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      Sonic Hedgehog Gene Delivery to the Rodent Heart Promotes Angiogenesis via iNOS/Netrin-1/PKC Pathway

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          Abstract

          Background

          We hypothesized that genetic modification of mesenchymal stem cells (MSCs) with Sonic Hedgehog (Shh) transgene, a morphogen during embryonic development and embryonic and adult stem cell growth, improved their survival and angiogenic potential in the ischemic heart via iNOS/netrin/PKC pathway.

          Methods/Principal Findings

          MSCs from young Fisher-344 rat bone marrow were purified and transfected with pCMV Shh plasmid ( ShhMSCs). Immunofluorescence, RT-PCR and Western blotting showed higher expression of Shh in ShhMSCs which also led to increased expression of angiogenic and pro-survival growth factors in ShhMSCs. Significantly improved migration and tube formation was seen in ShhMSCs as compared to empty vector transfected MSCs ( EmpMSCs). Significant upregulation of netrin-1 and iNOS was observed in ShhMSCs in PI3K independent but PKC dependent manner. For in vivo studies, acute myocardial infarction model was developed in Fisher-344 rats. The animals were grouped to receive 70 µl basal DMEM without cells (group-1) or containing 1×10 6 EmpMSCs (group-2) and ShhMSCs (group-3). Group-4 received recombinant netrin-1 protein injection into the infarcted heart. FISH and sry-quantification revealed improved survival of ShhMSCs post engraftment. Histological studies combined with fluorescent microspheres showed increased density of functionally competent blood vessels in group-3 and group-4. Echocardiography showed significantly preserved heart function indices post engraftment with ShhMSCs in group-3 animals.

          Conclusions/Significance

          Reprogramming of stem cells with Shh maximizes their survival and angiogenic potential in the heart via iNOS/netrin-1/PKC signaling.

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          Most cited references20

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          Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo.

          M Bitgood, A McMahon (1995)
          The mouse Hedgehog gene family consists of three members, Sonic, Desert, and Indian hedgehog (Shh, Dhh, and Ihh, respectively), relatives of the Drosophila segment polarity gene, hedgehog (hh). All encode secreted proteins implicated in cell-cell interactions. One of these, Shh, is expressed in and mediates the signaling activities of several key organizing centers which regulate central nervous system, limb, and somite polarity. However, nothing is known of the roles of Dhh or Ihh, nor of the possible function of Shh during later embryogenesis. We have used serial-section in situ hybridization to obtain a detailed profile of mouse Hh gene expression from 11.5 to 16.5 days post coitum. Apart from the gut, which expresses both Shh and Ihh, there is no overlap in the various Hh expression domains. Shh is predominantly expressed in epithelia at numerous sites of epithelial-mesenchymal interactions, including the tooth, hair, whisker, rugae, gut, bladder, urethra, vas deferens, and lung, Dhh in Schwann and Sertoli cell precursors, and Ihh in gut and cartilage. Thus, it is likely that Hh signaling plays a central role in a diverse array of morphogenetic processes. Furthermore, we have compared Hh expression with that of a second family of signaling molecules, the Bone morphogenetic proteins (Bmps), vertebrate relatives of decapentaplegic, a target of the Drosophila Hh signaling pathway. The frequent expression of Bmp-2, -4, and -6 in similar or adjacent cell populations suggests a conserved role for Hh/Bmp interactions in vertebrate development.
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            Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1.

