FGF-17 from Hypoxic Human Wharton's Jelly-Derived Mesenchymal Stem Cells Is Responsible for Maintenance of Cell Proliferation at Late Passages

BACKGROUND AND OBJECTIVES: Although it is well known that hypoxic culture conditions enhance proliferation of human mesenchymal stem cells, the exact mechanism is not fully understood. In this study, we investigated the effect of fibroblast growth factor (FGF)-17 from hypoxic human Wharton's Jelly-derived mesenchymal stem cells (hWJ-MSCs) on cell proliferation at late passages. METHODS AND RESULTS: hWJ-MSCs were cultured in α-MEM medium supplemented with 10% fetal bovine serum (FBS) in normoxic (21% O₂) and hypoxic (1% O₂) conditions. Protein antibody array was performed to analyze secretory proteins in conditioned medium from normoxic and hypoxic hWJ-MSCs at passage 10. Cell proliferation of hypoxic hWJ-MSCs was increased compared with normoxic hWJ-MSCs from passage 7 to 10, and expression of secretory FGF-17 was highly increased in conditioned medium from hypoxic hWJ-MSCs at passage 10. Knockdown of FGF-17 in hypoxic and normoxic hWJ-MSCs decreased cell proliferation, whereas treatment of hypoxic and normoxic hWJ-MSCs with recombinant protein FGF-17 increased their proliferation. Signal transduction of FGF-17 in hypoxic and normoxic hWJ-MSCs involved the ERK1/2 pathway. Cell phenotypes were not changed under either condition. Differentiation-related genes adiponectin, Runx2, and chondroadherin were downregulated in normoxic hWJ-MSCs treated with rFGF-17, and upregulated by siFGF-17. Expression of alkaline phosphatase (ALP), Runx2, and chondroadherin was upregulated in hypoxic hWJ-MSCs, and this effect was rescued by transfection with siFGF-17. Only chondroadherin was upregulated in hypoxic hWJ-MSCs with rFGF-17. CONCLUSIONS: In hypoxic culture conditions, FGF-17 from hypoxic hWJ-MSCs contributes to the maintenance of high proliferation at late passages through the ERK1/2 pathway.

Enhanced Anti-Cancer Effects of Conditioned Medium from Hypoxic Human Umbilical Cord–Derived Mesenchymal Stem Cells

BACKGROUND AND OBJECTIVES: There have been contradictory reports on the pro-cancer or anti-cancer effects of mesenchymal stem cells. In this study, we investigated whether conditioned medium (CM) from hypoxic human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) (H-CM) showed enhanced anti-cancer effects compared with CM from normoxic hUC-MSCs (N-CM). METHODS AND RESULTS: Compared with N-CM, H-CM not only strongly reduced cell viability and increased apoptosis of human cervical cancer cells (HeLa cells), but also increased caspase-3/7 activity, decreased mitochondrial membrane potential (MMP), and induced cell cycle arrest. In contrast, cell viability, apoptosis, MMP, and cell cycle of human dermal fibroblast (hDFs) were not significantly changed by either CM whereas caspase-3/7 activity was decreased by H-CM. Protein antibody array showed that activin A, Beta IG-H3, TIMP-2, RET, and IGFBP-3 were upregulated in H-CM compared with N-CM. Intracellular proteins that were upregulated by H-CM in HeLa cells were represented by apoptosis and cell cycle arrest terms of biological processes of Gene Ontology (GO), and by cell cycle of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. In hDFs, negative regulation of apoptosis in biological process of GO and PI3K-Akt signaling pathway of KEGG pathways were represented. CONCLUSIONS: H-CM showed enhanced anti-cancer effects on HeLa cells but did not influence cell viability or apoptosis of hDFs and these different effects were supported by profiling of secretory proteins in both kinds of CM and intracellular signaling of HeLa cells and hDFs.

