In the kidney, pericyte is the major source of myofibroblast (MyoF) in renal interstitium. It is reported that pericyte-myofibroblast transition（PMT）is one of the important pathomechanisms of renal interstitial fibrosis（RIF）. Among them, the main reasons for promoting RIF formation include pericyte recruitment, activation and isolation, as well as the lack of pericyte-derived erythropoietin. During the PMT startup process, pericyte activation and its separation from microvessels are controlled by multiple signal transduction pathways, such as transforming growth factor-β（TGF-β）pathway, vascular endothelial growth factor receptor (VEGFR) pathway and platelet derived growth factor receptor (PDGFR) pathway;Blocking of these signaling pathways can not only inhibit PMT, but also suppress renal capillaries reduction and further alleviate RIF. In clinic, many traditional Chinese medicine compound prescriptions, single traditional Chinese herbal medicine (CHM) and their extracts have the clear effects in alleviating RIF, and some of their intervention actions may be related to pericyte and its PMT. Therefore, the studies on PMT and its drug intervention will become the main development direction in the research field of anti-organ fibrosis by CHM.
Drugs, Chinese Herbal ; pharmacology ; Fibrosis ; Humans ; Kidney ; cytology ; drug effects ; pathology ; Myofibroblasts ; cytology ; Pericytes ; cytology ; Receptors, Platelet-Derived Growth Factor ; metabolism ; Signal Transduction ; Vascular Endothelial Growth Factor A ; metabolism

PURPOSE: Fibroblast growth factor (FGF) signals are important in carcinogenesis and progression of prostate cancer. Dovitinib is an oral, pan-class inhibitor of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, and fibroblast growth factor receptor (FGFR). We evaluated the efficacy and toxicity of dovitinib in men with metastatic castration resistant prostate cancer (mCRPC). MATERIALS AND METHODS: This study was a single-arm, phase II, open-label, multicenter trial of dovitinib 500 mg/day (5-days-on/2-days-off schedule). The primary endpoint was 16-week progression-free survival (PFS). Secondary endpoints were overall survival (OS), toxicity and prostate-specific antigen (PSA) response rate. Biomarker analyses for VEGFR2, FGF23, and FGFR2 using multiplex enzyme-linked immunosorbent assay was performed. RESULTS: Forty-four men were accrued from 11 hospitals. Eighty percent were post-docetaxel. Median PSA was 100 ng/dL, median age was 69, 82% had bone metastases, and 23% had liver metastases. Median cycles of dovitinib was 2 (range, 0 to 33). Median PFS was 3.67 months (95% confidence interval [CI], 1.36 to 5.98) and median OS was 13.70 months (95% CI, 0 to 27.41). Chemotherapy-naïve patients had longer PFS (17.90 months; 95% CI, 9.23 to 28.57) compared with docetaxel-treated patients (2.07 months; 95% CI, 1.73 to 2.41; p=0.001) and the patients with high serum VEGFR2 level over median level (7,800 pg/mL) showed longer PFS compared with others (6.03 months [95% CI, 4.26 to 7.80] vs. 1.97 months [95% CI, 1.79 to 2.15], p=0.023). Grade 3 related adverse events were seen in 40.9% of patients. Grade 1-2 nausea, diarrhea, fatigue, anorexia, and all grade thrombocytopenia are common. CONCLUSION: Dovitinib showed modest antitumor activity with manageable toxicities in men with mCRPC. Especially, patients who were chemo-naïve benefitted from dovitinib.
Anorexia ; Biomarkers ; Carcinogenesis ; Castration ; Diarrhea ; Disease-Free Survival ; Enzyme-Linked Immunosorbent Assay ; Fatigue ; Fibroblast Growth Factors ; Humans ; Liver ; Male ; Multicenter Studies as Topic ; Nausea ; Neoplasm Metastasis ; Prostate* ; Prostate-Specific Antigen ; Prostatic Neoplasms* ; Prostatic Neoplasms, Castration-Resistant ; Receptors, Fibroblast Growth Factor ; Receptors, Platelet-Derived Growth Factor ; Receptors, Vascular Endothelial Growth Factor ; Thrombocytopenia

