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Shen, Yue
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Publications (10 of 13) Show all publications
Fallah, M., Shen, Y., Brodén, J., Bäckman, A., Lundskog, B., Johansson, M., . . . Ny, T. (2018). Plasminogen activation is required for the development of radiation-induced dermatitis. Cell Death and Disease, 9(11), Article ID 1051.
Open this publication in new window or tab >>Plasminogen activation is required for the development of radiation-induced dermatitis
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2018 (English)In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 9, no 11, article id 1051Article in journal (Refereed) Published
Abstract [en]

Skin damage caused by radiation therapy (radiodermatitis) is a severe side effect of radiotherapy in cancer patients, and there is currently a lack of effective strategies to prevent or treat such skin damage. In this work, we show with several lines of evidence that plasminogen, a pro-inflammatory factor, is key for the development of radiodermatitis. After skin irradiation in wild type (plg+/+) mice, the plasminogen level increased in the radiated area, leading to severe skin damage such as ulcer formation. However, plasminogen-deficient (plg−/−) mice and mice lacking plasminogen activators were mostly resistant to radiodermatitis. Moreover, treatment with a plasminogen inhibitor, tranexamic acid, decreased radiodermatitis in plg+/+ mice and prevented radiodermatitis in plg+/ mice. Together with studies at the molecular level, we report that plasmin is required for the induction of inflammation after irradiation that leads to radiodermatitis, and we propose that inhibition of plasminogen activation can be a novel treatment strategy to reduce and prevent the occurrence of radiodermatitis in patients.

 

 

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Inflammation, plasminogen, radiation-induced dermatitis
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-152950 (URN)10.1038/s41419-018-1106-8 (DOI)000447324600005 ()30323258 (PubMedID)
Available from: 2018-10-31 Created: 2018-10-31 Last updated: 2018-11-01Bibliographically approved
Sulniute, R., Shen, Y., Guo, Y.-Z., Fallah, M., Ahlskog, N., Ny, L., . . . Ny, T. (2016). Plasminogen is a critical regulator of cutaneous wound healing. Thrombosis and Haemostasis, 115(5), 1001-1009
Open this publication in new window or tab >>Plasminogen is a critical regulator of cutaneous wound healing
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2016 (English)In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 115, no 5, p. 1001-1009Article in journal (Refereed) Published
Abstract [en]

Wound healing is a complicated biological process that consist of partially overlapping inflammatory, proliferation and tissue remodelling phases. A successful wound healing depends on a proper activation and subsequent termination of the inflammatory phase. The failure to terminate the inflammation halts the completion of wound healing and is a known reason for formation of chronic wounds. Previous studies have shown that wound closure is delayed in plasminogen deficient mice, and a role for plasminogen in dissection of extracellular matrix was suggested. However, our finding that plasminogen is transported to the wound by inflammatory cells early during the healing process, where it potentiates inflammation, indicates that plasminogen may also have other roles in the wound healing process. Here we report that plasminogen-deficient mice have extensive fibrin and neutrophil depositions in the wounded area long after re-epithelialisation, indicating inefficient debridement and chronic inflammation. Delayed formation of granulation tissue suggests that fibroblast function is impaired in the absence of plasminogen. Therefore, in addition to its role in the activation of inflammation, plasminogen is also crucial for subsequent steps, including resolution of inflammation and activation of the proliferation phase. Importantly, supplementation of plasminogen-deficient mice with human plasminogen leads to a restored healing process that is comparable to that in wild-type mice. Besides of being an activator of the inflammatory phase during wound healing, plasminogen is also required for the subsequent termination of inflammation. Based on these results, we propose that plasminogen may be an important future therapeutic agent for wound treatment.

