Abstract

Our previous studies showed that the combination of atorvastatin (ATV) and single injection of ATV‐pretreated mesenchymal stem cells (MSCs) (ATV‐MSCs) at 1 week post‐acute myocardial infarction (AMI) promoted MSC recruitment and survival. This study aimed to investigate whether the combinatorial therapy of intensive ATV with multiple injections of ATV‐MSCs has greater efficacy at different stages to better define the optimal strategy for MSC therapy in AMI. In order to determine the optimal time window for MSC treatment, we first assessed stromal cell‐derived factor‐1 (SDF‐1) dynamic expression and inflammation. Next, we compared MSC recruitment and differentiation, cardiac function, infarct size, and angiogenesis among animal groups with single, dual, and triple injections of ATV‐MSCs at early (Early1, Early2, Early3), mid‐term (Mid1, Mid2, Mid3), and late (Late1, Late2, Late3) stages. Compared with AMI control, intensive ATV significantly augmented SDF‐1 expression 1.5∼2.6‐fold in peri‐infarcted region with inhibited inflammation. ATV‐MSCs implantation with ATV administration further enhanced MSC recruitment rate by 3.9%∼24.0%, improved left ventricular ejection fraction (LVEF) by 2.0%∼16.2%, and reduced infarct size in all groups 6 weeks post‐AMI with most prominent improvement in mid groups and still effective in late groups. Mechanistically, ATV‐MSCs remarkably suppressed inflammation and apoptosis while increasing angiogenesis. Furthermore, triple injections of ATV‐MSCs were much more effective than single administration during early and mid‐term stages of AMI with the best effects in Mid3 group. We conclude that the optimal strategy is multiple injections of ATV‐MSCs combined with intensive ATV administration at mid‐term stage of AMI. The translational potential of this strategy is clinically promising. Stem Cells Translational Medicine 2019;8:1068–1083

Details

Title
Optimization of Timing and Times for Administration of Atorvastatin‐Pretreated Mesenchymal Stem Cells in a Preclinical Model of Acute Myocardial Infarction
Author
Xu, Jun 1 ; Yu‐Yan Xiong 2 ; Li, Qing 2 ; Meng‐Jin Hu 2 ; Pei‐Sen Huang 1 ; Jun‐Yan Xu 2 ; Xia‐Qiu Tian 2 ; Chen, Jin 2 ; Jian‐Dong Liu 3 ; Li, Qian 3 ; Yue‐Jin Yang 2   VIAFID ORCID Logo 

1  State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China; McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States 
2  State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China 
3  McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States 
Pages
1068-1083
Section
Standards, Protocols, Policies, and Regulations for Cell‐Based Therapies
Publication year
2019
Publication date
Oct 2019
Publisher
Oxford University Press
ISSN
21576564
e-ISSN
21576580
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1002/sctm.19-0013
ProQuest document ID
2299063151
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.