BACKGROUND: The pericytes in the blood vessel wall have recently been identified to be important in regulating vascular formation, stabilization, remodeling, and function. We isolated and identified pericyte-like platelet-derived growth factor receptor beta-positive (PDGFRβ+) cells from the stromal vascular fraction (SVF) of adipose tissue from critical limb ischemia (CLI) patients and investigated their potential as a reliable source of stem cells for cell-based therapy. METHODS: De-identified subcutaneous fat tissues were harvested after amputation in CLI patients. Freshly isolated SVF cells and culture-expanded adipose-derived stem cells (ADSCs) were quantified using flow cytometry. A matrigel tube formation assay and multi-lineage differentiation were performed to assess pericytic and mesenchymal stem cell (MSC)-like characteristics of PDGFRβ+ ADSCs. RESULTS: PDGFRβ+ cells were located in the pericytic area of various sizes of blood vessels and coexpressed mesenchymal stem cell markers. PDGFRβ+ cells in freshly isolated SVF cells expressed a higher level of stem cell markers (CD34 and CXCR4) and mesenchymal markers (CD13, CD44, CD54, and CD90) than PDGFRβ– cells. In vitro expansion of PDGFRβ+ cells resulted in enrichment of the perivascular mesenchymal stem-like (PDGFRβ+/CD90+/CD45–/CD31–) cell fractions. The Matrigel tube formation assay revealed that PDGFRβ+ cells were located in the peritubular area. CONCLUSIONS: PDGFRβ+ ADSCs cells demonstrated a good multilineage differentiation potential. Pericyte-like PDGFRβ+ cells from the SVF of adipose tissue from CLI patients had MSC-like characteristics and could be amplified by in vitro culture with preservation of their cell characteristics. We believe PDGFRβ+ cells in the SVF of adipose tissue can be used as a reliable source of stem cells even in CLI patients.
Adipose Tissue ; Adipose Tissue, White* ; Adult Stem Cells ; Amputation ; Blood Vessels ; Extremities* ; Flow Cytometry ; Humans ; In Vitro Techniques ; Ischemia* ; Mesenchymal Stromal Cells ; Pericytes ; Platelet-Derived Growth Factor* ; Receptors, Platelet-Derived Growth Factor ; Stem Cells ; Subcutaneous Fat

Myeloid neoplasia with eosinophilia and platelet-derived growth factor receptor beta (PDGFRB) rearrangements is an uncommon Philadelphia-negative myeloproliferative neoplasm. Their most common morphological diagnosis is chronic myelomonocytic leukemia with eosinophilia, which is associated with t(5;12)(q33;p13) and results in the formation of the ETV6-PDGFRB fusion gene. Here, we report a 49-year-old man with a myeloid neoplasm with a PDGFRB rearrangement, who was incidentally diagnosed with hyperleukocytosis and eosinophilia during a health screening. A chromosome analysis of a bone marrow sample revealed 46, XY, t(5;12)(q33;p13), and fluorescence in situ hybridization analysis revealed the PDGFRB gene rearrangement. The patient was treated with imatinib and subsequently achieved complete hematological and molecular remission.
Bone Marrow ; Diagnosis ; Eosinophilia* ; Fluorescence ; Gene Rearrangement ; Humans ; Imatinib Mesylate ; In Situ Hybridization ; Leukemia, Myelomonocytic, Chronic ; Mass Screening ; Middle Aged ; Myeloproliferative Disorders ; Receptor, Platelet-Derived Growth Factor beta* ; Receptors, Platelet-Derived Growth Factor