Heme Oxygenase-1 Induction and Anti-inflammatory Actions of Atractylodes macrocephala and Taraxacum herba Extracts Prevented Colitis and Was More Effective than Sulfasalazine in Preventing Relapse

BACKGROUND/AIMS: In inflammatory bowel disease (IBD), repeated bouts of remission and relapse occur in patients and can impose a risk of colitis-associated cancer. We hypothesized that plant extracts of Atractylodes macrocephala (AM) or Taraxacum herba (TH) may be better than sulfasalazine for treating this disease because these extracts can promote additional regeneration. METHODS: Murine intestinal epithelial IEC-6 cells were pretreated with AM or TH before a lipopolysaccharide (LPS)-induced challenge. Acute colitis was induced with 7 days of dextran sulfate sodium (DSS) in male C57BL/6 mice, and extracts of AM and TH were administered for 2 weeks before DSS administration. RESULTS: In vitro studies demonstrated that AM or TH treatment reduced LPS-induced COX-2 and tumor necrosis factor-α mRNA levels but increased heme oxygenase-1 (HO-1). Oral preadministration of AM and TH rescued mice from DSS-induced colitis by inhibiting inflammatory mediators via inactivated extracellular signal regulated kinase and repressed nuclear factor κB and signal transducer and activator of transcription 3, but the effect was weaker for sulfasalazine than that for the extracts. Anti-inflammatory activities occurred via the inhibition of macrophage and T lymphocyte infiltrations. Unlike sulfasalazine, which did not induce HO-1, TH extracts afforded significant HO-1 induction. CONCLUSIONS: Because the AM or TH extracts were far superior in preventing DSS-induced colitis than sulfasalazine, AM or TH extracts can be considered natural agents that can prevent IBD relapse.

Therapeutic Potential of Human Mesenchymal Stem Cells for Treating Ischemic Limb Diseases

Ischemic limb diseases are induced by different obstructions of peripheral arteries. These obstructions result in insufficient nutrient and oxygen supplies to the extremities, thereby leading to severe tissue damage that is in turn related to severe morbidities and mortalities. Mesenchymal stem cells (MSCs) have been isolated from various sources. These cells are multipotent with respect to differentiation and are also characterized by migration, immune suppression, and secretion of paracrine factors. Mesenchymal stem cells have been proposed to have therapeutic potential for the treatment of ischemic limb diseases. In preclinical experiments, injection of single MSCs has been shown to increase angiogenesis and blood flow in ischemic hindlimb animal models; several molecular mechanisms of angiogenesis have also been elucidated. Furthermore, modified strategies have been developed for enhancing angiogenesis and the efficacy of MSCs. These strategies have demonstrated significant effects in pre-clinical studies. In clinical trials, MSCs have shown significant effects in the treatment of ischemic limb diseases. In this review, we focus on the therapeutic properties of human MSCs and the modified methods for enhancing angiogenesis in pre-clinical experiments. We also discuss the clinical applications of MSCs for treating limb ischemia.

Vascular Calcification Scores are Associated with Arterial Stiffness, Inflammation, and Nutrition in Hemodialysis Patients / 대한내과학회지

BACKGROUND/AIMS: The vascular calcification (VC) score on a plain X-ray is associated with cardiovascular disease and mortality in hemodialysis (HD) patients. This study examined the correlations among the VC scores for the hands and pelvis X-rays, arterial stiffness, inflammation, and nutrition in HD patients. METHODS: VC was evaluated using plain x-rays of the hands and pelvis. Patients were categorized into the VC (+) (VC score > or = 3) or VC (-) (VC score < 3) groups. We measured the pulse wave velocity (PWV), ankle brachial index (ABI), and augmentation index (AI). RESULTS: The mean age of the patients was 55.6 +/- 13.2 years. The prevalence of diabetes mellitus (DM) was significantly higher in the VC (+) group than in the VC (-) group (87.5 vs. 34.2%, p < 0.05). The serum PTH (98.4 +/- 141.9 vs. 183.6 +/- 231.3 pg/mL, p < 0.05) and albumin (3.7 +/- 0.5 vs. 3.9 +/- 0.3 g/dL, p < 0.05) levels were significantly lower and PWV was significantly (p < 0.05) higher in the VC (+) group. In multiple linear regression analysis, only the presence of diabetes mellitus was significantly related to the VC score. CONCLUSIONS: The VC score was associated with the serum PTH and albumin, as well as with vascular stiffness. C-reactive protein did not show any significant association with the VC score.

Systemic Lupus Erythematosus with Initial Presentation of Ascites / 이화의대지

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of unknown etiology and is characterized by presence of variable pathogenic auto-antibodies and multiple organ involvement. Serositis is common in SLE, but peritoneal involvement is relatively rare. This is a case report of 28-year-old female who initially presented with abdominal pain and ascites. After ruling out many other possibilities such as liver cirrhosis, neoplasm, and infectious etiologies, we confirmed SLE with clinical features, serologic tests and radiological findings. To conclude, her abdominal pain and ascites were caused by lupus peritonitis. After administration of corticosteroid therapy, her symptoms fairly improved.

