94 results on '"Shido, K"'
Search Results
2. 321 The largest GWAS for IgE levels in a single population
- Author
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Shido, K., primary, Kojima, K., additional, Yamasaki, K., additional, Kinoshita, K., additional, and Asano, Y., additional
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- 2022
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3. A retrospective study evaluating the outcomes of high‐dose methylprednisolone pulse therapy for 483 patients with moderate‐to‐severe alopecia areata
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Wada‐Irimada, M., primary, Mizuashi, M., additional, Takahashi, T., additional, Tojo, G., additional, Onami, K., additional, Shido, K., additional, Otake, E., additional, Yusa, S., additional, Tanita, K., additional, Yamazaki, E., additional, Aiba, S., additional, and Yamasaki, K., additional
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- 2021
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4. 883 ‘DermAnnotation’ is All You Need; methodology to transfer knowledges of dermatologists to artificial intelligence
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Shido, K., primary, Kondo, E., additional, Kojima, K., additional, Yamasaki, K., additional, and Aiba, S., additional
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- 2020
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5. 297 Deep Ackerman a novel deep learning method to develop dermatopathology diagnosis by artificial intelligence
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Ota, Y., primary, Shido, K., additional, Kojimako, K., additional, Yamasaki, K., additional, Nagasaki, M., additional, and Aiba, S., additional
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- 2018
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6. 299 A genome-wide association study identifies a novel susceptibility locus for total IgE in a Japanese population from Tohoku Medical Megabank cohort study
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Shido, K., primary, Kojima, K., additional, Yamasaki, K., additional, Gervais, O., additional, Yen, W., additional, Nagasaki, M., additional, and Aiba, S., additional
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- 2018
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7. Erratum: Corrigendum: Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes
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Jin, D K, Shido, K, Kopp, H-G, Petit, I, Shmelkov, S V, Young, L M, Hooper, A T, Amano, H, Avecilla, S T, Heissig, B, Hattori, K, Zhang, F, Hicklin, D J, Wu, Y, Zhu, Z, Dunn, A, Salari, H, Werb, Z, Hackett, N R, Crystal, R G, Lyden, D, and Rafii, S
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- 2006
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8. 503 Genome-wide association study identifies novel susceptibility loci for tanning ability in Japanese population
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Shido, K., primary, Kojima, K., additional, Hozawa, A., additional, Ogishima, S., additional, Minegishi, N., additional, Kawai, Y., additional, Tamiya, G., additional, Tanno, K., additional, Yamasaki, K., additional, Aiba, S., additional, Suzuki, Y., additional, and Nagasaki, M., additional
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- 2017
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9. ChemInform Abstract: A Highly Convenient, One-Pot Synthesis of 3-Bromo-1,5- and -1,7- azulenequinones by Polybromination of Azulene.
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NOZOE, T., primary, WAKABAYASHI, H., additional, SHIDO, K., additional, KURIHARA, T., additional, ISHIKAWA, S., additional, and KAGEYAMA, M., additional
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- 2010
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10. Corrigendum: Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes
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Jin, D K, Shido, K, Kopp, H-G, Petit, I, Shmelkov, S V, Young, L M, Hooper, A T, Amano, H, Avecilla, S T, Heissig, B, Hattori, K, Zhang, F, Hicklin, D J, Wu, Y, Zhu, Z, Dunn, A, Salari, H, Werb, Z, Hackett, N R, Crystal, R G, Lyden, D, and Rafii, S
- Abstract
Author(s): D K Jin; K Shido; H-G Kopp; I Petit; S V Shmelkov; L M Young; A T Hooper; H Amano; S T Avecilla; B Heissig; K Hattori; F Zhang; [...]
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- 2006
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11. Angiotensin converting enzyme as a genetic risk factor for coronary artery spasm. Implication in the pathogenesis of myocardial infarction.
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Oike, Y, primary, Hata, A, additional, Ogata, Y, additional, Numata, Y, additional, Shido, K, additional, and Kondo, K, additional
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- 1995
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12. ChemInform Abstract: SYNTHESIS OF MUTAGENIC PRINCIPLES ISOLATED FROM L-GLUTAMIC ACID PYROLYZATE
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TAKEDA, K., primary, SHIDO, K., additional, OKAMOTO, T., additional, and KOSUGE, T., additional
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- 1979
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13. Stress Induced Changes of Neurotransmitters in the Brain of Rat
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SHIDO, K., primary
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- 1982
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14. The prevalence and incidence of pressure ulcers in home care setting in Japan.
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Okuwa M, Omote S, Nanba N, Sugama J, Shido K, Sumitani Y, Tsukada K, and Sanada H
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- 2009
15. Corrigendum: Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes.
- Author
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Jin, D K, Shido, K, Kopp, H-G, Petit, I, Shmelkov, S V, Young, L M, Hooper, A T, Amano, H, Avecilla, S T, Heissig, B, Hattori, K, Zhang, F, Hicklin, D J, Wu, Y, Zhu, Z, Dunn, A, Salari, H, Werb, Z, Hackett, N R, and Crystal, R G
- Subjects
- *
CANCER cells - Abstract
A correction to the article "Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes," by D. K. Jin and colleagues is presented.
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- 2006
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16. ChemInform Abstract: A Highly Convenient, One-Pot Synthesis of 3-Bromo-1,5- and -1,7- azulenequinones by Polybromination of Azulene.
- Author
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NOZOE, T., WAKABAYASHI, H., SHIDO, K., KURIHARA, T., ISHIKAWA, S., and KAGEYAMA, M.
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- 1995
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17. Cyclic CO 2 absorption/desorption property of Li 3 NaSiO 4 under the partial pressure of CO 2 for practical applications.
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Iwasaki S, Shido K, Fujishiro F, and Hashimoto T
- Abstract
The temperature for realizing the cyclic CO
2 absorption/desorption property of Li3 NaSiO4 by repetition of switching a CO2 /N2 gas mixture and N2 with a partial pressure of CO2 , P (CO2 ), of 0.1 bar was optimized using the pseudo van't Hoff plot of LiNaCO3 + Li2 SiO3 ↔ Li3 NaSiO4 + CO2 prepared by thermogravimetry at various P (CO2 ) values.- Published
- 2024
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18. Convolutional neural network-based skin image segmentation model to improve classification of skin diseases in conventional and non-standardized picture images.
- Author
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Yanagisawa Y, Shido K, Kojima K, and Yamasaki K
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- Humans, Neural Networks, Computer, Diagnosis, Computer-Assisted methods, Sensitivity and Specificity, Image Processing, Computer-Assisted methods, Skin Diseases diagnostic imaging, Skin Neoplasms diagnostic imaging
- Abstract
Background: For dermatological practices, non-standardized conventional photo images are taken and collected as a mixture of variable fields of the image view, including close-up images focusing on designated lesions and long-shot images including normal skin and background of the body surface. Computer-aided detection/diagnosis (CAD) models trained using non-standardized conventional photo images exhibit lower performance rates than CAD models that detect lesions in a localized small area, such as dermoscopic images., Objective: We aimed to develop a convolutional neural network (CNN) model for skin image segmentation to generate a skin disease image dataset suitable for CAD of multiple skin disease classification., Methods: We trained a DeepLabv3 + -based CNN segmentation model to detect skin and lesion areas and segmented out areas that satisfy the following conditions: more than 80% of the image will be the skin area, and more than 10% of the image will be the lesion area., Results: The generated CNN-segmented image database was examined using CAD of skin disease classification and achieved approximately 90% sensitivity and specificity to differentiate atopic dermatitis from malignant diseases and complications, such as mycosis fungoides, impetigo, and herpesvirus infection. The accuracy of skin disease classification in the CNN-segmented image dataset was almost equal to that of the manually cropped image dataset and higher than that of the original image dataset., Conclusion: Our CNN segmentation model, which automatically extracts lesions and segmented images of the skin area regardless of image fields, will reduce the burden of physician annotation and improve CAD performance., Competing Interests: Conflict of Interest The authors have no conflict of interest to declare. The study partially used a research grant from Maruho Co., Ltd., but Maruho does not have any influences on the design, results, and publication of the study., (Copyright © 2023 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)
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- 2023
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19. A new method for the preparation of high-purity CO 2 -absorbing Li 3 NaSiO 4 powder using lithium silicate and sodium carbonate.