Keywords
Plasminogen, wound healing, inflammation
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-121571 (URN)10.1160/TH15-08-0653 (DOI)000375372400015 ()
Available from: 2016-06-30 Created: 2016-06-03 Last updated: 2018-10-31Bibliographically approved
Cheng, F., Shen, Y., Mohanasundaram, P., Lindstrom, M., Ivaska, J., Ny, T. & Eriksson, J. E. (2016). Vimentin coordinates fibroblast proliferation and keratinocyte differentiation in wound healing via TGF-beta-Slug signaling. Proceedings of the National Academy of Sciences of the United States of America, 113(30), E4320-E4327
Open this publication in new window or tab >>Vimentin coordinates fibroblast proliferation and keratinocyte differentiation in wound healing via TGF-beta-Slug signaling
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2016 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 30, p. E4320-E4327Article in journal (Refereed) Published
Abstract [en]

Vimentin has been shown to be involved in wound healing, but its functional contribution to this process is poorly understood. Here we describe a previously unrecognized function of vimentin in coordinating fibroblast proliferation and keratinocyte differentiation during wound healing. Loss of vimentin led to a severe deficiency in fibroblast growth, which in turn inhibited the activation of two major initiators of epithelial-mesenchymal transition (EMT), TGF-beta 1 signaling and the Zinc finger transcriptional repressor protein Slug, in vimentin-deficient (VIM-/-) wounds. Correspondingly, VIM-/- wounds exhibited loss of EMT-like keratinocyte activation, limited keratinization, and slow reepithelialization. Furthermore, the fibroblast deficiency abolished collagen accumulation in the VIM-/- wounds. Vimentin reconstitution in VIM-/- fibroblasts restored both their proliferation and TGF-beta 1 production. Similarly, restoring paracrine TGF-beta-Slug-EMT signaling reactivated the transdifferentiation of keratinocytes, reviving their migratory properties, a critical feature for efficient healing. Our results demonstrate that vimentin orchestrates the healing by controlling fibroblast proliferation, TGF-beta 1-Slug signaling, collagen accumulation, and EMT processing, all of which in turn govern the required keratinocyte activation.

Keywords
vimentin intermediate filaments, wound healing, epithelial-mesenchymal transition, fibroblast proliferation, keratinocyte migration
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-124504 (URN)10.1073/pnas.1519197113 (DOI)000380346200011 ()27466403 (PubMedID)
Available from: 2016-08-22 Created: 2016-08-15 Last updated: 2018-06-07Bibliographically approved
Wu, Z., Shen, Y., Gong, K., Wu, Z., Zhang, T., Zhang, X. & Li, S. (2014). Increased osteopontin expression is associated with progression from vulvar precancerous lesions to vulvar squamous cell carcinoma. Archives of Gynecology and Obstetrics, 289(3), 637-644
Open this publication in new window or tab >>Increased osteopontin expression is associated with progression from vulvar precancerous lesions to vulvar squamous cell carcinoma
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2014 (English)In: Archives of Gynecology and Obstetrics, ISSN 0932-0067, E-ISSN 1432-0711, Vol. 289, no 3, p. 637-644Article in journal (Refereed) Published
Abstract [en]

Vulvar squamous cell carcinoma (VSCC) contributes to about 3-5 % of all gynecological cancers. Vulvar intraepithelial neoplasia (VIN) and vulvar lichen sclerosus (VLS) are regarded as precancerous lesions. Early detection and treatment of precancerous lesions may prevent development of VSCC. Osteopontin (OPN) has been shown to be involved in many physiological and pathological processes, such as tumor progression, by promoting cancer cell invasion and metastasis. As a result of these findings, OPN has been described as a potential marker for tumor progression in some malignancies. In this study, we investigated the expression of OPN in vulvar tissue specimens and compared its expression between different histopathological grades. In the present study, the expression patterns of OPN in 80 paraffin-embedded tissue specimens, including 25 VSCC samples, 21 VIN lesions and 21 VLS, in addition to 13 normal vulvar samples, were examined by the immunohistochemical method and chromogenic in situ hybridization. The intensity of OPN expression steadily increased according to the pathological grades. In addition, OPN staining was found in the extracellular matrix in VSCC. Expression levels of OPN increased from VLS and VIN to VSCC, and steadily increased with the pathological stage of VSCC. Our results suggest that OPN may be associated with the progression of VSCC.

