miR-210 Enhances the Therapeutic Potential of Bone-Marrow-Derived Circulating Proangiogenic Cells in the Setting of Limb Ischemia

Besnier, Marie; Gasparino, Stefano; Vono, Rosa; Sangalli, Elena; Facoetti, Amanda; Bollati, Valentina; Cantone, Laura; Zaccagnini, Germana; Maimone, Biagina; Fuschi, Paola; Silva, Daniel Da; Schiavulli, Michele; Aday, Sezin; Caputo, Massimo; Madeddu, Paolo; Emanueli, Costanza; Martelli, Fabio; Spinetti, Gaia

doi:10.1016/j.ymthe.2018.06.003

Cited by 35 publications

(36 citation statements)

References 71 publications

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“…These findings are in agreement with studies on the pro-angiogenic role of miR-210 observed in vitro [15,[31][32][33], as well as in miR-210 overexpression studies in mouse models of heart [20][21][22][23], limb [26], and brain ischemia [24,25,34]. Also concordant are studies showing that cord blood-derived cells expressing miR-210 display an increased potential in stimulating angiogenesis upon transplantation Taken together, these results indicate that miR-210 plays a pro-angiogenic role in vivo also in the absence of ischemic injury.…”

Section: Discussionsupporting

confidence: 92%

Hypoxia-Induced miR-210 Is Necessary for Vascular Regeneration upon Acute Limb Ischemia

Zaccagnini

Maimone

Fuschi

et al. 2019

IJMS

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Critical limb ischemia is the most serious form of peripheral artery disease, characterized by severe functional consequences, difficult clinical management and reduced life expectancy. The goal of this study was to investigate the miR-210 role in the neo-angiogenic response after acute limb ischemia. Complementary approaches were used in a mouse model of hindlimb ischemia: miR-210 loss-of-function was obtained by administration of LNA-oligonucleotides anti-miR-210; for miR-210 gain-of-function, a doxycycline-inducible miR-210 transgenic mouse was used. We tested miR-210 ability to stimulate vascular regeneration following ischemia. We found that miR-210 was necessary and sufficient to stimulate blood perfusion recovery, as well as arteriolar and capillary density increase, in the ischemic muscle. To clarify the molecular events underpinning miR-210 pro-angiogenic action, the transcriptomic changes in ischemic muscles upon miR-210 blocking were analyzed. We found that miR-210 impacted the transcriptome significantly, regulating pathways and functions linked to vascular regeneration. In agreement with a pro-angiogenic role, miR-210 also improved cardiac function and left ventricular remodeling after myocardial infarction. Moreover, miR-210 blocking decreased capillary density in a Matrigel plug assay, indicating that miR-210 is necessary for angiogenesis independently of ischemia. Collectively, these data indicate that miR-210 plays a pivotal role in promoting vascular regeneration.

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Section: Discussionsupporting

confidence: 92%

Hypoxia-Induced miR-210 Is Necessary for Vascular Regeneration upon Acute Limb Ischemia

Zaccagnini

Maimone

Fuschi

et al. 2019

IJMS

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“…In Vitro Angiogenesis BM-CD34 1 cells, their CCM, or isolated EVs were cocultured with HUVECs (1:1 ratio) on Matrigel (Corning Incorporated Life Sciences) (15).…”

Section: Immunostainingmentioning

confidence: 99%

MicroRNA-21/PDCD4 Proapoptotic Signaling From Circulating CD34+ Cells to Vascular Endothelial Cells: A Potential Contributor to Adverse Cardiovascular Outcomes in Patients With Critical Limb Ischemia