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Iwasaki S, Shido K, and Hashimoto T
- Abstract
The starting materials and temperature for the preparation of Li
3 NaSiO4 powder, which has attracted attention as a CO2 absorbent, were optimized in this study. Mixtures of Li2 CO3 , Na2 CO3 , and SiO2 as well as Li4 SiO4 , Li2 SiO3 , and Na2 CO3 were subjected to thermogravimetry-differential thermal analysis (TG-DTA) to elucidate their reaction mechanisms. The phase, morphology, specific surface area, and CO2 absorption characteristics of the powder specimens that were obtained by heating the two mixtures were examined by X-ray diffraction (XRD), secondary electron microscopy (SEM), N2 adsorption isotherm and isothermal TG-DTA. Melted LiNaCO3 was generated via the heat treatment of the Li2 CO3 , Na2 CO3 , and SiO2 powder mixture, yielding a low-purity bulk specimen with inhomogeneous particle size. However, the use of the Li4 SiO4 , Li2 SiO3 , and Na2 CO3 mixture as a starting material ensured that no liquid phase was generated during heat treatment and successfully yielded Li3 NaSiO4 powder which was purer than the product derived from the Li2 CO3 /Na2 CO3 /SiO2 mixture, presumably because of the lower volatility of Li and Na in the solid phase than that in the liquid phase of LiNaCO3 . The Li3 NaSiO4 powder derived from Li4 SiO4 , Li2 SiO3 , and Na2 CO3 showed a slightly larger surface area with homogeneous particle size and almost identical CO2 absorption kinetics compared to those of the product obtained from Li2 CO3 , Na2 CO3 , and SiO2 , in addition to absorbing a higher amount of CO2 owing to its higher purity.- Published
- 2022
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20. Publisher Correction: Histone variant H3.3 maintains adult haematopoietic stem cell homeostasis by enforcing chromatin adaptability.
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Guo P, Liu Y, Geng F, Daman AW, Liu X, Zhong L, Ravishankar A, Lis R, Barcia Durán JG, Itkin T, Tang F, Zhang T, Xiang J, Shido K, Ding BS, Wen D, Josefowicz SZ, and Rafii S
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- 2022
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21. Deep Neural Network for Early Image Diagnosis of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis.
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Fujimoto A, Iwai Y, Ishikawa T, Shinkuma S, Shido K, Yamasaki K, Fujisawa Y, Fujimoto M, Muramatsu S, and Abe R
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- Early Diagnosis, Humans, Neural Networks, Computer, Skin, Stevens-Johnson Syndrome diagnosis
- Abstract
Background: Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) is a life-threatening cutaneous adverse drug reaction (cADR). Distinguishing SJS/TEN from nonsevere cADRs is difficult, especially in the early stages of the disease., Objective: To overcome this limitation, we developed a computer-aided diagnosis system for the early diagnosis of SJS/TEN, powered by a deep convolutional neural network (DCNN)., Methods: We trained a DCNN using a dataset of 26,661 individual lesion images obtained from 123 patients with a diagnosis of SJS/TEN or nonsevere cADRs. The DCNN's accuracy of classification was compared with that of 10 board-certified dermatologists and 24 trainee dermatologists., Results: The DCNN achieved 84.6% sensitivity (95% confidence interval [CI], 80.6-88.6), whereas the sensitivities of the board-certified dermatologists and trainee dermatologists were 31.3 % (95% CI, 20.9-41.8; P < .0001) and 27.8% (95% CI, 22.6-32.5; P < .0001), respectively. The negative predictive value was 94.6% (95% CI, 93.2-96.0) for the DCNN, 68.1% (95% CI, 66.1-70.0; P < .0001) for the board-certified dermatologists, and 67.4% (95% CI, 66.1-68.7; P < .0001) for the trainee dermatologists. The area under the receiver operating characteristic curve of the DCNN for a SJS/TEN diagnosis was 0.873, which was significantly higher than that for all board-certified dermatologists and trainee dermatologists., Conclusions: We developed a DCNN to classify SJS/TEN and nonsevere cADRs based on individual lesion images of erythema. The DCNN performed significantly better than did dermatologists in classifying SJS/TEN from skin images., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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22. Histone variant H3.3 maintains adult haematopoietic stem cell homeostasis by enforcing chromatin adaptability.
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Guo P, Liu Y, Geng F, Daman AW, Liu X, Zhong L, Ravishankar A, Lis R, Barcia Durán JG, Itkin T, Tang F, Zhang T, Xiang J, Shido K, Ding BS, Wen D, Josefowicz SZ, and Rafii S
- Subjects
- Animals, CD8-Positive T-Lymphocytes cytology, Cell Cycle Proteins, Cell Line, Granulocytes cytology, Hematopoiesis physiology, Histone Chaperones, Human Umbilical Vein Endothelial Cells, Humans, Macrophages cytology, Methylation, Mice, Mice, Inbred C57BL, Mice, Knockout, Promoter Regions, Genetic genetics, Protein Processing, Post-Translational physiology, Transcription Factors, Chromatin metabolism, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Histones metabolism, Myelopoiesis physiology
- Abstract
Histone variants and the associated post-translational modifications that govern the stemness of haematopoietic stem cells (HSCs) and differentiation thereof into progenitors (HSPCs) have not been well defined. H3.3 is a replication-independent H3 histone variant in mammalian systems that is enriched at both H3K4me3- and H3K27me3-marked bivalent genes as well as H3K9me3-marked endogenous retroviral repeats. Here we show that H3.3, but not its chaperone Hira, prevents premature HSC exhaustion and differentiation into granulocyte-macrophage progenitors. H3.3-null HSPCs display reduced expression of stemness and lineage-specific genes with a predominant gain of H3K27me3 marks at their promoter regions. Concomitantly, loss of H3.3 leads to a reduction of H3K9me3 marks at endogenous retroviral repeats, opening up binding sites for the interferon regulatory factor family of transcription factors, allowing the survival of rare, persisting H3.3-null HSCs. We propose a model whereby H3.3 maintains adult HSC stemness by safeguarding the delicate interplay between H3K27me3 and H3K9me3 marks, enforcing chromatin adaptability., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2022
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23. Ehlers-Danlos syndrome type IV with a novel COL3A1 exon 14 skipping variation confirmed by Tohoku Medical Megabank Organization genomic database.
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Shido K, Kojima K, Yoshida-Akai S, Kikuchi K, Hatamochi A, Aiba S, and Yamasaki K
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- Cohort Studies, Collagen, Collagen Type III genetics, Exons, Female, Genomics, Humans, Mutation, Ehlers-Danlos Syndrome diagnosis, Ehlers-Danlos Syndrome genetics
- Abstract
A novel COL3A1 variant was identified in a Japanese case of Ehlers-Danlos syndrome type IV (EDS-IV) with a characteristic "Madonna" face, fragile uterus, and easy bruising in addition to a history of cavernous sinus fistula. We confirmed variable diameters of collagen fibrils in the dermis and decrease in type 3 collagen production from cultured fibroblasts. Genomic DNA sequencing of the COL3A1 region and COL3A1 cDNA sequence expressing in cultured fibroblasts identified that a nucleotide variation at c.951+2T>G on intron 14 leads to skipping of exon 14 in COL3A1 cDNA. The novel variation in the splice site of COL3A1 region g.IVS14+2T>G was not listed in the EDS-IV pathogenic genetic databases including Human Gene Mutation Database, ClinVar, and Leiden Open Variation Database. Using the whole genome sequence database of 8380 Japanese individuals reported by the Tohoku Medical Megabank Organization (ToMMo) cohort study, we also confirmed that COL3A1 g.IVS14+2T>G was not a common single nucleotide variation in the Japanese population, although 13 EDS-related COL3A1 variants were identified in the ToMMo database of 8380 Japanese individuals. These results demonstrated that our case of EDS-IV was a result of the novel variation of COL3A1 g.IVS14+2T>G. These statistical genetics approaches with the combination of the ToMMo database of 8380 Japanese individuals and pathogenic genetic databases are a useful method to confirm the uniqueness of novel variation in Japanese., (© 2021 Japanese Dermatological Association.)
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- 2021
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24. GWAS Identified IL4R and the Major Histocompatibility Complex Region as the Associated Loci of Total Serum IgE Levels in 9,260 Japanese Individuals.
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Shido K, Kojima K, Shirota M, Yamasaki K, Motoike IN, Hozawa A, Ogishima S, Minegishi N, Tanno K, Katsuoka F, Tamiya G, Aiba S, Yamamoto M, and Kinoshita K
- Subjects
- Genotype, Haplotypes, Humans, Polymorphism, Single Nucleotide, Genetic Loci, Genome-Wide Association Study, Hypersensitivity genetics, Immunoglobulin E blood, Interleukin-4 Receptor alpha Subunit genetics, Major Histocompatibility Complex
- Published
- 2021
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25. Classification of large-scale image database of various skin diseases using deep learning.