PURPOSE: Nephrogenesis is normally accompanied by a tightly regulated and efficient vascularization. We investigated the effect of angiotensin II inhibition on angiogenesis in the developing rat kidney. METHODS: Newborn rat pups were treated with enalapril (30 mg/kg/day) or vehicle (control) for 7 days after birth. Renal histological changes were checked using Hematoxylin & Eosin staining. We also investigated the intrarenal expression of vascular endothelial growth factor (VEGF)-A, VEGF receptor 1 (VEGFR1), VEGFR2, platelet-derived growth factor (PDGF)-B, and PDGF receptor-beta with Western blotting and immunohistochemical staining at postnatal day 8. Expression of the endothelial cell marker CD31 was examined to determine glomerular and peritubular capillary density. RESULTS: Enalapril-treated rat kidneys showed disrupted tubules and vessels when compared with the control rat kidneys. In the enalapril-treated group, intrarenal VEGF-A protein expression was significantly higher, whereas VEGFR1 protein expression was lower than that in the control group (P<0.05). The expression of VEGFR2, PDGF-B, and PDGF receptor-beta was not different between the 2 groups. The increased capillary CD31 expression on the western blots of enalapril-treated rat kidneys indicated that the total endothelial cell protein level was increased, while the cortical capillary density, assessed using CD31 immunohistochemical staining, was decreased. CONCLUSION: Impaired VEGF-VEGFR signaling and altered capillary repair may play a role in the deterioration of the kidney vasculature after blocking of angiotensin II during renal development.
Angiotensin II ; Animals ; Blotting, Western ; Capillaries ; Enalapril ; Endothelial Cells ; Eosine Yellowish-(YS) ; Growth and Development ; Hematoxylin ; Humans ; Infant, Newborn ; Kidney* ; Parturition ; Platelet-Derived Growth Factor ; Rats* ; Receptors, Vascular Endothelial Growth Factor ; Vascular Endothelial Growth Factor A

PURPOSE: The incidence of gastrointestinal stromal tumors (GISTs) harboring platelet-derived growth factor receptor alpha (PDGFRA) mutations is low, therefore further investigation of the efficacy of imatinib in this subgroup was needed. MATERIALS AND METHODS: Patients with PDGFRA-mutant GISTs who received imatinib as primary therapy for advanced disease between January 2000 and June 2012 were identified from the GIST registry of Asan Medical Center, Seoul, Korea. RESULTS: KIT and PDGFRA genotyping in 823 patients identified 18 patients (2%) with PDGFRA mutations who were treated with first-line imatinib. Exon 18 D842V substitution, non-D842V exon 18 mutations, and exon 12 mutations were detected in nine (50%), four (22%), and five (28%) patients, respectively. Objective response rate differed significantly between patients with the D842V mutation and those with non-D842V mutations (0% [0/5] vs. 71% [5/7], p=0.03). In all patients, median progression-free survival (PFS) and overall survival (OS) was 24.8 months (95% confidence interval [CI], 0.0 to 57.2) and 51.2 months (95% CI, 37.1 to 65.3), respectively. Significantly, poorer PFS was observed for patients with D842V-mutant GISTs than those with non-D842V PDGFRA-mutant GISTs: median 3.8 months (95% CI, 1.4 to 6.3) versus 29.5 months (95% CI, 18.3 to 40.7) (p < 0.001). Patients with the D842V mutation had poorer OS than those with non-D842V PDGFRA mutations: median 25.2 months (95% CI, 12.7 to 37.8) versus 59.8 months (95% CI, 43.0 to 76.5) (p=0.02). CONCLUSION: Imatinib is active against non-D842V PDGFRA-mutant GISTs, whereas GISTs harboring the D842V mutation are primarily resistant to imatinib.
Chungcheongnam-do ; Disease-Free Survival ; Exons ; Gastrointestinal Stromal Tumors ; Humans ; Incidence ; Korea ; Platelet-Derived Growth Factor* ; Receptors, Platelet-Derived Growth Factor* ; Seoul

