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Article: Immunomodulation by Systemic Administration of Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stromal Cells to Enhance the Therapeutic Efficacy of Cell-based Therapy for Treatment of Myocardial Infarction

TitleImmunomodulation by Systemic Administration of Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stromal Cells to Enhance the Therapeutic Efficacy of Cell-based Therapy for Treatment of Myocardial Infarction
Authors
Keywordshuman induced pluripotent stem cell
immunomodulation
mesenchymal stromal cell
cardiomyocyte
myocardial infarction
Issue Date2021
PublisherIvyspring International Publisher. The Journal's web site is located at http://www.thno.org/
Citation
Theranostics, 2021, v. 11 n. 4, p. 1641-1654 How to Cite?
AbstractRationale: Poor survival and engraftment are major hurdles of stem cell therapy in the treatment of myocardial infarction (MI). We sought to determine whether pre-transplantation systemic intravenous administration of human induced pluripotent stem cell (hiPSC)-derived mesenchymal stromal cells (hiPSC-MSCs) could improve the survival of hiPSC-MSCs or hiPSC-derived cardiomyocytes (hiPSC-CMs) following direct intramyocardial transplantation in a mouse model of MI. Methods: Mice were randomized to undergo intravenous administration of saline or 5×105 hiPSC-MSCs one week prior to MI, induced by ligation of the left anterior descending coronary artery. Mice were further assigned to undergo direct intramyocardial transplantation of hiPSC-MSCs (1×106) or hiPSC-CMs (1×106) 10 minutes following MI. Echocardiographic and invasive hemodynamic assessment were performed to determine cardiac function. In-vivo fluorescent imaging analysis, immunofluorescence staining and polymerase chain reaction were performed to detect cell engraftment. Flow cytometry of splenic regulatory T cells (Tregs) and natural killer (NK) cells was performed to assess the immunomodulatory effects. Results: Pre-transplantation systemic administration of hiPSC-MSCs increased systemic Tregs activation, decreased the number of splenic NK cells and inflammation, and enhanced survival of transplanted hiPSC-MSCs and hiPSC-CMs. These improvements were associated with increased neovascularization and decreased myocardial inflammation and apoptosis at the peri-infract zone with consequent improved left ventricular function four weeks later. Co-culture of splenic CD4 cells with hiPSC-MSCs also modulated their cytokine expression profile with a decreased level of interferon-γ, tumor necrosis factor-α, and interleukin (IL)-17A, but not IL-2, IL-6 and IL-10. Conclusion: Pre-transplantation systemic intravenous administration of hiPSC-MSCs induced immunomodulation and facilitated the survival of intramyocardially transplanted cells to improve cardiac function in MI. Keywords: human induced pluripotent stem cell, immunomodulation, mesenchymal stromal cell, cardiomyocyte, myocardial infarction
Persistent Identifierhttp://hdl.handle.net/10722/287356
ISSN
2020 Impact Factor: 11.556
2015 SCImago Journal Rankings: 2.702
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorSUN, S-
dc.contributor.authorLai, KWH-
dc.contributor.authorJIANG, Y-
dc.contributor.authorZhen, Z-
dc.contributor.authorWEI, R-
dc.contributor.authorLian, Q-
dc.contributor.authorLiao, S-
dc.contributor.authorTse, HF-
dc.date.accessioned2020-09-22T02:59:48Z-
dc.date.available2020-09-22T02:59:48Z-
dc.date.issued2021-
dc.identifier.citationTheranostics, 2021, v. 11 n. 4, p. 1641-1654-
dc.identifier.issn1838-7640-
dc.identifier.urihttp://hdl.handle.net/10722/287356-
dc.description.abstractRationale: Poor survival and engraftment are major hurdles of stem cell therapy in the treatment of myocardial infarction (MI). We sought to determine whether pre-transplantation systemic intravenous administration of human induced pluripotent stem cell (hiPSC)-derived mesenchymal stromal cells (hiPSC-MSCs) could improve the survival of hiPSC-MSCs or hiPSC-derived cardiomyocytes (hiPSC-CMs) following direct intramyocardial transplantation in a mouse model of MI. Methods: Mice were randomized to undergo intravenous administration of saline or 5×105 hiPSC-MSCs one week prior to MI, induced by ligation of the left anterior descending coronary artery. Mice were further assigned to undergo direct intramyocardial transplantation of hiPSC-MSCs (1×106) or hiPSC-CMs (1×106) 10 minutes following MI. Echocardiographic and invasive hemodynamic assessment were performed to determine cardiac function. In-vivo fluorescent imaging analysis, immunofluorescence staining and polymerase chain reaction were performed to detect cell engraftment. Flow cytometry of splenic regulatory T cells (Tregs) and natural killer (NK) cells was performed to assess the immunomodulatory effects. Results: Pre-transplantation systemic administration of hiPSC-MSCs increased systemic Tregs activation, decreased the number of splenic NK cells and inflammation, and enhanced survival of transplanted hiPSC-MSCs and hiPSC-CMs. These improvements were associated with increased neovascularization and decreased myocardial inflammation and apoptosis at the peri-infract zone with consequent improved left ventricular function four weeks later. Co-culture of splenic CD4 cells with hiPSC-MSCs also modulated their cytokine expression profile with a decreased level of interferon-γ, tumor necrosis factor-α, and interleukin (IL)-17A, but not IL-2, IL-6 and IL-10. Conclusion: Pre-transplantation systemic intravenous administration of hiPSC-MSCs induced immunomodulation and facilitated the survival of intramyocardially transplanted cells to improve cardiac function in MI. Keywords: human induced pluripotent stem cell, immunomodulation, mesenchymal stromal cell, cardiomyocyte, myocardial infarction-
dc.languageeng-
dc.publisherIvyspring International Publisher. The Journal's web site is located at http://www.thno.org/-
dc.relation.ispartofTheranostics-
dc.rightsTheranostics. Copyright © Ivyspring International Publisher.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjecthuman induced pluripotent stem cell-
dc.subjectimmunomodulation-
dc.subjectmesenchymal stromal cell-
dc.subjectcardiomyocyte-
dc.subjectmyocardial infarction-
dc.titleImmunomodulation by Systemic Administration of Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stromal Cells to Enhance the Therapeutic Efficacy of Cell-based Therapy for Treatment of Myocardial Infarction-
dc.typeArticle-
dc.identifier.emailLai, KWH: kwhlai@hku.hk-
dc.identifier.emailZhen, Z: zhenzhe@HKUCC-COM.hku.hk-
dc.identifier.emailLian, Q: qzlian@hkucc.hku.hk-
dc.identifier.emailLiao, S: lsy923@hku.hk-
dc.identifier.emailTse, HF: hftse@hkucc.hku.hk-
dc.identifier.authorityLian, Q=rp00267-
dc.identifier.authorityLiao, S=rp02244-
dc.identifier.authorityTse, HF=rp00428-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.7150/thno.46119-
dc.identifier.pmid33408772-
dc.identifier.pmcidPMC7778603-
dc.identifier.scopuseid_2-s2.0-85098641258-
dc.identifier.hkuros314398-
dc.identifier.volume11-
dc.identifier.issue4-
dc.identifier.spage1641-
dc.identifier.epage1654-
dc.identifier.isiWOS:000600553900009-
dc.publisher.placeAustralia-
dc.identifier.issnl1838-7640-

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