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Tanaka M, Saito A, Shido K, Fujisawa Y, Yamasaki K, Fujimoto M, Murao K, Ninomiya Y, Satoh S, and Shimizu A
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- Humans, Photography, Reproducibility of Results, Deep Learning, Skin Diseases diagnostic imaging, Skin Neoplasms
- Abstract
Purpose: The purpose of this study was to develop a deep learning-based computer-aided diagnosis system for skin disease classification using photographic images of patients. The targets are 59 skin diseases, including localized and diffuse diseases captured by photographic cameras, resulting in highly diverse images in terms of the appearance of the diseases or photographic conditions., Methods: ResNet-18 is used as a baseline model for classification and is reinforced by metric learning to boost generalization in classification by avoiding the overfitting of the training data and increasing the reliability of CADx for dermatologists. Patient-wise classification is performed by aggregating the inference vectors of all the input patient images., Results: The experiment using 70,196 images of 13,038 patients demonstrated that classification accuracy was significantly improved by both metric learning and aggregation, resulting in patient accuracies of 0.579 for Top-1, 0.793 for Top-3, and 0.863 for Top-5. The McNemar test showed that the improvements achieved by the proposed method were statistically significant., Conclusion: This study presents a deep learning-based classification of 59 skin diseases using multiple photographic images of a patient. The experimental results demonstrated that the proposed classification reinforced by metric learning and aggregation of multiple input images was effective in the classification of patients with diverse skin diseases and imaging conditions., (© 2021. CARS.)
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- 2021
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26. Facial UV photo imaging for skin pigmentation assessment using conditional generative adversarial networks.
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Kojima K, Shido K, Tamiya G, Yamasaki K, Kinoshita K, and Aiba S
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- Adolescent, Adult, Aged, Aged, 80 and over, Cheek diagnostic imaging, Child, Colorimetry methods, Female, Humans, Male, Middle Aged, Skin Neoplasms prevention & control, Ultraviolet Rays, Young Adult, Face diagnostic imaging, Image Interpretation, Computer-Assisted methods, Pigmentation Disorders diagnosis, Skin Pigmentation physiology
- Abstract
Skin pigmentation is associated with skin damages and skin cancers, and ultraviolet (UV) photography is used as a minimally invasive mean for the assessment of pigmentation. Since UV photography equipment is not usually available in general practice, technologies emphasizing pigmentation in color photo images are desired for daily care. We propose a new method using conditional generative adversarial networks, named UV-photo Net, to generate synthetic UV images from color photo images. Evaluations using color and UV photo image pairs taken by a UV photography system demonstrated that pigment spots were well reproduced in synthetic UV images by UV-photo Net, and some of the reproduced pigment spots were difficult to be recognized in color photo images. In the pigment spot detection analysis, the rate of pigment spot areas in cheek regions for synthetic UV images was highly correlated with the rate for UV photo images (Pearson's correlation coefficient 0.92). We also demonstrated that UV-photo Net was effective for floating up pigment spots for photo images taken by a smartphone camera. UV-photo Net enables an easy assessment of pigmentation from color photo images and will promote self-care of skin damages and early signs of skin cancers for preventive medicine.
- Published
- 2021
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27. Adaptable haemodynamic endothelial cells for organogenesis and tumorigenesis.
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Palikuqi B, Nguyen DT, Li G, Schreiner R, Pellegata AF, Liu Y, Redmond D, Geng F, Lin Y, Gómez-Salinero JM, Yokoyama M, Zumbo P, Zhang T, Kunar B, Witherspoon M, Han T, Tedeschi AM, Scottoni F, Lipkin SM, Dow L, Elemento O, Xiang JZ, Shido K, Spence JR, Zhou QJ, Schwartz RE, De Coppi P, Rabbany SY, and Rafii S
- Subjects
- Blood Vessels growth & development, Cell Culture Techniques instrumentation, Cell Culture Techniques methods, Chromatin metabolism, Epigenesis, Genetic, Epigenomics, Human Umbilical Vein Endothelial Cells, Humans, In Vitro Techniques, Islets of Langerhans blood supply, Models, Biological, Organ Specificity, RNA-Seq, Single-Cell Analysis, Transcription Factors, Transcriptome, Blood Vessels cytology, Carcinogenesis, Endothelial Cells cytology, Hemodynamics, Neoplasms blood supply, Organogenesis, Organoids blood supply
- Abstract
Endothelial cells adopt tissue-specific characteristics to instruct organ development and regeneration
1,2 . This adaptability is lost in cultured adult endothelial cells, which do not vascularize tissues in an organotypic manner. Here, we show that transient reactivation of the embryonic-restricted ETS variant transcription factor 2 (ETV2)3 in mature human endothelial cells cultured in a serum-free three-dimensional matrix composed of a mixture of laminin, entactin and type-IV collagen (LEC matrix) 'resets' these endothelial cells to adaptable, vasculogenic cells, which form perfusable and plastic vascular plexi. Through chromatin remodelling, ETV2 induces tubulogenic pathways, including the activation of RAP1, which promotes the formation of durable lumens4,5 . In three-dimensional matrices-which do not have the constraints of bioprinted scaffolds-the 'reset' vascular endothelial cells (R-VECs) self-assemble into stable, multilayered and branching vascular networks within scalable microfluidic chambers, which are capable of transporting human blood. In vivo, R-VECs implanted subcutaneously in mice self-organize into durable pericyte-coated vessels that functionally anastomose to the host circulation and exhibit long-lasting patterning, with no evidence of malformations or angiomas. R-VECs directly interact with cells within three-dimensional co-cultured organoids, removing the need for the restrictive synthetic semipermeable membranes that are required for organ-on-chip systems, therefore providing a physiological platform for vascularization, which we call 'Organ-On-VascularNet'. R-VECs enable perfusion of glucose-responsive insulin-secreting human pancreatic islets, vascularize decellularized rat intestines and arborize healthy or cancerous human colon organoids. Using single-cell RNA sequencing and epigenetic profiling, we demonstrate that R-VECs establish an adaptive vascular niche that differentially adjusts and conforms to organoids and tumoroids in a tissue-specific manner. Our Organ-On-VascularNet model will permit metabolic, immunological and physiochemical studies and screens to decipher the crosstalk between organotypic endothelial cells and parenchymal cells for identification of determinants of endothelial cell heterogeneity, and could lead to advances in therapeutic organ repair and tumour targeting.- Published
- 2020
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28. Subcutaneous granulomatous reaction with eosinophil infiltration to a silicone continuous ambulatory peritoneal dialysis Tenckhoff catheter.
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Hatchome N, Shido K, Kikuchi K, Terui H, Oba-Yabana I, Mori T, Yamasaki K, and Aiba S
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- Eosinophilia etiology, Female, Granuloma etiology, Humans, Hypersensitivity, Delayed etiology, Middle Aged, Patch Tests, Silicones, Subcutaneous Tissue pathology, Catheters adverse effects, Eosinophilia pathology, Granuloma pathology, Hypersensitivity, Delayed pathology, Peritoneal Dialysis, Continuous Ambulatory instrumentation
- Published
- 2020
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29. S100P regulates the collective invasion of pancreatic cancer cells into the lymphatic endothelial monolayer.
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Nakayama H, Ohuchida K, Yonenaga A, Sagara A, Ando Y, Kibe S, Takesue S, Abe T, Endo S, Koikawa K, Okumura T, Shido K, Miyoshi K, Nakata K, Moriyama T, Miyasaka Y, Inoue S, Ohtsuka T, Mizumoto K, and Nakamura M
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Cell Adhesion physiology, Cell Line, Tumor, Endothelial Cells metabolism, Female, Humans, Immunohistochemistry, Lymph Nodes metabolism, Lymph Nodes pathology, Lymphatic Metastasis, Male, Mice, Middle Aged, Neoplasm Invasiveness, Pancreatic Neoplasms metabolism, Spheroids, Cellular, Antigens, Nuclear metabolism, Autoantigens metabolism, Endothelial Cells pathology, Pancreatic Neoplasms pathology
- Abstract
Lymph node metastasis is an independent prognostic factor in pancreatic cancer. However, the mechanisms of lymph node colonization are unknown. As a mechanism of lymphatic metastasis, it has been reported for other types of cancer that spheroids from tumor cells cause circular chemorepellent‑induced defects (CCIDs) in lymphatic endothelial monolayers. In pancreatic cancer, such mechanisms of metastasis have not been elucidated. The present study evaluated the involvement of this new mechanism of metastasis in pancreatic cancer and investigated the associated factors. In human pancreatic cancer tissue, it was observed that clusters of cancer cells penetrated the wall of lymphatic ducts around the primary tumor. An in vitro co‑culture system was then used to analyze the mechanisms of tumor cell‑mediated disruption of lymphatic vessels. Time‑lapse microscopic imaging revealed that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. CCID formation ability differed depending on the cell line. Neither aggregation of spheroids nor adhesion to lymphatic endothelial cells (LECs) exhibited a significant correlation with this phenomenon. The addition of supernatant from cultured cancer cells enhanced CCID formation. Microarray analysis revealed that the expression of S100 calcium binding protein P (S100P) was significantly increased when LECs were treated with supernatant from cultured cancer cells. Addition of a S100P antagonist significantly suppressed the migration of LECs and CCID formation. The present findings demonstrated that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. These CCIDs in pancreatic cancer were partly regulated by S100P, suggesting that S100P may be a promising target to inhibit lymph node metastasis.