A Case of Pulmonary Artery Sarcoma Presented as Cavitary Pulmonary Lesions / 결핵및호흡기질환

Pulmonary artery sarcoma (PAS) is a rare, poorly differentiated malignancy arising from the intimal layer of the pulmonary artery. Contrast-enhanced chest computed tomography (CT) is a good diagnostic modality that shows a low-attenuation filling defect of the pulmonary artery in PAS patients. An 18-year-old man was referred to our hospital for the evaluation and management of cavitary pulmonary lesions that did not respond to treatment. A contrast-enhanced CT of the chest was performed, which showed a filling defect within the right interlobar pulmonary artery. The patient underwent a curative right pneumonectomy after confirmation of PAS. Although lung parenchymal lesions of PAS are generally nonspecific, it can be presented as cavities indicate pulmonary infarcts. Clinicians must consider the possibility of PAS as well as pulmonary thromboembolism in patients with pulmonary infarcts. So, we report the case with PAS that was diagnosed during the evaluation of cavitary pulmonary lesions and reviewed the literatures.

Life-Threatening Acute Fulminant Myocarditis Following a Coffee Diet Program / 대한구급학회지

Myocarditis is an inflammatory disease of the myocardium caused by various infectious or noninfectious triggers. Although viral infections are important causes of myocarditis, some drugs or toxins can also cause myocarditis. We report a case of life-threatening fulminant myocarditis which followed an extensive coffee diet program. Despite medical treatment, the patient was not able to maintain hemodynamic stability. She was supported by extracorporeal membrane oxygenation and completely recovered 3 months later.

Splenic Infarction as the Initial Manifestation of Antiphospholipid Syndrome in a Systemic Lupus Erythematosus Patient / 대한내과학회지

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. In patients with SLE, the prevalence of antiphospholipid antibodies is considerably higher, and is largely responsible for thrombosis. Splenic infarction is a rare complication of arterial thrombosis in patients with SLE. It is important to consider splenic infarction in a patient with SLE complaining of left upper quadrant (LUQ) pain because of the possibility of severe infarction-related complications, such as subcapsular hemorrhage and splenic rupture. We report a case of solitary splenic infarction in a patient with SLE. The only symptom was LUQ pain of 3-day duration. Lupus anticoagulant activity was positive and abdominal-pelvic computed tomography (CT) was consistent with splenic infarction. She did not show any other evidence of thrombotic events. The patient was diagnosed with antiphospholipid syndrome that presented as a splenic infarction in a SLE patient.

A Case of Invasive Pulmonary Aspergillosis with Direct Invasion of the Mediastinum and the Left Atrium in an Immunocompetent Patient / 결핵및호흡기질환

We report a case of invasive pulmonary aspergillosis invading the mediastinum and the left atrium. A 70-year-old woman was hospitalized for dyspnea. She had been well controlled for her diabetes mellitus and hypertension. The chest X-ray disclosed mediastinal widening, and the computed tomography scan of the chest showed that there was a large mediastinal mass and this lesion extended into the left atrium and right bronchus. The cardiac echocardiography showed that a huge mediastinal cystic mass compressed in the right atrium and a hyperechoic polypoid lesion in the left. The pathology from the bronchoscopic biopsy observed abundant fungal hyphae which was stained with periodic acid-Schiff and Gomori's methenamine silver. Despite the treatment with antifungal agents, she died from cardiac tamponade after three months. Invasive pulmonary aspergillosis, which involves the mediastinum and the heart, is very rare in immunocompetent patients.

A Case of Invasive Pulmonary Aspergillosis with Direct Invasion of the Mediastinum and the Left Atrium in an Immunocompetent Patient / 결핵및호흡기질환

We report a case of invasive pulmonary aspergillosis invading the mediastinum and the left atrium. A 70-year-old woman was hospitalized for dyspnea. She had been well controlled for her diabetes mellitus and hypertension. The chest X-ray disclosed mediastinal widening, and the computed tomography scan of the chest showed that there was a large mediastinal mass and this lesion extended into the left atrium and right bronchus. The cardiac echocardiography showed that a huge mediastinal cystic mass compressed in the right atrium and a hyperechoic polypoid lesion in the left. The pathology from the bronchoscopic biopsy observed abundant fungal hyphae which was stained with periodic acid-Schiff and Gomori's methenamine silver. Despite the treatment with antifungal agents, she died from cardiac tamponade after three months. Invasive pulmonary aspergillosis, which involves the mediastinum and the heart, is very rare in immunocompetent patients.