Age and Sex-Dependent Differences in Human Cardiac Matrix-Bound Exosomes Modulate Fibrosis through Synergistic miRNA Effects

Ronan, George; Bahçecioğlu, Gökhan; Yang, Jun; Zorlutuna, Pınar

doi:10.1101/2022.11.14.516464

Cited by 5 publications

(14 citation statements)

References 86 publications

(143 reference statements)

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“…We found that breast MBVs isolated from aged mice were around 140 nm whereas those isolated from young mice were 160 nm. While this difference is fairly small, previous studies from our group have shown that heart tissue MBVs isolated from aged human donors are smaller than those isolated from young donors, indicating that the size difference may not be tissue specific, but age specific 36 . This also aligns with the results from another study showing that the circulating EVs isolated from the plasma of aged mice were smaller in size than those from young mice 51 , supporting the claim that this size difference may be aging-related.…”

Section: Discussionmentioning

confidence: 53%

“…However, more recent studies shed light on an unconventional subgroup of EVs, termed matrix vesicles or matrix bound vesicles (MBVs), which are embedded within the ECM and could only be isolated through enzymatic digestion. Previous studies in a few different tissues (bladder, small intestinal submucosa, heart, and dermis) 35,36,37 confirmed the presence of these MBVs, and the effects of these MBVs and their small RNA cargos on regulating the cell behavior, including macrophage phenotype 38 , cell axon growth 39 , and disease progression 40 . Although MBVs have been discovered in studies with other tissues and organs, to date, no research has been done on breast ECM bound MBVs and their influence on breast cancer.…”

Section: Introductionmentioning

confidence: 65%

“…MBVs are a recently discovered subgroup of EVs embedded within the ECM that have currently been shown to be present in only a few tissues including bladder, SIS, dermis 37 and heart 36 . This present study shows for the first time in literature that MBVs are present in mouse breast tissues.…”

Section: Discussionmentioning

confidence: 99%

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Aged Breast Matrix Bound Vesicles Promote Breast Cancer Invasiveness

Yang

Bahçecioğlu

Ronan

et al. 2023

Preprint

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Aging is one of the inherent risk factors for breast cancer. Although the influence of age-related cellular alterations on breast cancer development has been extensively explored, little is known about the alterations in the aging breast tissue microenvironment, specifically the extracellular matrix (ECM). Here, for the first time in literature, we have identified tissue resident matrix bound vesicles (MBVs) within the healthy mouse breast ECM, investigated and compared their characteristics in young and aged healthy breast tissues, and studied the effects of these MBVs on normal (KTB21) and cancerous (MDA-MB-231) human mammary epithelial cells with respect to the tissue age that they are extracted from. Using vesicle labeling technology, we were able to visualize cellular uptake of the MBVs directly from the native decellularized tissue sections, showing that these MBVs have regulatory roles in the tissue microenvironment. We mimicked the ECM by embedding the MBVs in collagen gels, and showed that MBVs could be taken up by the cells. The miRNA and cytokine profiling showed that MBVs shifted towards a more tumorigenic and invasive phenotype with age, as evidenced by the more pronounced presence of cancer-associated cytokines, and higher expression levels of oncomiRs miR-10b, miR-30e, and miR-210 in MBVs isolated from aged mice. When treated with MBVs or these upregulated factors, KTB21 and MDA-MB-231 cells showed significantly higher motility and invasion compared to untreated controls. Treatment of cells with a cocktail of miRNAs (miR-10b, miR-30e, and miR-210) or with the agonist of adiponectin (AdipoRon), which both were enriched in the aged MBVs, recapitulated the effect of aged MBVs on cells. This study shows for the first time that the MBVs have a regulatory role in the tissue microenvironment and that the MBV contents change towards cancer-promoting upon aging. Studying the effects of MBVs and their cargos on cellular behavior could lead to a better understanding of the critical roles of MBVs played in breast cancer progression and metastasis.

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Section: Discussionmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 65%

See 1 more Smart Citation

Aged Breast Matrix Bound Vesicles Promote Breast Cancer Invasiveness

Yang

Bahçecioğlu

Ronan

et al. 2023

Preprint

Self Cite

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“…Other components of the heart ECM are laminin, fibronectin, elastin, fibrillin 1, and heparan sulfate proteoglycans [95,97,98] (table 2). Moreover, ECM is a reservoir for anchored signaling molecules including the GFs, cytokines, proteases, and noncoding RNAs such as miRNAs and long noncoding (ln) RNAs [97,[99][100][101].…”

Section: Heart Extracellular Matrixmentioning

confidence: 99%

Engineering the cardiac tissue microenvironment

Ronan,

Bahcecioglu,

Aliyev

et al. 2023

Prog. Biomed. Eng.