Place, publisher, year, edition, pages
Berlin: Springer, 2014
Keywords
Vulvar squamous cell carcinoma, Vulvar intraepithelial neoplasia, Vulvar lichen sclerosus, Osteopontin
National Category
Biochemistry and Molecular Biology Biophysics
Identifiers
urn:nbn:se:umu:diva-87391 (URN)10.1007/s00404-013-3009-3 (DOI)000331637100026 ()
Available from: 2014-03-31 Created: 2014-03-31 Last updated: 2018-06-08Bibliographically approved
Shen, Y., Guo, Y., Wilczynska, M., Li, J., Hellström, S. & Ny, T. (2014). Plasminogen initiates and potentiates the healing of acute and chronic tympanic membrane perforations in mice. Journal of Translational Medicine, 12, Article ID 5.
Open this publication in new window or tab >>Plasminogen initiates and potentiates the healing of acute and chronic tympanic membrane perforations in mice
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2014 (English)In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 12, article id 5Article in journal (Refereed) Published
Abstract [en]

Background: Most tympanic membrane (TM) perforations heal spontaneously, but approximately 10-20% remain open as chronic TM perforations. Chronic perforations can lead to an impaired hearing ability and recurrent middle ear infections. Traditionally, these perforations must be surgically closed, which is costly and time consuming. Therefore, there is a need for simpler therapeutic strategies. Previous studies by us have shown that plasminogen (plg) is a potent pro-inflammatory regulator that accelerates cutaneous wound healing in mice. We have also shown that the healing of TM perforations is completely arrested in plg-deficient (plg(-/-)) mice and that these mice develop chronic TM perforations. In the present study, we investigated the therapeutic potential of local plg injection in acute and chronic TM perforation mice models. Methods: Plg(-/-) mice and wild-type mice were subjected to standardized TM perforations followed by local injection of plg into the soft tissue surrounding the TM. TM perforations with chronic characteristics were induced by leaving TM perforations in plg(-/-) mice untreated for 9 days before treatment. The healing process was observed through otomicroscope and finally confirmed by immunostaining. The quality of TM healing was evaluated based on the morphology of the TM. Result: Daily local injections of plg into the soft tissue surrounding the TM restored the ability to heal TM perforations in plg(-/-) mice in a dose-dependent manner, and potentiated the healing rate and quality in wild-type mice. A single local injection of plg initiated the healing of the chronic-like TM perforations in these mice, resulting in a closed TM with a continuous but rather thick outer keratinocyte layer. However, three plg injections led to a completely healed TM with a thin keratinizing squamous epithelium covering a connective tissue layer. Conclusion: Our data suggests that plg is a promising drug candidate for the treatment of chronic TM perforations in humans.

Place, publisher, year, edition, pages
BioMed Central, 2014
Keywords
Plasminogen, wound healing, tympanic membrane perforations
National Category
Basic Medicine Otorhinolaryngology
Identifiers
urn:nbn:se:umu:diva-68759 (URN)10.1186/1479-5876-12-5 (DOI)000330279900001 ()24393366 (PubMedID)
Funder
Swedish Research Council, B0322301
Available from: 2013-04-25 Created: 2013-04-25 Last updated: 2018-06-08Bibliographically approved
Shen, Y. (2013). Plasminogen: a novel inflammatory regulator that promotes wound healing. (Doctoral dissertation). Umeå: Umeå University
Open this publication in new window or tab >>Plasminogen: a novel inflammatory regulator that promotes wound healing
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The plasminogen activator (PA) system has been shown to be intimately involved in wound healing. However, the role of this system in the initiation and resolution of inflammation during healing process remained to be determined. The aims of this thesis were to investigate the molecular mechanism underlying the interaction between the PA system and the inflammatory system during wound healing and to explore the therapeutic potential of plasminogen in various wound-healing models.

The role of plasminogen in the inflammatory phase of the healing process of acute and diabetic wounds was studied first. Our data showed that administration of additional plasminogen to wild-type mice accelerates the healing of acute wounds. After injury, both endogenous and exogenous plasminogen are bound to inflammatory cells and are transported to the wound site, which leads to activation of inflammatory cells. In diabetic db/db mice, wound-specific accumulation of plasminogen does not take place and the inflammatory response is impaired. However, when additional plasminogen is injected, plasminogen accumulates in the wound, the inflammatory response is enhanced, the signal transduction cascade is activated and the healing rate is significantly increased. These results indicate that administration of plasminogen may be a novel therapeutic strategy to treat different types of wounds, especially chronic wounds in diabetes.

The role of plasminogen at the later stage of wound healing was also studied in plasminogen-deficient mice. Our data showed that even if re-epithelialization is achieved in these mice, a prolonged inflammatory phase with abundant neutrophil accumulation and persistent fibrin deposition is observed at the wound site. These results indicate that plasminogen is also essential for the later phases of wound healing by clearing fibrin and resolving inflammation.

