Immunomodulatory Effect of Epidermal Growth Factor Secreted by Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells on Atopic Dermatitis

Background and Objectives@#Human mesenchymal stem cells (MSCs) are emerging as a treatment for atopic dermatitis (AD), a chronic inflammatory skin disorder that affects a large number of people across the world. Treatment of AD using human umbilical cord blood-derived MSCs (hUCB-MSCs) has recently been studied. However, the mechanism underlying their effect needs to be studied continuously. Thus, the objective of this study was to investigate the immunomodulatory effect of epidermal growth factor (EGF) secreted by hUCB-MSCs on AD. @*Methods@#and Results: To explore the mechanism involved in the therapeutic effect of MSCs for AD, a secretome array was performed using culture medium of hUCB-MSCs. Among the list of genes common for epithelium development and skin diseases, we focused on the function of EGF. To elucidate the effect of EGF secreted by hUCB-MSCs, EGF was downregulated in hUCB-MSCs using EGF-targeting small interfering RNA. These cells were then co-cultured with keratinocytes, Th2 cells, and mast cells. Depletion of EGF disrupted immunomodulatory effects of hUCB-MSCs on these AD-related inflammatory cells. In a Dermatophagoides farinae-induced AD mouse model, subcutaneous injection of hUCB-MSCs ameliorated gross scoring, histopathologic damage, and mast cell infiltration. It also significantly reduced levels of inflammatory cytokines including interleukin (IL)-4, tumor necrosis factor (TNF)-α, thymus and activation-regulated chemokine (TARC), and IL-22, as well as IgE levels. These therapeutic effects were significantly attenuated at all evaluation points in mice injected with EGF-depleted hUCB-MSCs. @*Conclusions@#EGF secreted by hUCB-MSCs can improve AD by regulating inflammatory responses of keratinocytes, Th2 cells, and mast cells.

Optimization of Microenvironments Inducing Differentiation of Tonsil-Derived Mesenchymal Stem Cells into Endothelial Cell-Like Cells

BACKGROUND: Stem cell engineering is appealing consideration for regenerating damaged endothelial cells (ECs) because stem cells can differentiate into EC-like cells. In this study, we demonstrate that tonsil-derived mesenchymal stem cells (TMSCs) can differentiate into EC-like cells under optimal physiochemical microenvironments.METHODS: TMSCs were preconditioned with Dulbecco's Modified Eagle Medium (DMEM) or EC growth medium (EGM) for 4 days and then replating them on Matrigel to observe the formation of a capillary-like network under light microscope. Microarray, quantitative real time polymerase chain reaction, Western blotting and immunofluorescence analyses were used to evaluate the expression of gene and protein of EC-related markers.RESULTS: Preconditioning TMSCs in EGM for 4 days and then replating them on Matrigel induced the formation of a capillary-like network in 3 h, but TMSCs preconditioned with DMEM did not form such a network. Genome analyses confirmed that EGM preconditioning significantly affected the expression of genes related to angiogenesis, blood vessel morphogenesis and development, and vascular development. Western blot analyses revealed that EGM preconditioning with gelatin coating induced the expression of endothelial nitric oxide synthase (eNOS), a mature EC-specific marker, as well as phosphorylated Akt at serine 473, a signaling molecule related to eNOS activation. Gelatin-coating during EGM preconditioning further enhanced the stability of the capillary-like network, and also resulted in the network more closely resembled to those observed in human umbilical vein endothelial cells.CONCLUSION: This study suggests that under specific conditions, i.e., EGM preconditioning with gelatin coating for 4 days followed by Matrigel, TMSCs could be a source of generating endothelial cells for treating vascular dysfunction.

Association of serum mineral parameters with mortality in hemodialysis patients: Data from the Korean end-stage renal disease registry

BACKGROUND: We investigated the associations between mineral metabolism parameters and mortality to identify optimal targets in Korean hemodialysis patients. METHODS: Among hemodialysis patients registered in the end-stage renal disease registry of the Korean Society of Nephrology between March 2012 and June 2017, those with serum calcium, phosphorus, and intact parathyroid hormone (iPTH) measured at enrollment were included. Association of serum levels of calcium, phosphorus, and iPTH with all-cause mortality was analyzed. RESULTS: Among 21,433 enrolled patients, 3,135 (14.6%) died during 24.8 ± 14.5 months of follow-up. After multivariable adjustment, patients in the first quintile of corrected calcium were associated with lower mortality (hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.71–0.99; P = 0.003), while those in the fifth quintile were associated with higher mortality (HR, 1.39; 95% CI, 1.20–1.61; P < 0.001) compared with those in the third quintile. For phosphorus, only the lowest quintile was significantly associated with increased mortality (HR, 1.24; 95% CI, 1.08–1.43; P = 0.003). The lowest (HR, 1.18; 95% CI, 1.02–1.36; P = 0.026) and highest quintiles of iPTH (HR, 1.24; 95% CI, 1.05–1.46; P = 0.013) were associated with increased mortality. For target counts achieved according to the Kidney Disease Outcomes Quality Initiative guideline, patients who did not achieve any mineral parameter targets hadhigher mortality than those who achieved all three targets (HR, 1.37; 95% CI, 1.12–1.67; P = 0.003). CONCLUSION: In Korean hemodialysis patients, high serum calcium, low phosphorus, and high and low iPTH levels were associated with increased all-cause mortality.