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- 2019
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30. Susceptibility Loci for Tanning Ability in the Japanese Population Identified by a Genome-Wide Association Study from the Tohoku Medical Megabank Project Cohort Study.
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Shido K, Kojima K, Yamasaki K, Hozawa A, Tamiya G, Ogishima S, Minegishi N, Kawai Y, Tanno K, Suzuki Y, Nagasaki M, and Aiba S
- Subjects
- Aged, Cohort Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Japan, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies, Skin, Skin Physiological Phenomena, Sunbathing, Sunlight, Asian People, Genetic Loci genetics, Skin Pigmentation genetics
- Published
- 2019
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31. Edible oil methods to remove asphalt on burns.
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Yamazaki E, Shido K, Yamasaki K, and Aiba S
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- Accidents, Anti-Infective Agents, Local therapeutic use, Burns etiology, Burns pathology, Humans, Skin pathology, Solvents therapeutic use, Treatment Outcome, Burns therapy, Hot Temperature adverse effects, Hydrocarbons, Mineral Oil therapeutic use, Plant Oils therapeutic use
- Abstract
Asphalt, also known as bitumen, is a viscous liquid or a semi-solid form of petroleum. In cases of hot liquid asphalt splash, asphalt broadly adheres to the skin surface and is hard to remove from skin. Because accidental burns from hot liquid asphalt splash rarely occur, there is no consensus about initial approaches to remove adherent asphalt from skin. We reviewed articles relating to asphalt burns and summarized methods to remove adherent asphalt from skin, including our present case in which we successfully removed adherent asphalt by edible butter and vegetable oil. We summarized information of 127 cases and classified agents used to remove asphalt in four categories: (i) medicines; (ii) health-care products; (iii) foods; and (iv) solvents. Before the 1990s, antimicrobial topical medicines were mainly reported to treat asphalt burns but it took half a day or more to remove asphalt. Mineral oils and edible oils such as butter and vegetable oil are easily available in grocery stores and could emulsify to remove asphalt in a few hours. From the review of articles and our experience, edible oils are useful agents for the first approach to remove asphalt from the point of view of efficacy, safety, availability and expense., (© 2018 Japanese Dermatological Association.)
- Published
- 2018
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32. Histone variant H3.3-mediated chromatin remodeling is essential for paternal genome activation in mouse preimplantation embryos.
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Kong Q, Banaszynski LA, Geng F, Zhang X, Zhang J, Zhang H, O'Neill CL, Yan P, Liu Z, Shido K, Palermo GD, Allis CD, Rafii S, Rosenwaks Z, and Wen D
- Subjects
- Animals, Blastocyst cytology, Blastomeres cytology, Blastomeres metabolism, Embryonic Development, Female, Gene Expression Regulation, Developmental, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Histones antagonists & inhibitors, Histones genetics, Male, Mice, Mice, Inbred ICR, Mice, Transgenic, Morula cytology, Morula metabolism, Octamer Transcription Factor-3 chemistry, Octamer Transcription Factor-3 genetics, Octamer Transcription Factor-3 metabolism, Protein Isoforms antagonists & inhibitors, Protein Isoforms genetics, Protein Isoforms metabolism, RNA Interference, Recombinant Fusion Proteins chemistry, Recombinant Fusion Proteins metabolism, Blastocyst metabolism, Chromatin Assembly and Disassembly, Histones metabolism, Paternal Inheritance, Transcriptional Activation
- Abstract
Derepression of chromatin-mediated transcriptional repression of paternal and maternal genomes is considered the first major step that initiates zygotic gene expression after fertilization. The histone variant H3.3 is present in both male and female gametes and is thought to be important for remodeling the paternal and maternal genomes for activation during both fertilization and embryogenesis. However, the underlying mechanisms remain poorly understood. Using our H3.3B-HA-tagged mouse model, engineered to report H3.3 expression in live animals and to distinguish different sources of H3.3 protein in embryos, we show here that sperm-derived H3.3 (sH3.3) protein is removed from the sperm genome shortly after fertilization and extruded from the zygotes via the second polar bodies (PBII) during embryogenesis. We also found that the maternal H3.3 (mH3.3) protein is incorporated into the paternal genome as early as 2 h postfertilization and is detectable in the paternal genome until the morula stage. Knockdown of maternal H3.3 resulted in compromised embryonic development both of fertilized embryos and of androgenetic haploid embryos. Furthermore, we report that mH3.3 depletion in oocytes impairs both activation of the Oct4 pluripotency marker gene and global de novo transcription from the paternal genome important for early embryonic development. Our results suggest that H3.3-mediated paternal chromatin remodeling is essential for the development of preimplantation embryos and the activation of the paternal genome during embryogenesis., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2018
- Full Text
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33. Endothelial jagged-2 sustains hematopoietic stem and progenitor reconstitution after myelosuppression.
- Author
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Guo P, Poulos MG, Palikuqi B, Badwe CR, Lis R, Kunar B, Ding BS, Rabbany SY, Shido K, Butler JM, and Rafii S
- Subjects
- Allografts, Animals, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Gene Deletion, Jagged-2 Protein genetics, Mice, Mice, Transgenic, Receptor, Notch2 genetics, Receptor, Notch2 metabolism, Transcription Factor HES-1 genetics, Transcription Factor HES-1 metabolism, Adult Stem Cells metabolism, Graft Survival, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells metabolism, Jagged-2 Protein biosynthesis, Signal Transduction
- Abstract
Angiocrine factors, such as Notch ligands, supplied by the specialized endothelial cells (ECs) within the bone marrow and splenic vascular niche play an essential role in modulating the physiology of adult hematopoietic stem and progenitor cells (HSPCs). However, the relative contribution of various Notch ligands, specifically jagged-2, to the homeostasis of HSPCs is unknown. Here, we show that under steady state, jagged-2 is differentially expressed in tissue-specific vascular beds, but its expression is induced in hematopoietic vascular niches after myelosuppressive injury. We used mice with EC-specific deletion of the gene encoding jagged-2 (Jag2) to demonstrate that while EC-derived jagged-2 was dispensable for maintaining the capacity of HSPCs to repopulate under steady-state conditions, by activating Notch2 it did contribute to the recovery of HSPCs in response to myelosuppressive conditions. Engraftment and/or expansion of HSPCs was dependent on the expression of endothelial-derived jagged-2 following myeloablation. Additionally, jagged-2 expressed in bone marrow ECs regulated HSPC cell cycle and quiescence during regeneration. Endothelial-deployed jagged-2 triggered Notch2/Hey1, while tempering Notch2/Hes1 signaling in HSPCs. Collectively, these data demonstrate that EC-derived jagged-2 activates Notch2 signaling in HSPCs to promote hematopoietic recovery and has potential as a therapeutic target to accelerate balanced hematopoietic reconstitution after myelosuppression.
- Published
- 2017
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- View/download PDF
34. Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis.
- Author
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Cao Z, Ye T, Sun Y, Ji G, Shido K, Chen Y, Luo L, Na F, Li X, Huang Z, Ko JL, Mittal V, Qiao L, Chen C, Martinez FJ, Rafii S, and Ding BS
- Subjects
- Endothelial Cells drug effects, Endothelial Cells metabolism, Epithelial Cells transplantation, Fibroblasts drug effects, Fibroblasts metabolism, Fibroblasts pathology, Hepatocyte Growth Factor pharmacology, Hepatocytes drug effects, Hepatocytes metabolism, Humans, Liver Cirrhosis pathology, Liver Regeneration drug effects, NADPH Oxidase 4 antagonists & inhibitors, NADPH Oxidase 4 metabolism, Parenchymal Tissue transplantation, Pulmonary Alveoli pathology, Pulmonary Fibrosis pathology, Liver Cirrhosis therapy, Neovascularization, Physiologic drug effects, Pulmonary Fibrosis therapy, Regenerative Medicine
- Abstract
The regenerative capacity of lung and liver is sometimes impaired by chronic or overwhelming injury. Orthotopic transplantation of parenchymal stem cells to damaged organs might reinstate their self-repair ability. However, parenchymal cell engraftment is frequently hampered by the microenvironment in diseased recipient organs. We show that targeting both the vascular niche and perivascular fibroblasts establishes "hospitable soil" to foster the incorporation of "seed," in this case, the engraftment of parenchymal cells in injured organs. Specifically, ectopic induction of endothelial cell (EC)-expressed paracrine/angiocrine hepatocyte growth factor (HGF) and inhibition of perivascular NOX4 [NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase 4] synergistically enabled reconstitution of mouse and human parenchymal cells in damaged organs. Reciprocally, genetic knockout of Hgf in mouse ECs ( Hgf
iΔEC/iΔEC ) aberrantly up-regulated perivascular NOX4 during liver and lung regeneration. Dysregulated HGF and NOX4 pathways subverted the function of vascular and perivascular cells from an epithelially inductive niche to a microenvironment that inhibited parenchymal reconstitution. Perivascular NOX4 induction in HgfiΔEC/iΔEC mice recapitulated the phenotype of human and mouse liver and lung fibrosis. Consequently, EC-directed HGF and NOX4 inhibitor GKT137831 stimulated regenerative integration of mouse and human parenchymal cells in chronically injured lung and liver. Our data suggest that targeting dysfunctional perivascular and vascular cells in diseased organs can bypass fibrosis and enable reparative cell engraftment to reinstate lung and liver regeneration., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2017
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35. Conversion of adult endothelium to immunocompetent haematopoietic stem cells.