The functional role of two physiological PAs during wound healing was further studied in a tympanic membrane (TM) wound-healing model. Our data showed that the healing process was clearly delayed in urokinase-type PA (uPA)-deficient mice but not in tissue-type PA (tPA)-deficient mice. Less pronounced keratinocyte migration, abundant neutrophil accumulation and persistent fibrin deposition were observed in uPA-deficient mice. These results indicate that uPA plays a central role in the generation of plasmin during the healing of TM perforations.

Finally the therapeutic potential of plasminogen in the TM wound-healing model was studied. Our data showed that local injection of plasminogen restores the ability to heal TM perforations in plasminogen-deficient mice in a dose-dependent manner. Plasminogen supplementation also potentiates healing of acute TM perforations in wild-type mice, independent of the administration method used. A single local injection of plasminogen in plasminogen-deficient mice can initiate healing of chronic TM perforations resulting in a closed TM with a continuous but rather thick outer keratinocyte layer. Three plasminogen injections lead to a completely healed TM with a thin keratinizing squamous epithelium covering a connective tissue layer that can start to reorganize and further mature to its normal appearance. In conclusion, our results suggest that plasminogen is a promising drug candidate for the treatment of chronic TM perforations in humans. 

Taken together, our data indicate that plasminogen is a novel inflammatory regulator that promotes wound healing.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2013. p. 58
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1575
Keywords
Plasminogen, inflammation, wound healing, diabetic wounds, tympanic membrane perforations
National Category
Basic Medicine Otorhinolaryngology Dermatology and Venereal Diseases Endocrinology and Diabetes
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-68755 (URN)978-91-7459-651-9 (ISBN)
Public defence
2013-05-24, KB3A9, KBC-huset, Umeå University, Umeå, 10:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council
Available from: 2013-05-03 Created: 2013-04-25 Last updated: 2018-06-08Bibliographically approved
Shen, Y., Guo, Y., Du, C., Wilczynska, M., Hellström, S. & Ny, T. (2012). Mice deficient in urokinase-type plasminogen activator have delayed healing of tympanic membrane perforations. PLoS ONE, 7(12), e51303
Open this publication in new window or tab >>Mice deficient in urokinase-type plasminogen activator have delayed healing of tympanic membrane perforations
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, p. e51303-Article in journal (Refereed) Published
Abstract [en]

Mice deficient in plasminogen, the precursor of plasmin, show completely arrested healing of tympanic membrane (TM) perforations, indicating that plasmin plays an essential role in TM healing. The activation of plasminogen to plasmin is performed by two plasminogen activators (PAs), urokinase-type PA (uPA) and tissue-type PA (tPA). To elucidate the functional roles of PAs in the healing of TM perforations, we investigated the phenotypes of single gene-deficient mice lacking uPA (uPA(-/-)) or tPA (tPA(-/-)) after TM perforation. Delayed healing of TM perforations was observed in uPA(-/-) mice but not tPA(-/-) mice. The migration of keratinocytes was clearly delayed and seemed to be misoriented in uPA(-/-) mice. Furthermore, fibrin deposition and the inflammatory response were persistent in these mice. Our findings demonstrate that uPA plays a role in the healing of TM perforations. The observed phenotypes in uPA(-/-) mice are most likely due to the reduced generation of plasmin.

Place, publisher, year, edition, pages
Public library of science, 2012
Keywords
receptor; upa; keratinocytes; system; gene; model
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-64176 (URN)10.1371/journal.pone.0051303 (DOI)000312064100090 ()23236466 (PubMedID)
Available from: 2013-01-17 Created: 2013-01-17 Last updated: 2018-06-08Bibliographically approved
Shen, Y., Guo, Y., Mikus, P., Sulniute, R., Wilczynska, M., Ny, T. & Li, J. (2012). Plasminogen is a key proinflammatory regulator that accelerates the healing of acute and diabetic wounds. Blood, 119(24), 5879-5887
Open this publication in new window or tab >>Plasminogen is a key proinflammatory regulator that accelerates the healing of acute and diabetic wounds
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2012 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 119, no 24, p. 5879-5887Article in journal (Refereed) Published
Abstract [en]

