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      Myocardium-targeted transplantation of PHD2 shRNA-modified bone mesenchymal stem cells through ultrasound-targeted microbubble destruction protects the heart from acute myocardial infarction

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          Abstract

          Ultrasound-targeted microbubble destruction (UTMD) is a promising approach to facilitate the precise delivery of bone marrow stem cells (BMSCs) to the ischemic myocardium. However, stem cell therapy for ischemic myocardium is challenging due to the poor survival of transplanted stem cells under severe ischemic conditions. In this study, we investigated whether myocardium-targeted transplantation of prolyl hydroxylase domain protein 2 (PHD2) shRNA-modified BMSCs by UTMD increases the viability of grafted cells, and enhances their cardioprotective effects in acute myocardial infarction.

          Methods: BMSCs were transduced with lentiviral PHD2 shRNA, and a novel microbubble formulation was prepared by a thin-film hydration method. In rats, BMSCs with or without PHD2 shRNA modification were transplanted by UTMD after inducing acute myocardium infarction. Effects of PHD2 shRNA on BMSC survival, myocardial apoptosis, angiogenesis, and cardiac function were evaluated. In vitro, anti-apoptotic effects and its mechanisms of PHD2 silencing on BMSC and BMSC-conditioned medium on H9C2 cell were detected.

          Results: PHD2 shRNA-modified BMSC transplantation by UTMD resulted in increased BMSC survival, reduced myocardial apoptosis, reduced infarct size, increased vascular density, and improved cardiac function compared to the control vector-modified BMSC transplantation by UTMD. PHD2 silencing increased BMSC survival through a HIF-1α-dependent mechanism. The decrease in cardiomyocyte apoptosis by conditioned medium from PHD2 shRNA-treated BMSCs was due to an increase in the expression of insulin-like growth factor (IGF)-1.

          Conclusions: The delivery of PHD2 shRNA-modified BMSCs by UTMD promoted grafted cell homing and activity, and increased myocardial angiogenesis in the infarcted heart, leading to improved cardiac function. This combination may provide a promising strategy for enhancing the effectiveness of stem cell therapy after acute myocardial infarction.

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          Most cited references22

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          Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions.

          Hypoxia-inducible factor (HIF-1) is an oxygen-dependent transcriptional activator, which plays crucial roles in the angiogenesis of tumors and mammalian development. HIF-1 consists of a constitutively expressed HIF-1beta subunit and one of three subunits (HIF-1alpha, HIF-2alpha or HIF-3alpha). The stability and activity of HIF-1alpha are regulated by various post-translational modifications, hydroxylation, acetylation, and phosphorylation. Therefore, HIF-1alpha interacts with several protein factors including PHD, pVHL, ARD-1, and p300/CBP. Under normoxia, the HIF-1alpha subunit is rapidly degraded via the von Hippel-Lindau tumor suppressor gene product (pVHL)- mediated ubiquitin-proteasome pathway. The association of pVHL and HIF-1alpha under normoxic conditions is triggered by the hydroxylation of prolines and the acetylation of lysine within a polypeptide segment known as the oxygen-dependent degradation (ODD) domain. On the contrary, in the hypoxia condition, HIF-1alpha subunit becomes stable and interacts with coactivators such as p300/CBP to modulate its transcriptional activity. Eventually, HIF-1 acts as a master regulator of numerous hypoxia-inducible genes under hypoxic conditions. The target genes of HIF-1 are especially related to angiogenesis, cell proliferation/survival, and glucose/iron metabolism. Moreover, it was reported that the activation of HIF-1alpha is closely associated with a variety of tumors and oncogenic pathways. Hence, the blocking of HIF-1a itself or HIF-1alpha interacting proteins inhibit tumor growth. Based on these findings, HIF-1 can be a prime target for anticancer therapies. This review summarizes the molecular mechanism of HIF-1a stability, the biological functions of HIF-1 and its potential applications of cancer therapies.
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            Paracrine mechanisms of stem cell reparative and regenerative actions in the heart.