- Author
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Lis R, Karrasch CC, Poulos MG, Kunar B, Redmond D, Duran JGB, Badwe CR, Schachterle W, Ginsberg M, Xiang J, Tabrizi AR, Shido K, Rosenwaks Z, Elemento O, Speck NA, Butler JM, Scandura JM, and Rafii S
- Subjects
- Adaptive Immunity, Aging genetics, Animals, Cell Line, Cell Lineage, Cell Self Renewal, Clone Cells cytology, Clone Cells transplantation, Core Binding Factor Alpha 2 Subunit genetics, Core Binding Factor Alpha 2 Subunit metabolism, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Endothelial Cells cytology, Endothelial Cells metabolism, Hematopoiesis, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells metabolism, Humans, Male, Mice, Mice, Inbred C57BL, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-fos genetics, Proto-Oncogene Proteins c-fos metabolism, Trans-Activators genetics, Trans-Activators metabolism, Transcription Factors genetics, Transcription Factors metabolism, Transcriptome, Cell Differentiation, Cellular Reprogramming, Endothelium cytology, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells immunology, T-Lymphocytes cytology, T-Lymphocytes immunology
- Abstract
Developmental pathways that orchestrate the fleeting transition of endothelial cells into haematopoietic stem cells remain undefined. Here we demonstrate a tractable approach for fully reprogramming adult mouse endothelial cells to haematopoietic stem cells (rEC-HSCs) through transient expression of the transcription-factor-encoding genes Fosb, Gfi1, Runx1, and Spi1 (collectively denoted hereafter as FGRS) and vascular-niche-derived angiocrine factors. The induction phase (days 0-8) of conversion is initiated by expression of FGRS in mature endothelial cells, which results in endogenous Runx1 expression. During the specification phase (days 8-20), RUNX1
+ FGRS-transduced endothelial cells commit to a haematopoietic fate, yielding rEC-HSCs that no longer require FGRS expression. The vascular niche drives a robust self-renewal and expansion phase of rEC-HSCs (days 20-28). rEC-HSCs have a transcriptome and long-term self-renewal capacity similar to those of adult haematopoietic stem cells, and can be used for clonal engraftment and serial primary and secondary multi-lineage reconstitution, including antigen-dependent adaptive immune function. Inhibition of TGFβ and CXCR7 or activation of BMP and CXCR4 signalling enhanced generation of rEC-HSCs. Pluripotency-independent conversion of endothelial cells into autologous authentic engraftable haematopoietic stem cells could aid treatment of haematological disorders.- Published
- 2017
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36. Molecular Checkpoint Decisions Made by Subverted Vascular Niche Transform Indolent Tumor Cells into Chemoresistant Cancer Stem Cells.
- Author
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Cao Z, Scandura JM, Inghirami GG, Shido K, Ding BS, and Rafii S
- Subjects
- Animals, Cell Transformation, Neoplastic, Drug Resistance, Neoplasm, Endothelial Cells physiology, Fibroblast Growth Factor 4 physiology, Humans, Insulin-Like Growth Factor I physiology, Mice, Proto-Oncogene Protein c-ets-2 physiology, Receptor, IGF Type 1 physiology, Insulin-Like Growth Factor Binding Proteins physiology, Neoplastic Stem Cells drug effects
- Abstract
Tumor-associated endothelial cells (TECs) regulate tumor cell aggressiveness. However, the core mechanism by which TECs confer stem cell-like activity to indolent tumors is unknown. Here, we used in vivo murine and human tumor models to identify the tumor-suppressive checkpoint role of TEC-expressed insulin growth factor (IGF) binding protein-7 (IGFBP7/angiomodulin). During tumorigenesis, IGFBP7 blocks IGF1 and inhibits expansion and aggresiveness of tumor stem-like cells (TSCs) expressing IGF1 receptor (IGF1R). However, chemotherapy triggers TECs to suppress IGFBP7, and this stimulates IGF1R
+ TSCs to express FGF4, inducing a feedforward FGFR1-ETS2 angiocrine cascade that obviates TEC IGFBP7. Thus, loss of IGFBP7 and upregulation of IGF1 activates the FGF4-FGFR1-ETS2 pathway in TECs and converts naive tumor cells to chemoresistant TSCs, thereby facilitating their invasiveness and progression., (Copyright © 2017 Elsevier Inc. All rights reserved.)- Published
- 2017
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37. Platelets prime hematopoietic and vascular niche to drive angiocrine-mediated liver regeneration.
- Author
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Shido K, Chavez D, Cao Z, Ko J, Rafii S, and Ding BS
- Abstract
In mammals, the livers regenerate after chemical injury or resection of hepatic lobe by hepatectomy. How liver regeneration is initiated after mass loss remains to be defined. Here, we report that following liver injury, activated platelets deploy SDF-1 and VEGF-A to stimulate CXCR7
+ liver sinusoidal endothelial cell (LSEC) and VEGFR1+ myeloid cell, orchestrating hepatic regeneration. After carbon tetrachloride (CCl4 ) injection or hepatectomy, platelets and CD11b+ VEGFR1+ myeloid cells were recruited LSEC, and liver regeneration in both models was impaired in thrombopoietin-deficient ( Thpo-/- ) mice lacking circulating platelets. This impeded regeneration phenotype was recapitulated in mice with either conditional ablation of Cxcr7 in LSEC ( Cxcr7iΔ/iΔ ) or Vegfr1 in myeloid cell ( Vegfr1lysM/lysM ). Both Vegfr1lysM/lysM and Cxcr7iΔ/iΔ mice exhibited suppressed expression of hepatocyte growth factor and Wnt2, two crucial trophogenic angiocrine factors instigating hepatocyte propagation. Of note, administration of recombinant thrombopoietin restored the prohibited liver regeneration in the tested genetic models. As such, our data suggest that platelets and myeloid cells jointly activate the vascular niche to produce pro-regenerative endothelial paracrine/angiocrine factors. Modulating this "hematopoietic-vascular niche" might help to develop regenerative therapy strategy for hepatic disorders.- Published
- 2017
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38. Plexiform Fibrohistiocytic Tumor on the Ear: Case Report and Immunohistochemical Investigation of Stromal Factor.
- Author
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Shido K, Fujimura T, Kakizaki A, Furudate S, Asano M, and Aiba S
- Abstract
Plexiform fibrohistiocytic tumor (PFT) is a rare mesenchymal neoplasm of intermediate malignant potential with a high local recurrence rate. In this report, we describe a case of PFT on the ear, which showed a dense deposition of periostin (POSTN) in the stromal areas of the tumor. In addition, dense infiltration of CD163+CD206- tumor-associated macrophages (TAMs) was detected in the same areas as POSTN. Since POSTN was previously reported to possess immunomodulatory effects on TAMs, our present report suggested the significance of the POSTN/TAMs axis in the progression of PFT.
- Published
- 2016
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39. Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis.
- Author
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Cao Z, Lis R, Ginsberg M, Chavez D, Shido K, Rabbany SY, Fong GH, Sakmar TP, Rafii S, and Ding BS
- Subjects
- Animals, Antibiotics, Antineoplastic toxicity, Bleomycin toxicity, Calcium-Binding Proteins antagonists & inhibitors, Capillaries drug effects, Endothelial Cells drug effects, Endothelial Cells physiology, Fibroblasts drug effects, Fibrosis, Fluorescent Antibody Technique, Humans, Hydrochloric Acid toxicity, Jagged-1 Protein, Lung drug effects, Lung pathology, Lung physiology, Macrophages drug effects, Macrophages metabolism, Membrane Proteins antagonists & inhibitors, Mice, Oligopeptides pharmacology, Pulmonary Artery drug effects, Pulmonary Artery metabolism, Pulmonary Circulation drug effects, Pulmonary Circulation physiology, RNA, Small Interfering pharmacology, Receptors, CXCR agonists, Receptors, Notch metabolism, Regeneration drug effects, Serrate-Jagged Proteins, Smad3 Protein drug effects, Smad3 Protein metabolism, Vascular Endothelial Growth Factor Receptor-1 metabolism, Wnt Signaling Pathway, Calcium-Binding Proteins metabolism, Capillaries metabolism, Endothelial Cells metabolism, Fibroblasts metabolism, Intercellular Signaling Peptides and Proteins metabolism, Lung metabolism, Lung Injury metabolism, Membrane Proteins metabolism, Pulmonary Fibrosis metabolism, Receptors, CXCR metabolism, Regeneration physiology
- Abstract
Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin-dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladapted hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis.
