Dataset Information

Young Bone-Marrow Sca-1⁺ Stem Cells Rejuvenate the Aged Heart and Improve Function after Injury through PDGFRβ-Akt pathway.

ABSTRACT: Bone marrow (BM) reconstitution with young BM cells in aged recipients restores the functionality of cardiac resident BM-derived progenitors. This study investigated the cell type primarily responsible for this effect. We reconstituted old mice with BM cells from young or old mice and found that the number of stem cell antigen 1 (Sca-1) cells homing to the heart was significantly greater in young than old chimeras. We then reconstituted old mice with young BM Sca-1⁺ or Sca-1^- cells. We found that Sca-1 cells repopulated the recipient BM and homed to the heart. The number of BM-derived cells in the aged myocardium co-expressing PDGFRβ was 3 times greater in Sca-1⁺ than Sca-1^- chimeric mice. Sca-1⁺ chimeras had more active cell proliferation in the infarcted heart and improved ventricular function after MI. The improved regeneration involved activation of the PDGFRβ/Akt/p27^Kip1 pathway. Sca-1⁺ stem cells rejuvenated cardiac tissue in aged mice. Restoration of the Sca-1⁺ subset of stem cells by BM reconstitution improved cardiac tissue regeneration after injury in aged mice.

SUBMITTER: Li SH

PROVIDER: S-EPMC5282531 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Young Bone-Marrow Sca-1+ Stem Cells Rejuvenate the Aged Heart and Improve Function after Injury through PDGFRβ-Akt pathway.

Li Shu-Hong SH Sun Lu L Yang Lei L Li Jiao J Shao Zhengbo Z Du Guo-Qing GQ Wu Jun J Weisel Richard D RD Li Ren-Ke RK

Scientific reports 20170131

Bone marrow (BM) reconstitution with young BM cells in aged recipients restores the functionality of cardiac resident BM-derived progenitors. This study investigated the cell type primarily responsible for this effect. We reconstituted old mice with BM cells from young or old mice and found that the number of stem cell antigen 1 (Sca-1) cells homing to the heart was significantly greater in young than old chimeras. We then reconstituted old mice with young BM Sca-1+ or Sca-1-</su ...[more]

PMID: 28139736

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Project description:BackgroundPolarization of microglia, the resident retinal immune cells, plays important roles in mediating both injury and repair responses post-retinal ischemia-reperfusion (I/R) injury, which is one of the main pathological mechanisms behind ganglion cell apoptosis. Aging could perturb microglial balances, resulting in lowered post-I/R retinal repair. Young bone marrow (BM) stem cell antigen 1-positive (Sca-1+) cells have been demonstrated to have higher reparative capabilities post-I/R retinal injury when transplanted into old mice, where they were able to home and differentiate into retinal microglia.MethodsExosomes were enriched from young Sca-1+ or Sca-1- cells, and injected into the vitreous humor of old mice post-retinal I/R. Bioinformatics analyses, including miRNA sequencing, was used to analyze exosome contents, which was confirmed by RT-qPCR. Western blot was then performed to examine expression levels of inflammatory factors and underlying signaling pathway proteins, while immunofluorescence staining was used to examine the extent of pro-inflammatory M1 microglial polarization. Fluoro-Gold labelling was then utilized to identify viable ganglion cells, while H&E staining was used to examine retinal morphology post-I/R and exosome treatment.ResultsSca-1+ exosome-injected mice yielded better visual functional preservation and lowered inflammatory factors, compared to Sca-1-, at days 1, 3, and 7 days post-I/R. miRNA sequencing found that Sca-1+ exosomes had higher miR-150-5p levels, compared to Sca-1- exosomes, which was confirmed by RT-qPCR. Mechanistic analysis found that miR-150-5p from Sca-1+ exosomes repressed the mitogen-activated protein kinase kinase kinase 3 (MEKK3)/JNK/c-Jun axis, leading to IL-6 and TNF-α downregulation, and subsequently reduced microglial polarization, all of which contributes to reduced ganglion cell apoptosis and preservation of proper retinal morphology.ConclusionThis study elucidates a potential new therapeutic approach for neuroprotection against I/R injury, via delivering miR-150-5p-enriched Sca-1+ exosomes, which targets the miR-150-5p/MEKK3/JNK/c-Jun axis, thereby serving as a cell-free remedy for treating retinal I/R injury and preserving visual functioning.

Project description:BackgroundPrevious research has indicated that extracellular vesicles (EVs) potentially play significant roles in multiple ageing phenotypes. This study uses a factorial experimental design to explore the interactions between circulating EVs and bone marrow-derived macrophages (BMDMs) isolated from young (7-12 weeks) and aged (70-90 weeks) mice.ResultsIn this study, plasma EVs from young (Y_EV) and aged (O_EV) mice were isolated and compared based on abundance, size, and miRNA cargo. Compared to some previous studies, we found relatively few differences in EV miRNA cargo between Y_EVs and O_EVs. Young and old EVs were then used to stimulate naïve BMDMs isolated from young (Y_BMDM) and aged (O_BMDM) mice. A panel of five "M1" and six "M2" macrophage markers were used to assess the degree of polarisation. Our results revealed differences in the immunomodulatory effects of Y_EVs and O_EVs in Y_BMDMs and O_BMDMs. Y_EVs induced less pro-inflammatory gene expression, while O_EVs exhibited a more varied impact, promoting both pro- and anti-inflammatory markers. However, neither EV population induced a clearly defined 'M1' or 'M2' macrophage phenotype. We also report that EVs elicited responses that differed markedly from those induced by whole plasma. Plasma from old mice had strong pro-inflammatory effects on Y_BMDMs, increasing Il1b, Nlrp3 and Tnfa. However, O_EVs did not have these effects, supporting current evidence that EVs are a separate component of circulating factors during ageing. More research is needed to elucidate specific factors involved in inflammageing processes.ConclusionsOur findings reveal age-related differences in EV cargo and function, with young EVs tending to suppress inflammatory markers more effectively than aged EVs. However, this is not straightforward, and EVs often promoted both M1 and M2 markers. These results suggest that EVs are a distinct component of circulating factors and hold potential for therapeutic strategies aimed at mitigating age-related inflammation and immune dysregulation.

Dataset Information

Young Bone-Marrow Sca-1⁺ Stem Cells Rejuvenate the Aged Heart and Improve Function after Injury through PDGFRβ-Akt pathway.

Publications

Young Bone-Marrow Sca-1<sup>+</sup> Stem Cells Rejuvenate the Aged Heart and Improve Function after Injury through PDGFRβ-Akt pathway.

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