This preprint is under consideration at Stem Cell Research & Therapy. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
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Research
Lianbo Shao
Department of Cardiovascular Surgery of the First Affiliated Hosptial and Institute for Cardiovascular Science
Corresponding Author
ORCiD: https://orcid.org/0000-0001-9322-9581
Shengshou Hu
Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute of Cardiovascular Science, Soochow University, Suzhou, China. Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Corresponding Author
Zhenya Shen
Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute of Cardiovascular Science, Soochow University, Suzhou, China
Corresponding Author
License:
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Background-
Exosomes derived from human umbilical cord mesenchymal stem cells (UMSCs-Exo) were recommended as ideal substitutes for cell-free cardiac regenerative medicine, which had presented encouraging effects in regulating inflammation and attenuating myocardial injury. The phenotype of macrophages resident in myocardium were regulated dynamically in response to environmental cues, which may either protect against injury or promote maladaptive remodeling. However, the underlying mechanisms about UMSCs-Exo regulating macrophage polarization are still not well understood. Herein, we aimed to explore the effects of UMSCs-Exo on macrophage polarization and their roles in cardiac repair after myocardial infarction (MI).
Methods and Results-
Exosomes were isolated from the supernatant of human umbilical cord mesenchymal stem cells (UMSCs) and transplanted by intramyocardial injection after MI. Our results showed that UMSCs-Exo improved cardiac function by increasing M2 macrophage polarization and reducing excessive inflammation. After depletion of macrophages with clodronate liposomes, the therapeutic effects of UMSCs-Exo were disrupted. Administrated with UMSC-Exo, macrophages are inclined to polarize towards M2 phenotype in inflammatory environment in vitro. The results of RNA-sequencing indicated Plcb3 was a key gene concerned in UMSCs-Exo facilitated M2 macrophage polarization. Further bioinformatics analysis revealed exosomal miR-24-3p as a potential effector mediated Plcb3 down regulation in macrophages. Increasing miR-24-3p expression in macrophages effectively enhanced M2 macrophage polarization by suppressing Plcb3 expression and NF-κB pathway activation in inflammatory environment. Furthermore, diminishing miR-24-3p expression in UMSCs-Exo attenuated the effects of UMSCs-Exo on M2 macrophage polarization.
Conclusions-
Our study demonstrated that macrophages, as important inflammatory regulators, participated in UMSCs-Exo mediated myocardial repair after MI. And the therapeutical effects were at least partially carried out by UMSCs-Exo promoting M2 macrophage polarization in an inflammatory microenvironment. Mechanically, exosomal miR-24-3p inhibits the expression of Plcb3 and NF-κB pathway activation to promote M2 macrophage polarization.
Keywords
myocardial infarction, exosomes, macrophage polarization, miR-24-3p, Plcb3
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CURRENT STATUS: Under Review
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Posted 19 Aug, 2021
Editorial decision: Minor Revision
On 19 Aug, 2021
Review #1 received
Received 11 Jul, 2021
Reviews received
Received 09 Jul, 2021
Reviewers invited
Invitations sent on 09 Jul, 2021
Editor assigned
On 09 Jul, 2021
Reviewer #1 agreed
On 08 Jul, 2021
Submission checks complete
On 08 Jul, 2021
Editor invited
On 08 Jul, 2021
First submitted
On 07 Jul, 2021
This version was not preprinted
Version (no preprint)
Posted 22 Apr, 2021
This version was not preprinted
Version 1
Posted 22 Apr, 2021
No community comments so far
Review #1 received
Received 02 Jun, 2021
Reviews received
Received 21 May, 2021
Reviewer #2 agreed
On 20 May, 2021
Reviewer #1 agreed
On 20 May, 2021
Reviewers invited
Invitations sent on 22 Apr, 2021
Submission checks complete
On 11 Apr, 2021
Editor invited
On 11 Apr, 2021
Editor assigned
On 10 Apr, 2021
First submitted
On 08 Apr, 2021