- Published
- 2016
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40. Somatic BRAF c.1799T>A p.V600E Mosaicism syndrome characterized by a linear syringocystadenoma papilliferum, anaplastic astrocytoma, and ocular abnormalities.
- Author
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Watanabe Y, Shido K, Niihori T, Niizuma H, Katata Y, Iizuka C, Oba D, Moriya K, Saito-Nanjo Y, Onuma M, Rikiishi T, Sasahara Y, Watanabe M, Aiba S, Saito R, Sonoda Y, Tominaga T, Aoki Y, and Kure S
- Subjects
- Adenoma, Sweat Gland drug therapy, Astrocytoma drug therapy, Brain Neoplasms drug therapy, Eye pathology, Eye Abnormalities genetics, Humans, Indoles therapeutic use, Infant, Mosaicism, Nevus, Sebaceous of Jadassohn genetics, Premature Birth, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Sulfonamides therapeutic use, Sweat Gland Neoplasms drug therapy, Vemurafenib, Adenoma, Sweat Gland genetics, Astrocytoma genetics, Brain Neoplasms genetics, Proto-Oncogene Proteins B-raf genetics, Sweat Gland Neoplasms genetics
- Abstract
Genetic mosaicism for somatic mutations of oncogenes is common in genodermatoses, which can be complicated with extra-cutaneous abnormalities. Here we describe an infant with a congenital anaplastic astrocytoma, a linear syringocystadenoma papilliferum, and ocular abnormalities. The BRAF c.1799T>A p.V600E mutation was detected in both the brain and skin tumor cells but not in the blood or normal skin cells, suggesting somatic mosaicsism for the mutation. Clinically, the brain tumor gradually became life threatening without any response to conventional chemotherapies including carboplatin, etoposide, and temozolomide. Vemurafenib, a BRAF p.V600E inhibitor, was administered daily after the detection of the BRAF mutation. This single-agent therapy was dramatically effective against the anaplastic astrocytoma; the tumor regressed, the cerebrospinal fluid cell count and protein levels decreased to normal levels, and hydrocephalus resolved. Moreover, other lesions including a corneal cyst also responded to vemurafenib. The brain tumor continued shrinking after 6 months of treatment. We present a genodermatosis syndrome associated with BRAF c.1799T>A p.V600E mosaicism. This syndrome may represent a new entity in the mosaic RASopathies, partly overlapping with Schimmelpenning-Feuerstein-Mims syndrome, which is driven by mosaicism of HRAS and/or KRAS activating mutations. Screening for BRAF c.1799T>A p.V600E is especially useful for those with malignant tumors, because it is one of the most-druggable targets., (© 2015 Wiley Periodicals, Inc.)
- Published
- 2016
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41. Direct conversion of human amniotic cells into endothelial cells without transitioning through a pluripotent state.
- Author
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Ginsberg M, Schachterle W, Shido K, and Rafii S
- Subjects
- Animals, Cell Culture Techniques methods, Cells, Cultured, Embryonic Stem Cells metabolism, Endothelial Cells metabolism, Endothelial Cells transplantation, Gene Expression Regulation, Developmental, Humans, Mice, SCID, Proto-Oncogene Protein c-fli-1 genetics, Transcription Factors genetics, Transforming Growth Factor beta antagonists & inhibitors, Amniotic Fluid cytology, Cell Transdifferentiation, Embryonic Stem Cells cytology, Endothelial Cells cytology
- Abstract
Endothelial cells (ECs) have essential roles in organ development and regeneration, and therefore they could be used for regenerative therapies. However, generation of abundant functional endothelium from pluripotent stem cells has been difficult because ECs generated by many existing strategies have limited proliferative potential and display vascular instability. The latter difficulty is of particular importance because cells that lose their identity over time could be unsuitable for therapeutic use. Here, we describe a 3-week platform for directly converting human mid-gestation lineage-committed amniotic fluid-derived cells (ACs) into a stable and expandable population of vascular ECs (rAC-VECs) without using pluripotency factors. By transient expression of the ETS transcription factor ETV2 for 2 weeks and constitutive expression the ETS transcription factors FLI1 and ERG1, concomitant with TGF-β inhibition for 3 weeks, epithelial and mesenchymal ACs are converted, with high efficiency, into functional rAC-VECs. These rAC-VECs maintain their vascular repertoire and morphology over numerous passages in vitro, and they form functional vessels when implanted in vivo. rAC-VECs can be detected in recipient mice months after implantation. Thus, rAC-VECs can be used to establish a cellular platform to uncover the molecular determinants of vascular development and heterogeneity and potentially represent ideal ECs for the treatment of regenerative disorders.
- Published
- 2015
- Full Text
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42. Platelet-derived SDF-1 primes the pulmonary capillary vascular niche to drive lung alveolar regeneration.
- Author
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Rafii S, Cao Z, Lis R, Siempos II, Chavez D, Shido K, Rabbany SY, and Ding BS
- Subjects
- Animals, Antigens, CD metabolism, Cadherins metabolism, Endothelial Cells enzymology, Epidermal Growth Factor metabolism, Gene Deletion, Ligands, Matrix Metalloproteinase 14 metabolism, Mice, Organ Specificity, Platelet Membrane Glycoprotein IIb metabolism, Pneumonectomy, Receptor, Fibroblast Growth Factor, Type 1 metabolism, Receptors, CXCR metabolism, Receptors, CXCR4, Signal Transduction, Thrombopoietin deficiency, Thrombopoietin metabolism, Vascular Endothelial Growth Factor Receptor-2 metabolism, Blood Platelets metabolism, Capillaries metabolism, Chemokine CXCL12 metabolism, Pulmonary Alveoli blood supply, Pulmonary Alveoli physiology, Regeneration
- Abstract
The lung alveoli regenerate after surgical removal of the left lobe by pneumonectomy (PNX). How this alveolar regrowth/regeneration is initiated remains unknown. We found that platelets trigger lung regeneration by supplying stromal-cell-derived factor-1 (SDF-1, also known as CXCL12). After PNX, activated platelets stimulate SDF-1 receptors CXCR4 and CXCR7 on pulmonary capillary endothelial cells (PCECs) to deploy the angiocrine membrane-type metalloproteinase MMP14, stimulating alveolar epithelial cell (AEC) expansion and neo-alveolarization. In mice lacking platelets or platelet Sdf1, PNX-induced alveologenesis was diminished. Reciprocally, infusion of Sdf1(+/+) but not Sdf1-deficient platelets rescued lung regeneration in platelet-depleted mice. Endothelial-specific ablation of Cxcr4 and Cxcr7 in adult mice similarly impeded lung regeneration. Notably, mice with endothelial-specific Mmp14 deletion exhibited impaired expansion of AECs but not PCECs after PNX, which was not rescued by platelet infusion. Therefore, platelets prime PCECs to initiate lung regeneration, extending beyond their haemostatic contribution. Therapeutic targeting of this haemo-vascular niche could enable regenerative therapy for lung diseases.
- Published
- 2015
- Full Text
- View/download PDF
43. Angiocrine factors deployed by tumor vascular niche induce B cell lymphoma invasiveness and chemoresistance.
- Author
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Cao Z, Ding BS, Guo P, Lee SB, Butler JM, Casey SC, Simons M, Tam W, Felsher DW, Shido K, Rafii A, Scandura JM, and Rafii S
- Subjects
- Animals, Burkitt Lymphoma genetics, Calcium-Binding Proteins genetics, Cell Cycle Proteins metabolism, Cell Proliferation, Endothelial Cells metabolism, Enzyme Activation, Genes, myc, Humans, Hyaluronan Receptors metabolism, Intercellular Signaling Peptides and Proteins genetics, Jagged-1 Protein, Membrane Proteins genetics, Mice, Mice, Transgenic, Neoplasm Invasiveness, RNA Interference, RNA, Small Interfering, Receptor, IGF Type 1 metabolism, Receptor, Macrophage Colony-Stimulating Factor metabolism, Serrate-Jagged Proteins, Signal Transduction genetics, Tumor Cells, Cultured, Up-Regulation, Burkitt Lymphoma metabolism, Burkitt Lymphoma pathology, Calcium-Binding Proteins metabolism, Drug Resistance, Neoplasm, Fibroblast Growth Factor 4 metabolism, Intercellular Signaling Peptides and Proteins metabolism, Membrane Proteins metabolism, Receptor, Fibroblast Growth Factor, Type 1 metabolism, Receptor, Notch2 metabolism
- Abstract
Tumor endothelial cells (ECs) promote cancer progression in ways beyond their role as conduits supporting metabolism. However, it is unknown how vascular niche-derived paracrine factors, defined as angiocrine factors, provoke tumor aggressiveness. Here, we show that FGF4 produced by B cell lymphoma cells (LCs) through activating FGFR1 upregulates the Notch ligand Jagged1 (Jag1) on neighboring ECs. In turn, upregulation of Jag1 on ECs reciprocally induces Notch2-Hey1 in LCs. This crosstalk enforces aggressive CD44(+)IGF1R(+)CSF1R(+) LC phenotypes, including extranodal invasion and chemoresistance. Inducible EC-selective deletion of Fgfr1 or Jag1 in the Eμ-Myc lymphoma model or impairing Notch2 signaling in mouse and human LCs diminished lymphoma aggressiveness and prolonged mouse survival. Thus, targeting the angiocrine FGF4-FGFR1/Jag1-Notch2 loop inhibits LC aggressiveness and enhances chemosensitivity., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
44. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis.