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In this article we review the microfabrication approaches, with a focus on bioprinting and organ-on-chip technologies, used to engineer cardiac tissue. First, we give a brief introduction to heart anatomy and physiology, and the developmental stages of the heart from fetal stages to adulthood. We also give information on the cardiac tissue microenvironment, including the cells residing in the heart, the biochemical composition and structural organization of the heart extracellular matrix, the signaling factors playing roles in heart development and maturation, and their interactions with one another. We then give a brief summary of both cardiovascular diseases and the current treatment methods used in the clinic to treat these diseases. Second, we explain how tissue engineering recapitulates the development and maturation of the normal or diseased heart microenvironment by spatially and temporally incorporating cultured cells, biomaterials, and growth factors (GF). We briefly expand on the cells, biomaterials, and GFs used to engineer the heart, and the limitations of their use. Next, we review the state-of-the-art tissue engineering approaches, with a special focus on bioprinting and heart-on-chip technologies, intended to (i) treat or replace the injured cardiac tissue, and (ii) create cardiac disease models to study the basic biology of heart diseases, develop drugs against these diseases, and create diagnostic tools to detect heart diseases. Third, we discuss the recent trends in cardiac tissue engineering, including the use of machine learning, CRISPR/Cas editing, exosomes and microRNAs, and immune modeling in engineering the heart. Finally, we conclude our article with a brief discussion on the limitations of cardiac tissue engineering and our suggestions to engineer more reliable and clinically relevant cardiac tissues.

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“…[20] In a more recent study, MBVs were isolated from human left ventricles ECM of young or aged men and women, and the data indicated that synergistic effects of miR-NAs from matrix-resident exosomes may influence the differential clinical response to myocardial infarction. [21] However, most studies generated MBVs from animal or human tissues. Human tissues are a limited resource, while animalderived MBVs raise safety concerns for clinical purposes.…”

Section: Introductionmentioning

confidence: 99%

Engineering Extracellular Matrix‐Bound Nanovesicles Secreted by Three‐Dimensional Human Mesenchymal Stem Cells

Liu

Chen

Liu

et al. 2023

Adv Healthcare Materials

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Extracellular matrix (ECM) in the human tissue contains vesicles, which are defined as matrix‐bound nanovesicles (MBVs). MBVs serve as one of the functional components in ECM, recapitulating part of the regulatory roles and in vivo microenvironment. In this study, extracellular vesicles from culture supernatants (SuEVs) and MBVs are isolated from the conditioned medium or ECM, respectively, of 3D human mesenchymal stem cells. Nanoparticle tracking analysis shows that MBVs are smaller than SuEVs (100–150 nm). Transmission electron microscopy captures the typical cup shape morphology for both SuEVs and MBVs. Western blot reveals that MBVs have low detection of some SuEV markers such as syntenin‐1. miRNA analysis of MBVs shows that 3D microenvironment enhances the expression of miRNAs such as miR‐19a and miR‐21. In vitro functional analysis shows that MBVs can facilitate human pluripotent stem cell‐derived forebrain organoid recovery after starvation and promote high passage fibroblast proliferation. In macrophage polarization, 2D MBVs tend to suppress the pro‐inflammatory cytokine IL‐12β, while 3D MBVs tend to enhance the anti‐inflammatory cytokine IL‐10. This study has the significance in advancing the understanding of the bio‐interface of nanovesicles with human tissue and the design of cell‐free therapy for treating neurological disorders such as ischemic stroke.

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Age and Sex-Dependent Differences in Human Cardiac Matrix-Bound Exosomes Modulate Fibrosis through Synergistic miRNA Effects

Cited by 5 publications

References 86 publications

Aged Breast Matrix Bound Vesicles Promote Breast Cancer Invasiveness

Aged Breast Matrix Bound Vesicles Promote Breast Cancer Invasiveness

Engineering the cardiac tissue microenvironment

Engineering Extracellular Matrix‐Bound Nanovesicles Secreted by Three‐Dimensional Human Mesenchymal Stem Cells

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