PURPOSE: The purpose of this study was to evaluate potential prognostic factors in patients with adenoid cystic carcinoma (ACC). MATERIALS AND METHODS: A total of 68 patients who underwent curative surgery and had available tissue were enrolled in this study. Their medical records and pathologic slides were reviewed and immunohistochemistry for basic fibroblast growth factor, fibroblast growth factor receptor (FGFR) 2, FGFR3, c-kit, Myb proto-oncogene protein, platelet-derived growth factor receptor beta, vascular endothelial growth factor (VEGF), and Ki-67 was performed. Univariate and multivariate analysis was performed for determination of disease-free survival (DFS) and overall survival (OS). RESULTS: In univariate analyses, primary site of nasal cavity and paranasal sinus (p=0.022) and Ki-67 expression of more than 7% (p=0.001) were statistically significant factors for poor DFS. Regarding OS, perineural invasion (p=0.032), high expression of VEGF (p=0.033), and high expression of Ki-67 (p=0.007) were poor prognostic factors. In multivariate analyses, primary site of nasal cavity and paranasal sinus (p=0.028) and high expression of Ki-67 (p=0.004) were independent risk factors for poor DFS, and high expression of VEGF (p=0.011) and Ki-67 (p=0.011) showed independent association with poor OS. CONCLUSION: High expression of VEGF and Ki-67 were independent poor prognostic factors for OS in ACC.
Adenoids* ; Carcinoma, Adenoid Cystic* ; Disease-Free Survival ; Fibroblast Growth Factor 2 ; Humans ; Immunohistochemistry ; Medical Records ; Multivariate Analysis ; Nasal Cavity ; Prognosis ; Proto-Oncogenes ; Receptors, Fibroblast Growth Factor ; Receptors, Platelet-Derived Growth Factor ; Risk Factors ; Vascular Endothelial Growth Factor A*

BACKGROUND/AIMS: Inhaled corticosteroids are the most effective treatment currently available for asthma, but their beneficial effect against airway remodeling is limited. The tyrosine kinase inhibitor nilotinib has inhibitory activity against c-kit and the platelet-derived growth factor receptor. We compared the effects of fluticasone and nilotinib on airway remodeling in a chronic asthma model. We also examined whether co-treatment with nilotinib and fluticasone had any synergistic effect in preventing airway remodeling. METHODS: We developed a mouse model of airway remodeling, including smooth muscle thickening, in which ovalbumin (OVA)-sensitized female BALB/c-mice were repeatedly exposed to intranasal OVA administration twice per week for 3 months. Mice were treated with fluticasone and/or nilotinib intranasally during the OVA challenge. RESULTS: Mice chronically exposed to OVA developed eosinophilic airway inflammation and showed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Both fluticasone and nilotinib attenuated airway smooth muscle thickening. However, only nilotinib suppressed fibrotic changes, demonstrating inhibition of collagen deposition. Fluticasone reduced pro-inflammatory cells, such as eosinophils, and several cytokines, such as interleukin 4 (IL-4), IL-5, and IL-13, induced by repeated OVA challenges. On the other hand, nilotinib reduced transforming growth factor β1 levels in bronchoalveolar lavage fluid and inhibited fibroblast proliferation significantly. CONCLUSIONS: These results suggest that fluticasone and nilotinib suppressed airway remodeling in this chronic asthma model through anti-inflammatory and anti-fibrotic pathways, respectively.
Adrenal Cortex Hormones ; Airway Remodeling ; Animals ; Asthma* ; Bronchoalveolar Lavage Fluid ; Collagen ; Cytokines ; Eosinophils ; Female ; Fibroblasts ; Fluticasone* ; Hand ; Humans ; Inflammation ; Interleukin-13 ; Interleukin-4 ; Interleukin-5 ; Mice ; Muscle, Smooth ; Ovalbumin ; Ovum ; Protein-Tyrosine Kinases ; Receptors, Platelet-Derived Growth Factor ; Transforming Growth Factors

