic ApoE-Knockout Mice. Plants (Basel, Switzerland)\| PubMed ID: 34834858	2021
MSC-Encapsulating in Situ Cross-Linkable Gelatin Hydrogels To Promote Myocardial Repair. ACS applied bio materials\| PubMed ID: 35021655	2020
Spatiotemporal dynamics of macrophage heterogeneity and a potential function of Trem2 macrophages in infarcted hearts. Nature communications\| PubMed ID: 35933399	2022

Eun-Hye Park

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