Enhanced Cardioprotection by Human Endometrium Mesenchymal Stem Cells Driven by Exosomal MicroRNA‐21

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Abstract

Our group recently reported positive therapeutic benefit of human endometrium‐derived mesenchymal stem cells (EnMSCs) delivered to infarcted rat myocardium, an effect that correlated with enhanced secretion of protective cytokines and growth factors compared with parallel cultures of human bone marrow MSCs (BMMSCs). To define more precisely the molecular mechanisms of EnMSC therapy, in the present study, we assessed in parallel the paracrine and therapeutic properties of MSCs derived from endometrium, bone marrow, and adipose tissues in a rat model of myocardial infarction (MI). EnMSCs, BMMSCs, and adipose‐derived MSCs (AdMSCs) were characterized by fluorescence‐activated cell sorting (FACS). Paracrine and cytoprotective actions were assessed in vitro by coculture with neonatal cardiomyocytes and human umbilical vein endothelial cells. A rat MI model was used to compare cell therapy by intramyocardial injection of BMMSCs, AdMSCs, and EnMSCs. We found that EnMSCs conferred superior cardioprotection relative to BMMSCs or AdMSCs and supported enhanced microvessel density. Inhibitor studies indicated that the enhanced paracrine actions of EnMSCs were mediated by secreted exosomes. Analyses of exosomal microRNAs (miRs) by miR array and quantitative polymerase chain reaction revealed that miR‐21 expression was selectively enhanced in exosomes derived from EnMSCs. Selective antagonism of miR‐21 by anti‐miR treatment abolished the antiapoptotic and angiogenic effects of EnMSCs with parallel effects on phosphatase and tensin homolog (PTEN), a miR‐21 target and downstream Akt. The results of the present study confirm the superior cardioprotection by EnMSCs relative to BMMSCs or AdMSCs and implicates miR‐21 as a potential mediator of EnMSC therapy by enhancing cell survival through the PTEN/Akt pathway. The endometrium might be a preferential source of MSCs for cardiovascular cell therapy. S tem C ells T ranslational M edicine 2017;6:209–222

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Most cited references 24

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A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction.

Joshua Hare, Jay Traverse, Timothy D Henry … (2009)

Our aim was to investigate the safety and efficacy of intravenous allogeneic human mesenchymal stem cells (hMSCs) in patients with myocardial infarction (MI). Bone marrow-derived hMSCs may ameliorate consequences of MI, and have the advantages of preparation ease, allogeneic use due to immunoprivilege, capacity to home to injured tissue, and extensive pre-clinical support. We performed a double-blind, placebo-controlled, dose-ranging (0.5, 1.6, and 5 million cells/kg) safety trial of intravenous allogeneic hMSCs (Prochymal, Osiris Therapeutics, Inc., Baltimore, Maryland) in reperfused MI patients (n=53). The primary end point was incidence of treatment-emergent adverse events within 6 months. Ejection fraction and left ventricular volumes determined by echocardiography and magnetic resonance imaging were exploratory efficacy end points. Adverse event rates were similar between the hMSC-treated (5.3 per patient) and placebo-treated (7.0 per patient) groups, and renal, hepatic, and hematologic laboratory indexes were not different. Ambulatory electrocardiogram monitoring demonstrated reduced ventricular tachycardia episodes (p=0.025), and pulmonary function testing demonstrated improved forced expiratory volume in 1 s (p=0.003) in the hMSC-treated patients. Global symptom score in all patients (p=0.027) and ejection fraction in the important subset of anterior MI patients were both significantly better in hMSCs versus placebo subjects. In the cardiac magnetic resonance imaging substudy, hMSC treatment, but not placebo, increased left ventricular ejection fraction and led to reverse remodeling. Intravenous allogeneic hMSCs are safe in patients after acute MI. This trial provides pivotal safety and provisional efficacy data for an allogeneic bone marrow-derived stem cell in post-infarction patients. (Safety Study of Adult Mesenchymal Stem Cells [MSC] to Treat Acute Myocardial Infarction; NCT00114452).

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Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease.

Adam Williams, Joshua Hare (2011)

Mesenchymal stem cells (MSCs) are a prototypical adult stem cell with capacity for self-renewal and differentiation with a broad tissue distribution. Initially described in bone marrow, MSCs have the capacity to differentiate into mesoderm- and nonmesoderm-derived tissues. The endogenous role for MSCs is maintenance of stem cell niches (classically the hematopoietic), and as such, MSCs participate in organ homeostasis, wound healing, and successful aging. From a therapeutic perspective, and facilitated by the ease of preparation and immunologic privilege, MSCs are emerging as an extremely promising therapeutic agent for tissue regeneration. Studies in animal models of myocardial infarction have demonstrated the ability of transplanted MSCs to engraft and differentiate into cardiomyocytes and vasculature cells, recruit endogenous cardiac stem cells, and secrete a wide array of paracrine factors. Together, these properties can be harnessed to both prevent and reverse remodeling in the ischemically injured ventricle. In proof-of-concept and phase I clinical trials, MSC therapy improved left ventricular function, induced reverse remodeling, and decreased scar size. This article reviews the current understanding of MSC biology, mechanism of action in cardiac repair, translational findings, and early clinical trial data of MSC therapy for cardiac disease.

