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Aged bone matrix-derived extracellular vesicles as a messenger for calcification paradox.

ABSTRACT: Adipocyte differentiation of bone marrow mesenchymal stem/stromal cells (BMSCs) instead of osteoblast formation contributes to age- and menopause-related marrow adiposity and osteoporosis. Vascular calcification often occurs with osteoporosis, a contradictory association called "calcification paradox". Here we show that extracellular vesicles derived from aged bone matrix (AB-EVs) during bone resorption favor BMSC adipogenesis rather than osteogenesis and augment calcification of vascular smooth muscle cells. Intravenous or intramedullary injection of AB-EVs promotes bone-fat imbalance and exacerbates Vitamin D3 (VD3)-induced vascular calcification in young or old mice. Alendronate (ALE), a bone resorption inhibitor, down-regulates AB-EVs release and attenuates aging- and ovariectomy-induced bone-fat imbalance. In the VD3-treated aged mice, ALE suppresses the ovariectomy-induced aggravation of vascular calcification. MiR-483-5p and miR-2861 are enriched in AB-EVs and essential for the AB-EVs-induced bone-fat imbalance and exacerbation of vascular calcification. Our study uncovers the role of AB-EVs as a messenger for calcification paradox by transferring miR-483-5p and miR-2861.

SUBMITTER: Wang ZX

PROVIDER: S-EPMC8933454 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Aged bone matrix-derived extracellular vesicles as a messenger for calcification paradox.

Wang Zhen-Xing ZX Luo Zhong-Wei ZW Li Fu-Xing-Zi FX Cao Jia J Rao Shan-Shan SS Liu Yi-Wei YW Wang Yi-Yi YY Zhu Guo-Qiang GQ Gong Jiang-Shan JS Zou Jing-Tao JT Wang Qiang Q Tan Yi-Juan YJ Zhang Yan Y Hu Yin Y Li You-You YY Yin Hao H Wang Xiao-Kai XK He Ze-Hui ZH Ren Lu L Liu Zheng-Zhao ZZ Hu Xiong-Ke XK Yuan Ling-Qing LQ Xu Ran R Chen Chun-Yuan CY Xie Hui H

Nature communications 20220318 1

Adipocyte differentiation of bone marrow mesenchymal stem/stromal cells (BMSCs) instead of osteoblast formation contributes to age- and menopause-related marrow adiposity and osteoporosis. Vascular calcification often occurs with osteoporosis, a contradictory association called "calcification paradox". Here we show that extracellular vesicles derived from aged bone matrix (AB-EVs) during bone resorption favor BMSC adipogenesis rather than osteogenesis and augment calcification of vascular smooth ...[more]

PMID: 35304471

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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.

Project description:Abdominal aortic aneurysms (AAA) are localized expansions of the abdominal aorta that develop due to chronic proteolytic disruption of the structural extracellular matrix (ECM) components (elastin and collagen) within the aorta wall. Major limitations in arresting or reversing AAAs lie in naturally poor and aberrant regeneration and repair of elastic matrix structures in the aorta wall. Bone marrow derived mesenchymal stem cells (BM-MSCs) have emerged as a promising regenerative tool and their therapeutic effects are also known to be effected through their paracrine secretions. Extracellular vesicles (EVs) present in these secretions have emerged as critical cellular component in facilitating many therapeutic benefits of MSCs. EV treatment is thus potentially appealing as a stem cell-inspired cell-free approach to avoid possible phenotypic plasticity of MSCs in vivo. In this study, we investigated the thus far unknown effects of BM-MSC derived EVs on vascular elastic matrix repair in the context of AAA treatment. EVs isolated from BM-MSC source were characterized and their pro-regenerative and their anti-proteolytic effects were evaluated on our established in vitro experimental conditions derived from AAA rat model. Our studies revealed the efficacy of BM-MSC derived EVs in attenuating the proteolytic activity and also in imparting elastic matrix regenerative benefits under aneurysmal environment. Interestingly, compared to cell culture conditioned media (CCM), EVs demonstrated superior regenerative and anti-proteolytic benefits in a proteolytic injury culture model of AAA. From these studies, it appears that EVs derived from BM-MSCs could be beneficial in undertaking a reparative effort in AAA induced degeneration of vascular tissue. Statement of Significance Abdominal aortic aneurysms (AAAs) are localized, rupture-prone expansions of the aorta which result from loss of wall flexibility due to enzymatic breakdown of elastic fibers. There are no established alternatives to surgery, which possess high risk for the mostly elderly patients. Our previous studies have established the elastic regenerative and reparative effect of cell culture secretions derived from adult stem cell source. In this study, we propose to isolate extracellular vesicles (exosomes) from these secretions and evaluate their regenerative benefits in AAA smooth muscle cell culture model. This simple and innovative treatment approach has the potential to arrest or reverse AAA growth to rupture, not possible so far.

Project description:Cortical injury, such as stroke, causes neurotoxic cascades that lead to rapid death and/or damage to neurons and glia. Axonal and myelin damage in particular, are critical factors that lead to neuronal dysfunction and impair recovery of function after injury. These factors can be exacerbated in the aged brain where white matter damage is prevalent. Therapies that can ameliorate myelin damage and promote repair by targeting oligodendroglia, the cells that produce and maintain myelin, may facilitate recovery after injury, especially in the aged brain where these processes are already compromised. We previously reported that a novel therapeutic, Mesenchymal Stem Cell derived extracellular vesicles (MSC-EVs), administered intravenously at both 24 h and 14 days after cortical injury, reduced microgliosis (Go et al. 2019), reduced neuronal pathology (Medalla et al. 2020), and improved motor recovery (Moore et al. 2019) in aged female rhesus monkeys. Here, we evaluated the effect of MSC-EV treatment on changes in oligodendrocyte maturation and associated myelin markers in the sublesional white matter using immunohistochemistry, confocal microscopy, stereology, qRT-PCR, and ELISA. Compared to vehicle control monkeys, EV-treated monkeys showed a reduction in the density of damaged oligodendrocytes. Further, EV-treatment was associated with enhanced myelin maintenance, evidenced by upregulation of myelin-related genes and increases in actively myelinating oligodendrocytes in sublesional white matter. These changes in myelination correlate with the rate of motor recovery, suggesting that improved myelin maintenance facilitates this recovery. Overall, our results suggest that EVs act on oligodendrocytes to support myelination and improves functional recovery after injury in the aged brain. SIGNIFICANCE: We previously reported that EVs facilitate recovery of function after cortical injury in the aged monkey brain, while also reducing neuronal pathology (Medalla et al. 2020) and microgliosis (Go et al. 2019). However, the effect of injury and EVs on oligodendrocytes and myelination has not been characterized in the primate brain (Dewar et al. 1999; Sozmen et al. 2012; Zhang et al. 2013). In the present study, we assessed changes in myelination after cortical injury in aged monkeys. Our results show, for the first time, that MSC-EVs support recovery of function after cortical injury by enhancing myelin maintenance in the aged primate brain.

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Aged bone matrix-derived extracellular vesicles as a messenger for calcification paradox.

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Aged bone matrix-derived extracellular vesicles as a messenger for calcification paradox.

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