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Gallini, Radiosa
Publications (4 of 4) Show all publications
Gallini, R., Huusko, J., Yla-Herttuala, S., Betsholtz, C. & Andrae, J. (2016). Isoform-Specific Modulation of Inflammation Induced by Adenoviral Mediated Delivery of Platelet-Derived Growth Factors in the Adult Mouse Heart. PLoS ONE, 11(8), Article ID e0160930.
Open this publication in new window or tab >>Isoform-Specific Modulation of Inflammation Induced by Adenoviral Mediated Delivery of Platelet-Derived Growth Factors in the Adult Mouse Heart
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 8, article id e0160930Article in journal (Refereed) Published
Abstract [en]

Platelet-derived growth factors (PDGFs) are key regulators of mesenchymal cells in vertebrate development. To what extent PDGFs also exert beneficial homeostatic or reparative roles in adult organs, as opposed to adverse fibrogenic responses in pathology, are unclear. PDGF signaling plays critical roles during heart development, during which forced overexpression of PDGFs induces detrimental cardiac fibrosis; other studies have implicated PDGF signaling in post-infarct myocardial repair. Different PDGFs may exert different effects mediated through the two PDGF receptors (PDGFR alpha and PDGFR beta) in different cell types. Here, we assessed responses induced by five known PDGF isoforms in the adult mouse heart in the context of adenovirus vector-mediated inflammation. Our results show that different PDGFs have different, in some cases even opposing, effects. Strikingly, whereas the major PDGFRa agonists (PDGF-A and -C) decreased the amount of scar tissue and increased the numbers of PDGFR alpha-positive fibroblasts, PDGFR beta agonists either induced large scars with extensive inflammation (PDGF-B) or dampened the adenovirusinduced inflammation and produced a small and dense scar (PDGF-D). These results provide evidence for PDGF isoform-specific inflammation-modulating functions that may have therapeutic implications. They also illustrate a surprising complexity in the PDGF-mediated pathophysiological responses.

National Category
Immunology in the medical area Cell and Molecular Biology Neurosciences
Identifiers
urn:nbn:se:uu:diva-304217 (URN)10.1371/journal.pone.0160930 (DOI)000381381100090 ()27513343 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilKnut and Alice Wallenberg FoundationTorsten Söderbergs stiftelseRagnar Söderbergs stiftelseThe Karolinska Institutet's Research Foundation
Note

Radiosa Gallini and Jenni Huusko contributed equally to this work.

Available from: 2016-11-21 Created: 2016-10-03 Last updated: 2018-05-18Bibliographically approved
Gallini, R., Lindblom, P., Bondjers, C., Betsholtz, C. & Andrae, J. (2016). PDGF-A and PDGF-B induces cardiac fibrosis in transgenic mice. Experimental Cell Research, 349(2), 282-290
Open this publication in new window or tab >>PDGF-A and PDGF-B induces cardiac fibrosis in transgenic mice
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2016 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 349, no 2, p. 282-290Article in journal (Refereed) Published
Abstract [en]

Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) contribute to normal heart development. Deficient or abnormal expression of Pdgf and Pdgfr genes have a negative impact on cardiac development and function. The cellular effects of PDGFs in the hearts of Pdgf/Pdgfr mutants and the pathogenesis of the resulting abnormalities are poorly understood, but different PDGF isoforms induce varying effects. Here, we generated three new transgenic mouse types which complete a set of studies, where all different PDGF ligands have been expressed under the same heart specific alpha-myosin heavy chain promoter. Transgenic expression of the natural isoforms of Pdgfa and Pdgfb resulted in isoform specific fibrotic reactions and cardiac hypertrophy. Pdgfa overexpression resulted in a severe fibrotic reaction with up to 8-fold increase in cardiac size, leading to lethal cardiac failure within a few weeks after birth. In contrast, Pdgfb overexpression led to focal fibrosis and moderate cardiac hypertrophy. As PDGF-A and PDGF-B have different affinity for the two PDGF receptors, we analyzed the expression of the receptors and the histology of the fibrotic hearts. Our data suggest that the stronger fibrotic effect generated by Pdgfa overexpression was mediated by Pdgfra in cardiac interstitial mesenchymal cells, i.e. the likely source of extracellular matrix depostion and fibrotic reaction. The apparent sensitivity of the heart to ectopic PDGFR alpha agonists supports a role for endogenous PDGFRa agonists in the pathogenesis of cardiac fibrosis.