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Endometrial regenerative cells: A novel stem cell population

Xiaolong Meng, Thomas E Ichim, Jie-Hui Zhong … (2007)

Angiogenesis is a critical component of the proliferative endometrial phase of the menstrual cycle. Thus, we hypothesized that a stem cell-like population exist and can be isolated from menstrual blood. Mononuclear cells collected from the menstrual blood contained a subpopulation of adherent cells which could be maintained in tissue culture for >68 doublings and retained expression of the markers CD9, CD29, CD41a, CD44, CD59, CD73, CD90 and CD105, without karyotypic abnormalities. Proliferative rate of the cells was significantly higher than control umbilical cord derived mesenchymal stem cells, with doubling occurring every 19.4 hours. These cells, which we termed "Endometrial Regenerative Cells" (ERC) were capable of differentiating into 9 lineages: cardiomyocytic, respiratory epithelial, neurocytic, myocytic, endothelial, pancreatic, hepatic, adipocytic, and osteogenic. Additionally, ERC produced MMP3, MMP10, GM-CSF, angiopoietin-2 and PDGF-BB at 10–100,000 fold higher levels than two control cord blood derived mesenchymal stem cell lines. Given the ease of extraction and pluripotency of this cell population, we propose ERC as a novel alternative to current stem cells sources.

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Author and article information

Contributors

Xinyang Hu: hxy0507@126.com

Jian'an Wang: jian_an_wang@yahoo.com

Journal

Journal ID (nlm-ta): Stem Cells Transl Med

Journal ID (iso-abbrev): Stem Cells Transl Med

Journal ID (doi): 10.1002/(ISSN)2157-6580

Journal ID (publisher-id): SCT3

Title: Stem Cells Translational Medicine

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 2157-6564

ISSN (Electronic): 2157-6580

Publication date (Electronic): 29 August 2016

Publication date (Print): January 2017

Volume: 6

Issue: 1 ( doiID: 10.1002/sct3.2017.6.issue-1 )

Pages: 209-222

Affiliations

[ ¹ ]Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China

[ ² ]Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, People's Republic of China

[ ³ ]Department of Cardiology, Guizhou Provincial People's Hospital, Guiyang, People's Republic of China

[ ⁴ ]Vascular Biology Institute, Miller School of Medicine, University of Miami, Miami, Florida, USA

[ ⁵ ]The Institute of Translational Medicine, Zhejiang University, Hangzhou, People's Republic of China

[ ⁶ ]Zhejiang‐California International Nanosystems Institute, Zhejiang University, Hangzhou, People's Republic of China

Author notes

[*] [* ]Correspondence: Jian'an Wang, M.D., Ph.D., Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University and Cardiovascular Key Laboratory of Zhejiang Province, 88 Jiefang Road, Hangzhou 310009, People's Republic of China. Telephone: 86 571‐87783992; e‐mail: jian_an_wang@ 123456yahoo.com ; or Xinyang Hu, Ph.D., Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University and Cardiovascular Key Laboratory of Zhejiang Province, 88 Jiefang Road, Hangzhou, 310009, People's Republic of China. Telephone: 86 571‐87783992; e‐mail: hxy0507@ 123456126.com

Article

Publisher ID: SCT312042

DOI: 10.5966/sctm.2015-0386

PMC ID: 5442741

PubMed ID: 28170197

SO-VID: ffb4f3b1-a5e3-4319-9c2e-3824ec34ec6d

License:

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date received : 05 December 2015

Date accepted : 15 July 2016

Page count

Figures: 7, Tables: 0, Pages: 14, Words: 7905

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source-schema-version-number 2.0

component-id sct312042

cover-date January 2017

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.9 mode:remove_FC converted:23.05.2017

Keywords: mesenchymal stem cells,endometrium,bone marrow,adipose,myocardial infarction,cell therapy

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Keywords: mesenchymal stem cells, endometrium, bone marrow, adipose, myocardial infarction, cell therapy

Enhanced Cardioprotection by Human Endometrium Mesenchymal Stem Cells Driven by Exosomal MicroRNA‐21

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Abstract

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Stress signalling in stem cells

Most cited references 24

A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction.

Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease.

Endometrial regenerative cells: A novel stem cell population

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