Despite decades of research on wound healing, effective biologic agents for the treatment of chronic wounds, especially diabetic wounds, are still lacking. In the present study, we report that the inert plasma protein plasminogen (plg) acts as a key regulatory molecule that potentiates wound healing in mice. Early in the healing process, plg bound to inflammatory cells is transported to the wound area, where the level of plg is increased locally, leading to the induction of cytokines and intracellular signaling events and to a potentiation of the early inflammatory response. Systemic administration of additional plg not only accelerates the healing of acute burn wounds in wild-type mice, but also improves the healing of chronic diabetic wounds in a mouse model of diabetes. Our results suggest that the administration of plg may be a novel therapeutic strategy to treat many different types of wounds, especially chronic wounds such as those caused by diabetes. (Blood. 2012; 119(24):5879-5887)

Place, publisher, year, edition, pages
Washington, USA: American society of hematology, 2012
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-58921 (URN)10.1182/blood-2012-01-407825 (DOI)000307396500041 ()
Available from: 2012-09-07 Created: 2012-09-06 Last updated: 2018-06-08Bibliographically approved
Zheng, W., Gorre, N., Shen, Y., Noda, T., Ogawa, W., Lundin, E. & Liu, K. (2010). Maternal phosphatidylinositol 3-kinase signalling is crucial for embryonic genome activation and preimplantation embryogenesis. EMBO Reports, 11(11), 890-895
Open this publication in new window or tab >>Maternal phosphatidylinositol 3-kinase signalling is crucial for embryonic genome activation and preimplantation embryogenesis
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2010 (English)In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 11, no 11, p. 890-895Article in journal (Refereed) Published
Abstract [en]

Maternal effect factors derived from oocytes are important for sustaining early embryonic development before the major wave of embryonic genome activation (EGA). In this study, we report a two-cell-stage arrest of embryos lacking maternal 3-phosphoinositide-dependent protein kinase 1 as a result of suppressed EGA. Concurrent deletion of maternal Pten completely rescued the suppressed EGA and embryonic progression through restored AKT signalling, which fully restored the fertility of double-mutant females. Our study identifies maternal phosphatidylinositol 3-kinase signalling as a new maternal effect factor that regulates EGA and preimplantation embryogenesis in mice.

Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-46368 (URN)10.1038/embor.2010.144 (DOI)000283507900016 ()20930845 (PubMedID)
Available from: 2011-08-31 Created: 2011-08-31 Last updated: 2018-06-08Bibliographically approved
Adhikari, D., Zheng, W., Shen, Y., Gorre, N., Hämäläinen, T., Cooney, A. J., . . . Liu, K. (2010). Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles. Human Molecular Genetics, 19(3), 397-410
Open this publication in new window or tab >>Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles
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2010 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 19, no 3, p. 397-410Article in journal (Refereed) Published
Abstract [en]

To maintain the female reproductive lifespan, the majority of ovarian primordial follicles are preserved in a quiescent state in order to provide ova for later reproductive life. However, the molecular mechanism that maintains the long quiescence of primordial follicles is poorly understood. Here we provide genetic evidence to show that the tumor suppressor tuberous sclerosis complex 1 (Tsc1), which negatively regulates mammalian target of rapamycin complex 1 (mTORC1), functions in oocytes to maintain the quiescence of primordial follicles. In mutant mice lacking the Tsc1 gene in oocytes, the entire pool of primordial follicles is activated prematurely due to elevated mTORC1 activity in the oocyte, ending up with follicular depletion in early adulthood and causing premature ovarian failure (POF). We further show that maintenance of the quiescence of primordial follicles requires synergistic, collaborative functioning of both Tsc and PTEN (phosphatase and tensin homolog deleted on chromosome 10) and that these two molecules suppress follicular activation through distinct ways. Our results suggest that Tsc/mTORC1 signaling and PTEN/PI3K (phosphatidylinositol 3 kinase) signaling synergistically regulate the dormancy and activation of primordial follicles, and together ensure the proper length of female reproductive life. Deregulation of these signaling pathways in oocytes results in pathological conditions of the ovary, including POF and infertility.

Identifiers
urn:nbn:se:umu:diva-42927 (URN)10.1093/hmg/ddp483 (DOI)000273227200001 ()19843540 (PubMedID)
Available from: 2011-04-14 Created: 2011-04-14 Last updated: 2018-06-08Bibliographically approved
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