            L Kogerman, Anna-Lena Undén, Peter Zaphiropoulos … (1999)
            Sonic hedgehog, Patched and Gli are components of a mammalian signalling pathway that has been conserved during evolution and which has a central role in the control of pattern formation and cellular proliferation during development. Here we identify the human Suppressor-of-Fused (SUFUH) complementary DNA and show that the gene product interacts physically with the transcriptional effector GLI-1, can sequester GLI-1 in the cytoplasm, but can also interact with GLI-1 on DNA. Functionally, SUFUH inhibits transcriptional activation by GLI-1, as well as osteogenic differentiation in response to signalling from Sonic hedgehog. Localization of GLI-1 is influenced by the presence of a nuclear-export signal, and GLI-1 becomes constitutively nuclear when this signal is mutated or nuclear export is inhibited. These results show that SUFUH is a conserved negative regulator of GLI-1 signalling that may affect nuclear-cytoplasmic shuttling of GLI-1 or the activity of GLI-1 in the nucleus and thereby modulate cellular responses.
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              IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1alpha/CXCR4 signaling to promote myocardial repair.

              Adil Haider, Shujia Jiang, Muhammad Ashraf … (2008)
              We hypothesized that mesenchymal stem cells (MSCs) overexpressing insulin-like growth factor (IGF)-1 showed improved survival and engraftment in the infarcted heart and promoted stem cell recruitment through paracrine release of stromal cell-derived factor (SDF)-1alpha. Rat bone marrow-derived MSCs were used as nontransduced ((Norm)MSCs) or transduced with adenoviral-null vector ((Null)MSCs) or vector encoding for IGF-1 ((IGF-1)MSCs). (IGF-1)MSCs secreted higher IGF-1 until 12 days of observation (P<0.001 versus (Null)MSCs). Molecular studies revealed activation of phosphoinositide 3-kinase, Akt, and Bcl.xL and inhibition of glycogen synthase kinase 3beta besides release of SDF-1alpha in parallel with IGF-1 expression in (IGF-1)MSCs. For in vivo studies, 70 muL of DMEM without cells (group 1) or containing 1.5x10(6) (Null)MSCs (group 2) or (IGF-1)MSCs (group 3) were implanted intramyocardially in a female rat model of permanent coronary artery occlusion. One week later, immunoblot on rat heart tissue (n=4 per group) showed elevated myocardial IGF-1 and phospho-Akt in group 3 and higher survival of (IGF-1)MSCs (P<0.06 versus (Null)MSCs) (n=6 per group). SDF-1alpha was increased in group 3 animal hearts (20-fold versus group 2), with massive mobilization and homing of ckit(+), MDR1(+), CD31(+), and CD34(+) cells into the infarcted heart. Infarction size was significantly reduced in cell transplanted groups compared with the control. Confocal imaging after immunostaining for myosin heavy chain, actinin, connexin-43, and von Willebrand factor VIII showed extensive angiomyogenesis in the infarcted heart. Indices of left ventricular function, including ejection fraction and fractional shortening, were improved in group 3 as compared with group 1 (P<0.05). In conclusion, the strategy of IGF-1 transgene expression induced massive stem cell mobilization via SDF-1alpha signaling and culminated in extensive angiomyogenesis in the infarcted heart.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2010
                Publication date (Electronic): 5 January 2010
                Volume: 5
                Issue: 1
                Electronic Location Identifier: e8576
                Affiliations
                [1]Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America
                Harvard Medical School, United States of America
                Author notes

                Conceived and designed the experiments: RPA KHH MA. Performed the experiments: RPA JS MRA. Analyzed the data: RPA KHH JS MRA MA. Contributed reagents/materials/analysis tools: KHH MA. Wrote the paper: KHH MA. Financial support: KHH, MA.

                Article
                Publisher ID: 09-PONE-RA-12908R1
                DOI: 10.1371/journal.pone.0008576
                PMC ID: 2797399
                PubMed ID: 20052412
                SO-VID: af781df8-9798-460c-9cee-5eb8c1702a82
                Copyright © Ahmed et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 14 September 2009
                Date accepted : 2 November 2009
                Page count
                Pages: 11
                Categories
                Subject: Research Article
                Subject: Biochemistry/Cell Signaling and Trafficking Structures
                Subject: Cell Biology/Gene Expression
                Subject: Developmental Biology/Stem Cells

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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