            Stem cells play an important role in restoring cardiac function in the damaged heart. In order to mediate repair, stem cells need to replace injured tissue by differentiating into specialized cardiac cell lineages and/or manipulating the cell and molecular mechanisms governing repair. Despite early reports describing engraftment and successful regeneration of cardiac tissue in animal models of heart failure, these events appear to be infrequent and yield too few new cardiomyocytes to account for the degree of improved cardiac function observed. Instead, mounting evidence suggests that stem cell mediated repair takes place via the release of paracrine factors into the surrounding tissue that subsequently direct a number of restorative processes including myocardial protection, neovascularization, cardiac remodeling, and differentiation. The potential for diverse stem cell populations to moderate many of the same processes as well as key paracrine factors and molecular pathways involved in stem cell-mediated cardiac repair will be discussed in this review. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited". Copyright © 2010 Elsevier Ltd. All rights reserved.
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              Survival and development of neonatal rat cardiomyocytes transplanted into adult myocardium.

              Transplantation of neonatal cardiomyocytes is a novel approach for the treatment of heart failure and myocardial infarction, but quantitative information on long-term cell survival and development is limited. Male donor cardiomyocytes were isolated from neonatal Fischer 344 rats (1-2 days), purified, and injected into the left ventricular wall of female syngeneic adult rats. One hour to 12 weeks later, genomic DNA was isolated from recipient hearts. The amount of male DNA per sample was determined by quantitative real-time TaqMan PCR of the male-specific Sry gene. Transplanted cell survival was 57 +/- 9% at 0-1 h, 24 +/- 6% at 24 h, 28 +/- 11% at 7 days, 27 +/- 3% at 14 days, 23 +/- 8% at 4 weeks and 15 +/- 3% at 12 weeks. The caspase inhibitor AcYVADcmk failed to improve transplanted cell survival at 24 h, suggesting that apoptosis did not play a major role in cell loss. Histology revealed that transplanted cells became more elongated over time, developed cross-striations, and that their nuclei increased in size. However, at 12 weeks, transplanted cells and their nuclei were still smaller than those of host myocardium. We established a quantitative survival profile for neonatal cardiomyocytes transplanted into normal adult myocardium. There was significant loss of cells within 24 h, but 15% of transplanted cells survived 12 weeks. Those cells that did survive underwent differentiation and developed visible sarcomeres, suggesting a potential contribution toward ventricular function. Copyright 2002 Academic Press.
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                Author and article information

                Journal
                Theranostics
                Theranostics
                thno
                Theranostics
                Ivyspring International Publisher (Sydney )
                1838-7640
                2020
                6 April 2020
                : 10
                : 11
                : 4967-4982
                Affiliations
                [1 ]Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
                [2 ]Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
                [3 ]College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
                Author notes
                ✉ Corresponding authors: Mingxing Xie, MD, Ph.D.; 1277 Jiefang Avenue, Wuhan, China. Tel: 86-27-85726430; Fax: 86-27-85726386. E-mail address: xiemx@ 123456hust.edu.cn . Or Li Zhang, MD, Ph.D.; 1277 Jiefang Avenue, Wuhan, China. Tel: 86-27-85726430; Fax: 86-27-85726386. E-mail address: zli429@ 123456hust.edu.cn .

                * These authors contributed equally to this article.

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                thnov10p4967
                10.7150/thno.43233
                7163444
                32308762
                b1f55524-7690-4f04-8c42-f4a376bfb85b
                © The author(s)

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 19 December 2019
                : 22 March 2020
                Categories
                Research Paper

                Molecular medicine
                utmd,bone marrow stem cell,phd2 shrna,acute myocardial infarction
                Molecular medicine
                utmd, bone marrow stem cell, phd2 shrna, acute myocardial infarction

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