| Activation of host tissue trophic factors through JAK-STAT3 signaling: a mechanism of mesenchymal stem cell-mediated cardiac repair. | |
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MedLine Citation:
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PMID: 20852053 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We recently demonstrated a cardiac therapeutic regimen based on injection of bone marrow mesenchymal stem cells (MSCs) into the skeletal muscle. Although the injected MSCs were trapped in the local musculature, the extracardiac cell delivery approach repaired the failing hamster heart. This finding uncovers a tissue repair mechanism mediated by trophic factors derived from the injected MSCs and local musculature that can be explored for minimally invasive stem cell therapy. However, the trophic factors involved in cardiac repair and their actions remain largely undefined. We demonstrate here a role of MSC-derived IL-6-type cytokines in cardiac repair through engagement of the skeletal muscle JAK-STAT3 axis. The MSC IL-6-type cytokines activated JAK-STAT3 signaling in cultured C2C12 skeletal myocytes and caused increased expression of the STAT3 target genes hepatocyte growth factor (HGF) and VEGF, which was inhibited by glycoprotein 130 (gp130) blockade. These in vitro findings were corroborated by in vivo studies, showing that the MSC-injected hamstrings exhibited activated JAK-STAT3 signaling and increased growth factor/cytokine production. Elevated host tissue growth factor levels were also detected in quadriceps, liver, and brain, suggesting a possible global trophic effect. Paracrine actions of these host tissue-derived factors activated the endogenous cardiac repair mechanisms in the diseased heart mediated by Akt, ERK, and JAK-STAT3. Administration of the cell-permeable JAK-STAT inhibitor WP1066 abrogated MSC-mediated host tissue growth factor expression and functional improvement. The study illustrates that the host tissue trophic factor network can be activated by MSC-mediated JAK-STAT3 signaling for tissue repair. |
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Authors:
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Arsalan Shabbir; David Zisa; Huey Lin; Michalis Mastri; Gregory Roloff; Gen Suzuki; Techung Lee |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-09-17 |
Journal Detail:
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Title: American journal of physiology. Heart and circulatory physiology Volume: 299 ISSN: 1522-1539 ISO Abbreviation: Am. J. Physiol. Heart Circ. Physiol. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-01 Completed Date: 2010-11-29 Revised Date: 2011-11-01 |
Medline Journal Info:
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Nlm Unique ID: 100901228 Medline TA: Am J Physiol Heart Circ Physiol Country: United States |
Other Details:
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Languages: eng Pagination: H1428-38 Citation Subset: IM |
Affiliation:
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Department of Biochemistry and Center for Research in Cardiovascular Medicine, University at Buffalo, New York 14214, USA. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cells, Cultured Cricetinae Cytokines / metabolism Hepatocyte Growth Factor / metabolism* Janus Kinases / antagonists & inhibitors, metabolism* Male Mesenchymal Stem Cell Transplantation Mesenchymal Stem Cells / cytology, metabolism* Models, Animal Muscle Fibers, Skeletal / cytology, metabolism* Myocardium / metabolism Pyridines / pharmacology STAT3 Transcription Factor / antagonists & inhibitors, metabolism* Signal Transduction / drug effects, physiology* Tyrphostins / pharmacology Vascular Endothelial Growth Factor A / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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HL-84590/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cytokines; 0/Pyridines; 0/STAT3 Transcription Factor; 0/Tyrphostins; 0/Vascular Endothelial Growth Factor A; 0/WP1066; 67256-21-7/Hepatocyte Growth Factor; EC 2.7.10.2/Janus Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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