et al. 2020

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In patients with type 2 diabetes (T2D) and critical limb ischemia (CLI), migration of circulating CD34 1 cells predicted cardiovascular mortality at 18 months after revascularization. This study aimed to provide long-term validation and mechanistic understanding of the biomarker. RESEARCH DESIGN AND METHODS The association between CD34 1 cell migration and cardiovascular mortality was reassessed at 6 years after revascularization. In a new series of T2D-CLI and control subjects, immuno-sorted bone marrow CD34 1 cells were profiled for miRNA expression and assessed for apoptosis and angiogenesis activity. The differentially regulated miRNA-21 and its proapoptotic target, PDCD4, were titrated to verify their contribution in transferring damaging signals from CD34 1 cells to endothelial cells. RESULTS Multivariable regression analysis confirmed that CD34 1 cell migration forecasts long-term cardiovascular mortality. CD34 1 cells from T2D-CLI patients were more apoptotic and less proangiogenic than those from control subjects and featured miRNA-21 downregulation, modulation of several long noncoding RNAs acting as miRNA-21 sponges, and upregulation of the miRNA-21 proapoptotic target PDCD4. Silencing miR-21 in control CD34 1 cells phenocopied the T2D-CLI cell behavior. In coculture, T2D-CLI CD34 1 cells imprinted naive endothelial cells, increasing apoptosis, reducing network formation, and modulating the TUG1 sponge/miRNA-21/PDCD4 axis. Silencing PDCD4 or scavenging reactive oxygen species protected endothelial cells from the negative influence of T2D-CLI CD34 1 cells. CONCLUSIONS Migration of CD34 1 cells predicts long-term cardiovascular mortality in T2D-CLI patients. An altered paracrine signaling conveys antiangiogenic and proapoptotic features from CD34 1 cells to the endothelium. This damaging interaction may increase the risk for life-threatening complications.

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“…microRNA (miR)-21 and miR-210 antagomirs were purchased from Ambion; Thermo Fisher Scientific, Inc. and the scrambled negative control (anti-miR-scr) was obtained from Shanghai GenePharma Co. Ltd. These antagomirs have been previously described and verified (13)(14)(15). Cells were transfected with 50 nM miR-21/-210 antagomir or 25 nM anti-miR-scr using RNAifectin™ (ABM, Inc.), according to the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

HECTD1 regulates the expression of SNAIL: Implications for epithelial‑mesenchymal transition

et al. 2020

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As a transcription factor, SNAIL plays a crucial role in embryonic development and cancer progression by mediating epithelial-mesenchymal transition (EMT); however, post-translational modifications, such as ubiquitination, which control the degradation of SNAIL have been observed to affect its functional role in EMT. In a previous study by the authors, it was demonstrated that the HECT domain E3 ubiquitin ligase 1 (HECTD1) regulated the dynamic nature of adhesive structures. In the present study, HECTD1 was observed to interact with SNAIL and regulate its stability through ubiquitination, and the knockdown of HECTD1 increased the expression levels of SNAIL. HECTD1 was discovered to contain putative nuclear localization and export signals that facilitated its translocation between the cytoplasm and nucleus, a process regulated by epidermal growth factor (EGF). Treatment with leptomycin B resulted in the nuclear retention of HECTD1, which was associated with the loss of SNAIL expression. The knockdown of HECTD1 in HeLa cells increased cell migration and induced a mesenchymal phenotype, in addition to demonstrating sustained EGF signaling, which was observed through increased phosphorylated ERK expression levels. Under hypoxic conditions, HECTD1 expression levels were decreased by microRNA (miRNA or miR)-210. Upon the observation of genetic abnormalities in the HECTD1 gene in cervical cancer specimens, it was observed that the decreased expression levels of HECTD1 were significantly associated with a poor patient survival. Thus, it was hypothesized that HECTD1 may regulate EMT through the hypoxia/hypoxia inducible factor 1α/miR-210/HECTD1/SNAIL signaling pathway and the EGF/EGF receptor/HECTD1/ERK/SNAIL signaling pathway in cervical cancer. On the whole, the data of the present study indicated that HECTD1 serves as an E3 ubiquitin ligase to mediate the stability of SNAIL proteins.

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miR-210 Enhances the Therapeutic Potential of Bone-Marrow-Derived Circulating Proangiogenic Cells in the Setting of Limb Ischemia

Cited by 35 publications

References 71 publications

Hypoxia-Induced miR-210 Is Necessary for Vascular Regeneration upon Acute Limb Ischemia

Hypoxia-Induced miR-210 Is Necessary for Vascular Regeneration upon Acute Limb Ischemia

MicroRNA-21/PDCD4 Proapoptotic Signaling From Circulating CD34+ Cells to Vascular Endothelial Cells: A Potential Contributor to Adverse Cardiovascular Outcomes in Patients With Critical Limb Ischemia

HECTD1 regulates the expression of SNAIL: Implications for epithelial‑mesenchymal transition

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