Esophageal Artery Pseudoaneurysm and Takayasu Arteritis in a Patient with Autosomal Dominant Polycystic Kidney Disease

A 47-year-old female previously diagnosed with ADPKD visited the hospital due to sudden pain in her upper abdomen and back. Esophagogastroduodenoscopy, contrast-enhanced abdominal computed tomography (CT), and CT angiography identified an esophageal artery pseudoaneurysm and hematoma in the esophagus. Urgent angiography and embolization were performed. After the procedure, CT angiography and positron emission tomography were performed due to differences in blood pressure between the arms. The patient was also found to have Takayasu arteritis and subsequently received outpatient follow-up care. The possible mechanisms that cause vascular abnormalities in ADPKD patients include damaged vascular integrity due to abnormal polycystin expression caused by PKD mutations and connective tissue abnormalities. Further research is needed to confirm these mechanisms, and ADPKD patients should be assessed for vascular abnormalities.

Acute Kidney Injury Following Chemical Burns Caused by Hexavalent Chromium / 대한내과학회지

The metal chromium is widely used in industry. Hexavalent chromium is a strong oxidizing agent, and exposure to some hexavalent compounds can cause serious problems, such as skin ulcers, acute gastroenteritis, acute tubular necrosis with renal failure, and hepatic necrosis. We report a case of acute kidney injury following skin exposure to hexavalent chromium, which burned a relatively small percentage of the total body surface area (TBSA). A 49-year-old man developed oliguria and acute kidney injury 3 days after burning about 5% of his TBSA with chromic acid solution, causing second-to third-degree chemical burns. His creatinine level increased to 12.5 mg/dL. The patient underwent hemodialysis with supportive care. His renal function improved and the dialysis was discontinued. The serum and urine chromium concentrations also decreased.

Successful Infliximab Therapy in a Patient with Refractory Takayasu's Arteritis

Takayasu's arteritis (TA), a granulomatous vasculitis, affects the aorta and its major branches. Glucocorticoids are an effective treatment for patients with active TA, but some patients fail to achieve or maintain remission with the conventional therapy, and side effects resulting from long-term glucocorticoid therapy are potentially serious. Anti-tumor necrosis factor-alpha agents, such as infliximab, may be efficient in patients with refractory TA. We report on a 24-year-old female patient with refractory TA who was treated successfully with infliximab. Clinical remission was induced as determined by repeated 18F-fluoro-2-deoxy-D-glucose positron emission tomography scans combined with assay of serological inflammatory markers.

Expression of Tenocyte Lineage-Related Factors from Tonsil-Derived Mesenchymal Stem Cells

Human palatine tonsil-derived mesenchymal stem cells (TMSCs) are known to be a new source of progenitor cells. Using waste tissue after tonsillectomy as a cell provider can be the biggest benefit of TMSCs, compared with other stem cells. The purpose of this study was to investigate tenogenic differentiation of TMSCs and to access the differential effects of transforming growth factor beta 3 (TGF-β3) on the tenogenesis of TMSCs. Human tonsil was obtained after tonsillectomy. Using a cytometric analysis, we were able to find that the TMSCs had typical mesenchymal stem cell markers: positive for CD73, CD90, and CD105, and negative for CD14, CD34, and CD45. Using TGF-β3, the expressions of tenocyte-specific genes and proteins, such as collagen type 1 (COL1), tenomodulin (TNMD), and scleraxis (SCX), were measured by a quantitative polymerase chain reaction (PCR), immunofluorescence staining, immunohistochemistry and Western blot analyses. Quantitative PCR assay showed that TGF-β3 significantly increased the expressions of tenocyte lineage marker genes, including COL1, TNMD, and SCX, at a 3-day treatment, compared with control. However, these increases were not found at long-term exposures (7 or 10 days), except that TNMD expression was maintained at 50 ng/mL at a 7-day exposure to TGF-β3. Like genes, the protein expression levels of COL1, TNMD, and SCX were also induced in TGF-β3-treated TMSCs in a 3-day treatment, which were maintained for 10 days, as evidenced by immunofluorescence staining, immunohistochemistry and Western blot analyses. This study demonstrated that TMSCs in tenogenic stimulation with TGF-β3 have a high tenogenic differentiation potential.