Keywords
PDGF, Transgene, Myosin heavy chain, Fibrosis, Heart
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-312037 (URN)10.1016/j.yexcr.2016.10.022 (DOI)000389163200009 ()27816607 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilNovo NordiskKnut and Alice Wallenberg FoundationTorsten Söderbergs stiftelseRagnar Söderbergs stiftelse
Available from: 2017-01-05 Created: 2017-01-04 Last updated: 2018-05-18Bibliographically approved
Andrae, J., Ehrencrona, H., Gallini, R., Lal, M., Ding, H. & Betsholtz, C. (2013). Analysis of Mice Lacking the Heparin-Binding Splice Isoform of Platelet-Derived Growth Factor A. Molecular and Cellular Biology, 33(20), 4030-4040
Open this publication in new window or tab >>Analysis of Mice Lacking the Heparin-Binding Splice Isoform of Platelet-Derived Growth Factor A
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2013 (English)In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 33, no 20, p. 4030-4040Article in journal (Refereed) Published
Abstract [en]

Platelet-derived growth factor A-chain (PDGF-A) exists in two evolutionarily conserved isoforms, PDGF-Along and PDGF-Ashort, generated by alternative RNA splicing. They differ by the presence (in PDGF-Along) or absence (in PDGF-Ashort) of a carboxyterminal heparin/heparan sulfate proteoglycan-binding motif. In mice, similar motifs present in other members of the PDGF and vascular endothelial growth factor (VEGF) families have been functionally analyzed in vivo, but the specific physiological importance of PDGF-A(long) has not been explored previously. Here, we analyzed the absolute and relative expression of the two PDGF-A splice isoforms during early postnatal organ development in the mouse and report on the generation of a Pdgfa allele (Pdgfa(Delta ex6) incapable of producing PDGF-A(long) due to a deletion of the exon 6 splice acceptor site. In situations of limiting PDGF-A signaling through PDGF receptor alpha (PDGFR alpha), or in mice lacking PDGF-C, homozygous carriers of Pdgfa(Delta ex6) showed abnormal development of the lung, intestine, and vertebral column, pinpointing developmental processes where PDGF-A(long) may play a physiological role.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-210593 (URN)10.1128/MCB.00749-13 (DOI)000324912000007 ()
Available from: 2013-11-11 Created: 2013-11-11 Last updated: 2018-05-18Bibliographically approved
Lönn, P., Al-Amin, R. A., Heldin, J., Gallini, R., Björkesten, J., Oelrich, J., . . . Landegren, U.High-throughput in situ mapping of phosphorylated protein complexes across the cell cycle and in response to drugs.
Open this publication in new window or tab >>High-throughput in situ mapping of phosphorylated protein complexes across the cell cycle and in response to drugs
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Interactions and posttranslational modifications (PTMs) of proteins orchestrate cellular responses to cytokines, drugs or other agents, but it has been difficult to monitor and characterize these dynamic events at high-throughput. Here, we have established a semi-automated system for large-scale in situ proximity ligation assays (isPLA). The protocol combines isPLA in microtiter wells with automated microscopy and computer-based image analysis whereby specific protein phosphorylations and interactions are digitally recorded in cells, along with measurements of morphological features. We demonstrate how this platform can improve analysis of cellular signaling by investigating TGF-b responsive Smad2 linker phosphorylations and complex formations over time and across millions of individual cells. We depict single cell responses in relation to e.g. local cell crowding and cell cycle progression via measurements of DNA content and nuclear size. Finally, we illustrate the application of the protocol for demonstrating drug effects by screening a library of phosphatase inhibitors. In summary, our approach expands the scope for image-based single cell analyses by combining observations of protein interactions and modifications with morphological details of individual cells at high throughput.

National Category
Natural Sciences
Research subject
Biochemistry; Molecular Cellbiology; Molecular Biotechnology
Identifiers
urn:nbn:se:uu:diva-374248 (URN)
Available from: 2019-01-18 Created: 2019-01-18 Last updated: 2019-01-21
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