Mesenchymal stem cell (MSC)-mediated therapy has been shown to be clinically effective in regenerating tissue defects. For improved regenerative therapy, it is critical to isolate homogenous populations of MSCs with high capacity to differentiate into appropriate tissues. The utilization of stem cell surface antigens provides a means to identify MSCs from various tissues. However, few surface markers that consistently isolate highly regenerative MSCs have been validated, making it challenging for routine clinical applications and making it all the more imperative to identify reliable surface markers. In this study, we used three surface marker combinations: CD51/CD140α, CD271, and STRO-1/CD146 for the isolation of homogenous populations of dental mesenchymal stem cells (DMSCs) from heterogeneous periodontal ligament cells (PDLCs). Fluorescence-activated cell sorting analysis revealed that 24% of PDLCs were CD51(+)/CD140α(+), 0.8% were CD271(+), and 2.4% were STRO-1(+)/CD146(+). Sorted cell populations were further assessed for their multipotent properties by inducing osteogenic and chondrogenic differentiation. All three subsets of isolated DMSCs exhibited differentiation capacity into osteogenic and chondrogenic lineages but with varying degrees. CD271(+) DMSCs demonstrated the greatest osteogenic potential with strong induction of osteogenic markers such as DLX5, RUNX2, and BGLAP. Our study provides evidence that surface marker combinations used in this study are sufficient markers for the isolation of DMSCs from PDLCs. These results provide important insight into using specific surface markers for identifying homogenous populations of DMSCs for their improved utilization in regenerative medicine.
Adaptor Proteins, Signal Transducing ; analysis ; Adult ; Aggrecans ; analysis ; Antigens, CD ; analysis ; Antigens, Surface ; analysis ; CD146 Antigen ; analysis ; Cell Differentiation ; physiology ; Cell Lineage ; Cell Separation ; methods ; Cells, Cultured ; Chondrogenesis ; physiology ; Collagen Type II ; analysis ; Core Binding Factor Alpha 1 Subunit ; analysis ; Flow Cytometry ; methods ; Homeodomain Proteins ; analysis ; Humans ; Integrin alphaV ; analysis ; Mesenchymal Stromal Cells ; cytology ; physiology ; Multipotent Stem Cells ; cytology ; physiology ; Nerve Tissue Proteins ; analysis ; Osteogenesis ; physiology ; Periodontal Ligament ; cytology ; Receptor, Platelet-Derived Growth Factor alpha ; analysis ; Receptors, Nerve Growth Factor ; analysis ; SOX9 Transcription Factor ; analysis ; Time Factors ; Transcription Factors ; analysis

Mesenchymal stem cells (MSCs) are a promising tool in regenerative medicine due to their capacity to differentiate into multiple lineages. In addition to MSCs isolated from bone marrow (BMSCs), adult MSCs are isolated from craniofacial tissues including dental pulp tissues (DPs) using various stem cell surface markers. However, there has been a lack of consensus on a set of surface makers that are reproducibly effective at isolating putative multipotent dental mesenchymal stem cells (DMSCs). In this study, we used different combinations of surface markers (CD51/CD140α, CD271, and STRO-1/CD146) to isolate homogeneous populations of DMSCs from heterogeneous dental pulp cells (DPCs) obtained from DP and compared their capacity to undergo multilineage differentiation. Fluorescence-activated cell sorting revealed that 27.3% of DPCs were CD51(+)/CD140α(+), 10.6% were CD271(+), and 0.3% were STRO-1(+)/CD146(+). Under odontogenic conditions, all three subsets of isolated DMSCs exhibited differentiation capacity into odontogenic lineages. Among these isolated subsets of DMSCs, CD271(+) DMSCs demonstrated the greatest odontogenic potential. While all three combinations of surface markers in this study successfully isolated DMSCs from DPCs, the single CD271 marker presents the most effective stem cell surface marker for identification of DMSCs with high odontogenic potential. Isolated CD271(+) DMSCs could potentially be utilized for future clinical applications in dentistry and regenerative medicine.
Adult ; Adult Stem Cells ; cytology ; Antigens, CD ; analysis ; Antigens, Surface ; analysis ; Biomarkers ; analysis ; CD146 Antigen ; analysis ; Cell Culture Techniques ; Cell Differentiation ; physiology ; Cell Lineage ; Cell Separation ; methods ; Cells, Cultured ; Chondrogenesis ; physiology ; Dental Pulp ; cytology ; Flow Cytometry ; methods ; Humans ; Integrin alphaV ; analysis ; Mesenchymal Stromal Cells ; cytology ; Multipotent Stem Cells ; cytology ; Nerve Tissue Proteins ; analysis ; Odontogenesis ; physiology ; Receptor, Platelet-Derived Growth Factor alpha ; analysis ; Receptors, Nerve Growth Factor ; analysis