- Author
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Ding BS, Cao Z, Lis R, Nolan DJ, Guo P, Simons M, Penfold ME, Shido K, Rabbany SY, and Rafii S
- Subjects
- Acute Disease, Animals, Bile Ducts surgery, Carbon Tetrachloride, Chemical and Drug Induced Liver Injury, Chronic metabolism, Chemical and Drug Induced Liver Injury, Chronic pathology, Chemokine CXCL12 metabolism, Chronic Disease, Disease Models, Animal, Endothelial Cells cytology, Endothelial Cells metabolism, Endothelial Cells pathology, Ligation, Mice, Receptor, Fibroblast Growth Factor, Type 1 metabolism, Liver Cirrhosis pathology, Liver Regeneration physiology, Receptors, CXCR metabolism, Receptors, CXCR4 metabolism, Signal Transduction
- Abstract
Chemical or traumatic damage to the liver is frequently associated with aberrant healing (fibrosis) that overrides liver regeneration. The mechanism by which hepatic niche cells differentially modulate regeneration and fibrosis during liver repair remains to be defined. Hepatic vascular niche predominantly represented by liver sinusoidal endothelial cells deploys paracrine trophogens, known as angiocrine factors, to stimulate regeneration. Nevertheless, it is not known how pro-regenerative angiocrine signals from liver sinusoidal endothelial cells is subverted to promote fibrosis. Here, by combining an inducible endothelial-cell-specific mouse gene deletion strategy and complementary models of acute and chronic liver injury, we show that divergent angiocrine signals from liver sinusoidal endothelial cells stimulate regeneration after immediate injury and provoke fibrosis after chronic insult. The pro-fibrotic transition of vascular niche results from differential expression of stromal-derived factor-1 receptors, CXCR7 and CXCR4 (refs 18, 19, 20, 21), in liver sinusoidal endothelial cells. After acute injury, CXCR7 upregulation in liver sinusoidal endothelial cells acts with CXCR4 to induce transcription factor Id1, deploying pro-regenerative angiocrine factors and triggering regeneration. Inducible deletion of Cxcr7 in sinusoidal endothelial cells (Cxcr7(iΔEC/iΔEC)) from the adult mouse liver impaired liver regeneration by diminishing Id1-mediated production of angiocrine factors. By contrast, after chronic injury inflicted by iterative hepatotoxin (carbon tetrachloride) injection and bile duct ligation, constitutive FGFR1 signalling in liver sinusoidal endothelial cells counterbalanced CXCR7-dependent pro-regenerative response and augmented CXCR4 expression. This predominance of CXCR4 over CXCR7 expression shifted angiocrine response of liver sinusoidal endothelial cells, stimulating proliferation of desmin(+) hepatic stellate-like cells and enforcing a pro-fibrotic vascular niche. Endothelial-cell-specific ablation of either Fgfr1 (Fgfr1(iΔEC/iΔEC)) or Cxcr4 (Cxcr4(iΔEC/iΔEC)) in mice restored the pro-regenerative pathway and prevented FGFR1-mediated maladaptive subversion of angiocrine factors. Similarly, selective CXCR7 activation in liver sinusoidal endothelial cells abrogated fibrogenesis. Thus, we demonstrate that in response to liver injury, differential recruitment of pro-regenerative CXCR7-Id1 versus pro-fibrotic FGFR1-CXCR4 angiocrine pathways in vascular niche balances regeneration and fibrosis. These results provide a therapeutic roadmap to achieve hepatic regeneration without provoking fibrosis.
- Published
- 2014
- Full Text
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45. Molecular signatures of tissue-specific microvascular endothelial cell heterogeneity in organ maintenance and regeneration.
- Author
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Nolan DJ, Ginsberg M, Israely E, Palikuqi B, Poulos MG, James D, Ding BS, Schachterle W, Liu Y, Rosenwaks Z, Butler JM, Xiang J, Rafii A, Shido K, Rabbany SY, Elemento O, and Rafii S
- Subjects
- Animals, Cell Adhesion Molecules biosynthesis, Cell Differentiation, Cells, Cultured, Chemokines biosynthesis, Embryonic Stem Cells cytology, Embryonic Stem Cells metabolism, Embryonic Stem Cells transplantation, Endothelial Cells cytology, Humans, Intercellular Signaling Peptides and Proteins biosynthesis, Mice, Microvessels metabolism, Transcription Factors biosynthesis, Cell Adhesion Molecules metabolism, Chemokines metabolism, Endothelial Cells metabolism, Intercellular Signaling Peptides and Proteins metabolism, Regeneration, Transcription Factors metabolism
- Abstract
Microvascular endothelial cells (ECs) within different tissues are endowed with distinct but as yet unrecognized structural, phenotypic, and functional attributes. We devised EC purification, cultivation, profiling, and transplantation models that establish tissue-specific molecular libraries of ECs devoid of lymphatic ECs or parenchymal cells. These libraries identify attributes that confer ECs with their organotypic features. We show that clusters of transcription factors, angiocrine growth factors, adhesion molecules, and chemokines are expressed in unique combinations by ECs of each organ. Furthermore, ECs respond distinctly in tissue regeneration models, hepatectomy, and myeloablation. To test the data set, we developed a transplantation model that employs generic ECs differentiated from embryonic stem cells. Transplanted generic ECs engraft into regenerating tissues and acquire features of organotypic ECs. Collectively, we demonstrate the utility of informational databases of ECs toward uncovering the extravascular and intrinsic signals that define EC heterogeneity. These factors could be exploited therapeutically to engineer tissue-specific ECs for regeneration., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
46. Efficient direct reprogramming of mature amniotic cells into endothelial cells by ETS factors and TGFβ suppression.
- Author
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Ginsberg M, James D, Ding BS, Nolan D, Geng F, Butler JM, Schachterle W, Pulijaal VR, Mathew S, Chasen ST, Xiang J, Rosenwaks Z, Shido K, Elemento O, Rabbany SY, and Rafii S
- Subjects
- Embryonic Stem Cells cytology, Embryonic Stem Cells metabolism, Humans, Amniotic Fluid cytology, Cell Differentiation, Endothelial Cells cytology, Proto-Oncogene Proteins c-ets metabolism, Retroviridae Proteins, Oncogenic metabolism, Transforming Growth Factor beta metabolism
- Abstract
ETS transcription factors ETV2, FLI1, and ERG1 specify pluripotent stem cells into induced vascular endothelial cells (iVECs). However, iVECs are unstable and drift toward nonvascular cells. We show that human midgestation c-Kit(-) lineage-committed amniotic cells (ACs) can be reprogrammed into vascular endothelial cells (rAC-VECs) without transitioning through a pluripotent state. Transient ETV2 expression in ACs generates immature rAC-VECs, whereas coexpression with FLI1/ERG1 endows rAC-VECs with a vascular repertoire and morphology matching mature endothelial cells (ECs). Brief TGFβ-inhibition functionalizes VEGFR2 signaling, augmenting specification of ACs into rAC-VECs. Genome-wide transcriptional analyses showed that rAC-VECs are similar to adult ECs in which vascular-specific genes are expressed and nonvascular genes are silenced. Functionally, rAC-VECs form stable vasculature in Matrigel plugs and regenerating livers. Therefore, short-term ETV2 expression and TGFβ inhibition with constitutive ERG1/FLI1 coexpression reprogram mature ACs into durable rAC-VECs with clinical-scale expansion potential. Banking of HLA-typed rAC-VECs establishes a vascular inventory for treatment of diverse disorders., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
