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Article: Regulatory T-cells regulate neonatal heart regeneration by potentiating cardiomyocyte proliferation in a paracrine manner

TitleRegulatory T-cells regulate neonatal heart regeneration by potentiating cardiomyocyte proliferation in a paracrine manner
Authors
KeywordsCD4+ regulatory T-cells
Heart regeneration
Cardiomyocyte proliferation
Cardiac fibrosis
Macrophages
Single-cell RNA-seq
Issue Date2019
PublisherIvyspring International Publisher. The Journal's web site is located at http://www.thno.org/
Citation
Theranostics, 2019, v. 9 n. 15, p. 4324-4341 How to Cite?
AbstractThe neonatal mouse heart is capable of transiently regenerating after injury from postnatal day (P) 0-7 and macrophages are found important in this process. However, whether macrophages alone are sufficient to orchestrate this regeneration; what regulates cardiomyocyte proliferation; why cardiomyocytes do not proliferate after P7; and whether adaptive immune cells such as regulatory T-cells (Treg) influence neonatal heart regeneration have less studied. Methods: We employed both loss- and gain-of-function transgenic mouse models to study the role of Treg in neonatal heart regeneration. In loss-of-function studies, we treated mice with the lytic anti-CD25 antibody that specifically depletes Treg; or we treated FOXP3DTR with diphtheria toxin that specifically ablates Treg. In gain-of-function studies, we adoptively transferred hCD2+ Treg from NOD.Foxp3hCD2 to NOD/SCID that contain Treg as the only T-cell population. Furthermore, we performed single-cell RNA-sequencing of Treg to uncover paracrine factors essential for cardiomyocyte proliferation. Results: Unlike their wild type counterparts, NOD/SCID mice that are deficient in T-cells but harbor macrophages fail to regenerate their injured myocardium at as early as P3. During the first week of injury, Treg are recruited to the injured cardiac muscle but their depletion contributes to more severe cardiac fibrosis. On the other hand, adoptive transfer of Treg results in mitigated fibrosis and enhanced proliferation and function of the injured cardiac muscle. Mechanistically, single-cell transcriptomic profiling reveals that Treg could be a source of regenerative factors. Treg directly promote proliferation of both mouse and human cardiomyocytes in a paracrine manner; and their secreted factors such as CCL24, GAS6 or AREG potentiate neonatal cardiomyocyte proliferation. By comparing the regenerating P3 and non-regenerating P8 heart, there is a significant increase in the absolute number of intracardiac Treg but the whole transcriptomes of these Treg do not differ regardless of whether the neonatal heart regenerates. Furthermore, even adult Treg, given sufficient quantity, possess the same regenerative capability. Conclusion: Our results demonstrate a regenerative role of Treg in neonatal heart regeneration. Treg can directly facilitate cardiomyocyte proliferation in a paracrine manner.
Persistent Identifierhttp://hdl.handle.net/10722/288536
ISSN
2019 Impact Factor: 8.579
2015 SCImago Journal Rankings: 2.702
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLi, J-
dc.contributor.authorYang, KY-
dc.contributor.authorTam, RCY-
dc.contributor.authorChan, VW-
dc.contributor.authorLan, HY-
dc.contributor.authorHori, S-
dc.contributor.authorZhou, B-
dc.contributor.authorLui, KO-
dc.date.accessioned2020-10-07T03:17:59Z-
dc.date.available2020-10-07T03:17:59Z-
dc.date.issued2019-
dc.identifier.citationTheranostics, 2019, v. 9 n. 15, p. 4324-4341-
dc.identifier.issn1838-7640-
dc.identifier.urihttp://hdl.handle.net/10722/288536-
dc.description.abstractThe neonatal mouse heart is capable of transiently regenerating after injury from postnatal day (P) 0-7 and macrophages are found important in this process. However, whether macrophages alone are sufficient to orchestrate this regeneration; what regulates cardiomyocyte proliferation; why cardiomyocytes do not proliferate after P7; and whether adaptive immune cells such as regulatory T-cells (Treg) influence neonatal heart regeneration have less studied. Methods: We employed both loss- and gain-of-function transgenic mouse models to study the role of Treg in neonatal heart regeneration. In loss-of-function studies, we treated mice with the lytic anti-CD25 antibody that specifically depletes Treg; or we treated FOXP3DTR with diphtheria toxin that specifically ablates Treg. In gain-of-function studies, we adoptively transferred hCD2+ Treg from NOD.Foxp3hCD2 to NOD/SCID that contain Treg as the only T-cell population. Furthermore, we performed single-cell RNA-sequencing of Treg to uncover paracrine factors essential for cardiomyocyte proliferation. Results: Unlike their wild type counterparts, NOD/SCID mice that are deficient in T-cells but harbor macrophages fail to regenerate their injured myocardium at as early as P3. During the first week of injury, Treg are recruited to the injured cardiac muscle but their depletion contributes to more severe cardiac fibrosis. On the other hand, adoptive transfer of Treg results in mitigated fibrosis and enhanced proliferation and function of the injured cardiac muscle. Mechanistically, single-cell transcriptomic profiling reveals that Treg could be a source of regenerative factors. Treg directly promote proliferation of both mouse and human cardiomyocytes in a paracrine manner; and their secreted factors such as CCL24, GAS6 or AREG potentiate neonatal cardiomyocyte proliferation. By comparing the regenerating P3 and non-regenerating P8 heart, there is a significant increase in the absolute number of intracardiac Treg but the whole transcriptomes of these Treg do not differ regardless of whether the neonatal heart regenerates. Furthermore, even adult Treg, given sufficient quantity, possess the same regenerative capability. Conclusion: Our results demonstrate a regenerative role of Treg in neonatal heart regeneration. Treg can directly facilitate cardiomyocyte proliferation in a paracrine manner.-
dc.languageeng-
dc.publisherIvyspring International Publisher. The Journal's web site is located at http://www.thno.org/-
dc.relation.ispartofTheranostics-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectCD4+ regulatory T-cells-
dc.subjectHeart regeneration-
dc.subjectCardiomyocyte proliferation-
dc.subjectCardiac fibrosis-
dc.subjectMacrophages-
dc.subjectSingle-cell RNA-seq-
dc.titleRegulatory T-cells regulate neonatal heart regeneration by potentiating cardiomyocyte proliferation in a paracrine manner-
dc.typeArticle-
dc.identifier.emailTam, RCY: rach2011@hku.hk-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.7150/thno.32734-
dc.identifier.pmid31285764-
dc.identifier.pmcidPMC6599663-
dc.identifier.scopuseid_2-s2.0-85069315953-
dc.identifier.hkuros315713-
dc.identifier.volume9-
dc.identifier.issue15-
dc.identifier.spage4324-
dc.identifier.epage4341-
dc.identifier.isiWOS:000472482600005-
dc.publisher.placeAustralia-

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