Massive Hemoptysis due to Endotracheal Hemangioma: A Case Report and Literature Review / 결핵및호흡기질환

Tracheal hemangioma is a rare benign vascular tumor in adults. We reported a case of massive hemoptysis caused by a cavernous hemangioma in a 75-year-old man. This is the first report, to our knowledge, of a tracheal cavernous hemangioma that presented with massive hemoptysis. The lesion was removed with a CO2 laser under rigid laryngoscopy. Endovascular tumors, such as tracheobronchial hemangiomas, should be considered a diagnostic option in cases of massive hemoptysis without a significant underlying lung lesion.

A Case of Delayed Diagnosis of Pulmonary Paragonimiasis due to Improvement after Anti-tuberculosis Therapy / 결핵및호흡기질환

Here, we report a case of pulmonary paragonimiasis that was improved with initial anti-tuberculosis (TB) therapy but confused with reactivated pulmonary TB. A 53-year-old Chinese female presented with a persistent productive cough with foul smelling phlegm and blood streaked sputum. Radiologic findings showed subpleural cavitary consolidation in the right upper lobe (RUL). Bronchoscopic and cytological examination showed no remarkable medical feature. She was diagnosed with smear-negative TB, and her radiologic findings improved after receiving a 6-month anti-TB therapy. The chest CT scans, however, obtained at 4 months after completion of anti-TB therapy showed a newly developed subpleural consolidation in the RUL. She refused pathologic confirmation and was re-treated with anti-TB medication. Nevertheless, her chest CT scans revealed newly developed cavitary nodules at 5 months after re-treatment. She underwent thoracoscopic wedge resection; the pathological examination reported that granuloma caused by Paragonimus westermani. Paragonimiasis should also be considered in patients assessed with smear-negative pulmonary TB.

The Analysis of Vitamin C Concentration in Organs of Gulo-/- Mice Upon Vitamin C Withdrawal

BACKGROUND: Vitamin C is an essential nutrient for maintaining human life. Vitamin C insufficiency in the plasma is closely related with the development of scurvy. However, in vivo kinetics of vitamin C regarding its storage and consumption is still largely unknown. METHODS: We used Gulo-/- mice, which cannot synthesize vitamin C like human. Vitamin C level in plasma and organs from Gulo-/- mice was examined, and it compared with the level of wild-type mice during 5 weeks. RESULTS: The significant weight loss of Gulo-/- mice was shown at 3 weeks after vitamin C withdrawal. However, there was no differences between wild-type and vitamin C-supplemented Gulo-/- mice (3.3 g/L in drinking water). The concentration of vitamin C in plasma and organs was significantly decreased at 1 week after vitamin C withdrawal. Vitamin C is preferentially deposited in adrenal gland, lymph node, lung, and brain. There were no significant changes in the numbers and CD4/CD8 ratio of splenocytes in Gulo-/- mice with vitamin C withdrawal for 4 weeks. And the architecture of spleen in Gulo-/- mice was disrupted at 5 weeks after vitamin C withdrawal. CONCLUSION: The vitamin C level of Gulo-/- mice was considerably decreased from 1 week after vitamin C withdrawal. Vitamin C is preferentially stored in some organs such as brain, adrenal gland and lung.

The Anti-tumor Activity of Vitamin C via the Increase of Fas (CD95) and MHC I Expression on Human Stomach Cancer Cell Line, SNU1

BACKGROUND: It is already known that high concentration of vitamin C induces apoptosis on tumor cells. However, there is no report regarding the function of vitamin C on the modulation of immune susceptibility of cancer. Therefore, we investigated whether vitamin C can modulate immune susceptibility of tumor cells, especially on the induction of Fas-mediated apoptosis. METHODS: First, the optimal concentration of vitamin C, which cannot induce damages on tumor cells for 36 hrs. We found that 2 mM of vitamin C did not show harmful effect. In addition, the optimal concentration of agonistic anti-Fas Abs for 18 hrs was examined. RESULTS: As a result, 400 ng/ml of agonistic anti-Fas Abs did not induce apoptosis on tumor cells. Next, we tried to find the effect of 2 mM of vitamin C on the modulation of the susceptibility to agonistic anti-Fas Abs. When tumor cells were cultured with 400 ng/ml of agonistic anti-Fas Abs for 18 hrs, after pre-treatment with 2 mM of vitamin C for 24 hrs, viability of cells was decreased. Interestingly, we found that the expression of Fas (CD95) and MHC class I was increased by the treatment of vitamin C. CONCLUSION: Taken together, vitamin C increases the susceptibility of tumor cells to anti-Fas Abs and the expression of Fas (CD95) and MHC class I on tumor cells.