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Young Bone Marrow Sca-1 Cells Rejuvenate the Aged Heart by Promoting Epithelial-to-Mesenchymal Transition.

ABSTRACT: Background: To improve the regenerative capacity of aged individuals, we reconstituted bone marrow (BM) of aged mice with young Sca-1 cells, which repopulated cardiac progenitors and prevented cardiac dysfunction after a myocardial infarction (MI). However, the mechanisms involved were incompletely elucidated. This study aimed to investigate whether young, highly regenerative BM Sca-1 cells exert their cardio-protective effects on the aged heart through reactivation of the epithelial-to-mesenchymal transition (EMT) process. Methods:In vitro, BM Sca-1 cells were co-cultured with epicardial-derived cells (EPDCs) under hypoxia condition; mRNA and protein levels of EMT genes were measured along with cellular proliferation and migration. In vivo, BM Sca-1+ or Sca-1- cells from young mice (2-3 months) were transplanted into lethally-irradiated old mice (20-22 months) to generate chimeras. In addition, Sca-1 knockout (KO) mice were reconstituted with wild type (WT) BM Sca-1+ cells. The effects of BM Sca-1 cell on EMT reactivation and improvement of cardiac function after MI were evaluated. Results:In vitro, BM Sca-1+ cells increased EPDC proliferation, migration, and EMT relative to Sca-1- cells and these effects were inhibited by a TGF-? blocker. In vivo, more young BM Sca-1+ than Sca-1- cells homed to the epicardium and induced greater host EPDC proliferation, migration, and EMT after MI. Furthermore, reconstitution of Sca-1 KO mice with WT Sca-1+ cells was associated with the reactivation of EMT and improved cardiac function after MI. Conclusions: Young BM Sca-1+ cells improved cardiac regeneration through promoting EPDC proliferation, migration and reactivation of EMT via the TGF-? signaling pathway.

SUBMITTER: Li J

PROVIDER: S-EPMC5858499 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Young Bone Marrow Sca-1 Cells Rejuvenate the Aged Heart by Promoting Epithelial-to-Mesenchymal Transition.

Li Jiao J Li Shu-Hong SH Wu Jun J Weisel Richard D RD Yao Alina A Stanford William L WL Liu Shi-Ming SM Li Ren-Ke RK

Theranostics 20180212 7

<b>Background:</b> To improve the regenerative capacity of aged individuals, we reconstituted bone marrow (BM) of aged mice with young Sca-1 cells, which repopulated cardiac progenitors and prevented cardiac dysfunction after a myocardial infarction (MI). However, the mechanisms involved were incompletely elucidated. This study aimed to investigate whether young, highly regenerative BM Sca-1 cells exert their cardio-protective effects on the aged heart through reactivation of the epithelial-to-m ...[more]

PMID: 29556355

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Project description:IntroductionThe prevalence of renal fibrosis is higher in older than in younger individuals. Through paracrine activity, bone marrow mesenchymal stem cell-derived microvesicles (BM-MSC-MVs) influence the process of renal fibrosis. Differences in microRNA (miRNA) expression of BM-MSC-MVs that correlate with the age of the subjects and the correlation between miRNA expression and the process of renal fibrosis have not been established. The present study aimed to analyze differences in miRNA expression of BM-MSC-MVs between young or older rats and its influence on tumor growth factor-beta 1 (TGF-β1)-mediated epithelial-mesenchymal transition (EMT) of HK2 cells to explore the causes of renal fibrosis in aged tissues.MethodsmiRCURY LNA Array (version 18.0) was used to identify differentially expressed miRNAs in BM-MSC-MVs of 3- and 24-month-old Fisher344 rats. Reverse transcription-polymerase chain reaction was used to verify miRNA levels in BM-MSC-MVs and in the serum of rats. A TGF-β1-mediated EMT model was used to study the effects of BM-MSC-MVs and differentially expressed miRNAs on EMT.ResultsBM-MSCs from older rats showed more severe aging phenotypes compared with those of young rats. In addition, the growth rate and cell migration of BM-MSCs derived from older rats were significantly reduced. In secreted BM-MSC-MVs, the expression of miR-344a, miR-133b-3p, miR-294, miR-423-3p, and miR-872-3p was significantly downregulated in older rats than in younger rats (P < 0.05), and the serum level of these miRNAs exhibited the same patterns. Intervention using BM-MSC-MVs resulted in the weakening of TGF-β1-mediated EMT in the aged rats. MiR-344a, miR-133b-3p, and miR-294 affected TGF-β1-mediated EMT in HK2 cells. Among these, miR-133b-3p and miR-294 significantly inhibited TGF-β1-mediated EMT in HK2 cells (P < 0.05).ConclusionsIn older rats, the inhibitory effect of BM-MSC-MVs on TGF-β1-mediated HK2 cell EMT was weaker than that observed in younger rats. In addition, miR-133b-3p and miR-294, which were downregulated in BM-MSC-MVs of older rats, remarkably inhibited TGF-β1-mediated EMT in HK2 cells, suggesting that these may play a role in the fibrosis of aging renal tissues.

Dataset Information

Young Bone Marrow Sca-1 Cells Rejuvenate the Aged Heart by Promoting Epithelial-to-Mesenchymal Transition.

Publications

Young Bone Marrow Sca-1 Cells Rejuvenate the Aged Heart by Promoting Epithelial-to-Mesenchymal Transition.

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