47. Endothelial-derived angiocrine signals induce and sustain regenerative lung alveolarization.
- Author
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Ding BS, Nolan DJ, Guo P, Babazadeh AO, Cao Z, Rosenwaks Z, Crystal RG, Simons M, Sato TN, Worgall S, Shido K, Rabbany SY, and Rafii S
- Subjects
- Animals, Endothelial Cells metabolism, Epithelial Cells cytology, Epithelial Cells metabolism, Matrix Metalloproteinase 14 metabolism, Mice, Mice, Knockout, Neovascularization, Physiologic, Pneumonectomy, Receptor, Fibroblast Growth Factor, Type 1 genetics, Receptor, Fibroblast Growth Factor, Type 1 metabolism, Regeneration, Stem Cells metabolism, Tissue Culture Techniques, Vascular Endothelial Growth Factor Receptor-2 genetics, Vascular Endothelial Growth Factor Receptor-2 metabolism, Endothelial Growth Factors metabolism, Lung cytology, Lung physiology, Pulmonary Alveoli cytology
- Abstract
To identify pathways involved in adult lung regeneration, we employ a unilateral pneumonectomy (PNX) model that promotes regenerative alveolarization in the remaining intact lung. We show that PNX stimulates pulmonary capillary endothelial cells (PCECs) to produce angiocrine growth factors that induce proliferation of epithelial progenitor cells supporting alveologenesis. Endothelial cells trigger expansion of cocultured epithelial cells, forming three-dimensional angiospheres reminiscent of alveolar-capillary sacs. After PNX, endothelial-specific inducible genetic ablation of Vegfr2 and Fgfr1 in mice inhibits production of MMP14, impairing alveolarization. MMP14 promotes expansion of epithelial progenitor cells by unmasking cryptic EGF-like ectodomains that activate the EGF receptor (EGFR). Consistent with this, neutralization of MMP14 impairs EGFR-mediated alveolar regeneration, whereas administration of EGF or intravascular transplantation of MMP14(+) PCECs into pneumonectomized Vegfr2/Fgfr1-deficient mice restores alveologenesis and lung inspiratory volume and compliance function. VEGFR2 and FGFR1 activation in PCECs therefore increases MMP14-dependent bioavailability of EGFR ligands to initiate and sustain alveologenesis., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
48. Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration.
- Author
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Ding BS, Nolan DJ, Butler JM, James D, Babazadeh AO, Rosenwaks Z, Mittal V, Kobayashi H, Shido K, Lyden D, Sato TN, Rabbany SY, and Rafii S
- Subjects
- Animals, Cell Proliferation, Coculture Techniques, Endothelium cytology, Hepatectomy, Hepatocyte Growth Factor metabolism, Hepatocytes cytology, Inhibitor of Differentiation Protein 1 deficiency, Inhibitor of Differentiation Protein 1 genetics, Inhibitor of Differentiation Protein 1 metabolism, Mice, Phenotype, Up-Regulation, Vascular Endothelial Growth Factor Receptor-2 metabolism, Wnt2 Protein metabolism, Endothelium metabolism, Liver blood supply, Liver cytology, Liver Regeneration physiology, Neovascularization, Physiologic physiology, Signal Transduction
- Abstract
During embryogenesis, endothelial cells induce organogenesis before the development of circulation. These findings suggest that endothelial cells not only form passive conduits to deliver nutrients and oxygen, but also establish an instructive vascular niche, which through elaboration of paracrine trophogens stimulates organ regeneration, in a manner similar to endothelial-cell-derived angiocrine factors that support haematopoiesis. However, the precise mechanism by which tissue-specific subsets of endothelial cells promote organogenesis in adults is unknown. Here we demonstrate that liver sinusoidal endothelial cells (LSECs) constitute a unique population of phenotypically and functionally defined VEGFR3(+)CD34(-)VEGFR2(+)VE-cadherin(+)FactorVIII(+)CD45(-) endothelial cells, which through the release of angiocrine trophogens initiate and sustain liver regeneration induced by 70% partial hepatectomy. After partial hepatectomy, residual liver vasculature remains intact without experiencing hypoxia or structural damage, which allows study of physiological liver regeneration. Using this model, we show that inducible genetic ablation of vascular endothelial growth factor (VEGF)-A receptor-2 (VEGFR2) in the LSECs impairs the initial burst of hepatocyte proliferation (days 1-3 after partial hepatectomy) and subsequent reconstitution of the hepatovascular mass (days 4-8 after partial hepatectomy) by inhibiting upregulation of the endothelial-cell-specific transcription factor Id1. Accordingly, Id1-deficient mice also manifest defects throughout liver regeneration, owing to diminished expression of LSEC-derived angiocrine factors, including hepatocyte growth factor (HGF) and Wnt2. Notably, in in vitro co-cultures, VEGFR2-Id1 activation in LSECs stimulates hepatocyte proliferation. Indeed, intrasplenic transplantation of Id1(+/+) or Id1(-/-) LSECs transduced with Wnt2 and HGF (Id1(-/-)Wnt2(+)HGF(+) LSECs) re-establishes an inductive vascular niche in the liver sinusoids of the Id1(-/-) mice, initiating and restoring hepatovascular regeneration. Therefore, in the early phases of physiological liver regeneration, VEGFR2-Id1-mediated inductive angiogenesis in LSECs through release of angiocrine factors Wnt2 and HGF provokes hepatic proliferation. Subsequently, VEGFR2-Id1-dependent proliferative angiogenesis reconstitutes liver mass. Therapeutic co-transplantation of inductive VEGFR2(+)Id1(+)Wnt2(+)HGF(+) LSECs with hepatocytes provides an effective strategy to achieve durable liver regeneration.
- Published
- 2010
- Full Text
- View/download PDF
49. Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells.
- Author
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Kobayashi H, Butler JM, O'Donnell R, Kobayashi M, Ding BS, Bonner B, Chiu VK, Nolan DJ, Shido K, Benjamin L, and Rafii S
- Subjects
- Animals, Cell Communication, Cell Lineage, Cell Proliferation, Cells, Cultured, Enzyme Activation, Hematopoiesis, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mitogen-Activated Protein Kinases metabolism, TOR Serine-Threonine Kinases metabolism, Cell Differentiation, Endothelial Cells metabolism, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Paracrine Communication, Proto-Oncogene Proteins c-akt metabolism, Transforming Growth Factors metabolism
- Abstract
Endothelial cells establish an instructive vascular niche that reconstitutes haematopoietic stem and progenitor cells (HSPCs) through release of specific paracrine growth factors, known as angiocrine factors. However, the mechanism by which endothelial cells balance the rate of proliferation and lineage-specific differentiation of HSPCs is unknown. Here, we demonstrate that Akt activation in endothelial cells, through recruitment of mTOR, but not the FoxO pathway, upregulates specific angiocrine factors that support expansion of CD34(-)Flt3(-) KLS HSPCs with long-term haematopoietic stem cell (LT-HSC) repopulation capacity. Conversely, co-activation of Akt-stimulated endothelial cells with p42/44 MAPK shifts the balance towards maintenance and differentiation of the HSPCs. Selective activation of Akt1 in the endothelial cells of adult mice increased the number of colony forming units in the spleen and CD34(-)Flt3(-) KLS HSPCs with LT-HSC activity in the bone marrow, accelerating haematopoietic recovery. Therefore, the activation state of endothelial cells modulates reconstitution of HSPCs through the modulation of angiocrine factors, with Akt-mTOR-activated endothelial cells supporting the self-renewal of LT-HSCs and expansion of HSPCs, whereas MAPK co-activation favours maintenance and lineage-specific differentiation of HSPCs.
- Published
- 2010
- Full Text
- View/download PDF
50. Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells.
- Author
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Butler JM, Nolan DJ, Vertes EL, Varnum-Finney B, Kobayashi H, Hooper AT, Seandel M, Shido K, White IA, Kobayashi M, Witte L, May C, Shawber C, Kimura Y, Kitajewski J, Rosenwaks Z, Bernstein ID, and Rafii S
- Subjects
- Animals, Cell Communication, Cell Lineage, Cell Proliferation, Cells, Cultured, Coculture Techniques, Culture Media, Conditioned, Ligands, Mice, Mice, Knockout, Receptor, Notch1 deficiency, Receptor, Notch1 metabolism, Receptor, Notch2 deficiency, Receptor, Notch2 metabolism, Endothelial Cells cytology, Endothelial Cells metabolism, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Signal Transduction
- Abstract
Bone marrow endothelial cells (ECs) are essential for reconstitution of hematopoiesis, but their role in self-renewal of long-term hematopoietic stem cells (LT-HSCs) is unknown. We have developed angiogenic models to demonstrate that EC-derived angiocrine growth factors support in vitro self-renewal and in vivo repopulation of authentic LT-HSCs. In serum/cytokine-free cocultures, ECs, through direct cellular contact, stimulated incremental expansion of repopulating CD34(-)Flt3(-)cKit(+)Lineage(-)Sca1(+) LT-HSCs, which retained their self-renewal ability, as determined by single-cell and serial transplantation assays. Angiocrine expression of Notch ligands by ECs promoted proliferation and prevented exhaustion of LT-HSCs derived from wild-type, but not Notch1/Notch2-deficient, mice. In transgenic notch-reporter (TNR.Gfp) mice, regenerating TNR.Gfp(+) LT-HSCs were detected in cellular contact with sinusoidal ECs. Interference with angiocrine, but not perfusion, function of SECs impaired repopulation of TNR.Gfp(+) LT-HSCs. ECs establish an instructive vascular niche for clinical-scale expansion of LT-HSCs and a cellular platform to identify stem cell-active trophogens., (2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
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