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This preprint is under consideration at Stem Cell Research & Therapy. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Lianbo Shao
Department of Cardiovascular Surgery of the First Affiliated Hosptial and Institute for Cardiovascular Science
Corresponding Author
ORCiD: https://orcid.org/0000-0001-9322-9581
Shengshou Hu
Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute of Cardiovascular Science, Soochow University, Suzhou, China. Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Corresponding Author
Zhenya Shen
Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute of Cardiovascular Science, Soochow University, Suzhou, China
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version (no preprint)
Posted 19 Aug, 2021
Editorial decision: Minor Revision
On 19 Aug, 2021
Review #1 received
Received 11 Jul, 2021
Reviews received
Received 09 Jul, 2021
Reviewers invited
Invitations sent on 09 Jul, 2021
Editor assigned
On 09 Jul, 2021
Reviewer #1 agreed
On 08 Jul, 2021
Submission checks complete
On 08 Jul, 2021
Editor invited
On 08 Jul, 2021
First submitted
On 07 Jul, 2021
This version was not preprinted
Version (no preprint)
Posted 22 Apr, 2021
This version was not preprinted
Version 1
Posted 22 Apr, 2021
No community comments so far
Review #1 received
Received 02 Jun, 2021
Reviews received
Received 21 May, 2021
Reviewer #2 agreed
On 20 May, 2021
Reviewer #1 agreed
On 20 May, 2021
Reviewers invited
Invitations sent on 22 Apr, 2021
Submission checks complete
On 11 Apr, 2021
Editor invited
On 11 Apr, 2021
Editor assigned
On 10 Apr, 2021
First submitted
On 08 Apr, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Stem Cell & Developmental Cell Biology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background-
Exosomes derived from human umbilical cord mesenchymal stem cells (UMSCs-Exo) were recommended as ideal substitutes for cell-free cardiac regenerative medicine, which had presented encouraging effects in regulating inflammation and attenuating myocardial injury. The phenotype of macrophages resident in myocardium were regulated dynamically in response to environmental cues, which may either protect against injury or promote maladaptive remodeling. However, the underlying mechanisms about UMSCs-Exo regulating macrophage polarization are still not well understood. Herein, we aimed to explore the effects of UMSCs-Exo on macrophage polarization and their roles in cardiac repair after myocardial infarction (MI).
Methods and Results-
Exosomes were isolated from the supernatant of human umbilical cord mesenchymal stem cells (UMSCs) and transplanted by intramyocardial injection after MI. Our results showed that UMSCs-Exo improved cardiac function by increasing M2 macrophage polarization and reducing excessive inflammation. After depletion of macrophages with clodronate liposomes, the therapeutic effects of UMSCs-Exo were disrupted. Administrated with UMSC-Exo, macrophages are inclined to polarize towards M2 phenotype in inflammatory environment in vitro. The results of RNA-sequencing indicated Plcb3 was a key gene concerned in UMSCs-Exo facilitated M2 macrophage polarization. Further bioinformatics analysis revealed exosomal miR-24-3p as a potential effector mediated Plcb3 down regulation in macrophages. Increasing miR-24-3p expression in macrophages effectively enhanced M2 macrophage polarization by suppressing Plcb3 expression and NF-κB pathway activation in inflammatory environment. Furthermore, diminishing miR-24-3p expression in UMSCs-Exo attenuated the effects of UMSCs-Exo on M2 macrophage polarization.
Conclusions-
Our study demonstrated that macrophages, as important inflammatory regulators, participated in UMSCs-Exo mediated myocardial repair after MI. And the therapeutical effects were at least partially carried out by UMSCs-Exo promoting M2 macrophage polarization in an inflammatory microenvironment. Mechanically, exosomal miR-24-3p inhibits the expression of Plcb3 and NF-κB pathway activation to promote M2 macrophage polarization.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
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