Endothelial Progenitor Cell Secretome and Oligovascular Repair in a Mouse Model of Prolonged Cerebral Hypoperfusion

Maki, Takakuni; Morancho, Anna; Segundo, Pablo Martínez San; Hayakawa, Kazuhide; Takase, Hajime; Liang, Anna C.; Gabriel-Salazar, Marina; Medina-Gutiérrez, Esperanza; Washida, Kazuo; Montaner, Joan; Lok, Josephine; Lo, Eng H.; Arai, Ken; Rosell, Anna

doi:10.1161/strokeaha.117.019346

Cited by 70 publications

(79 citation statements)

References 50 publications

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“…Less than 1% of the nuclei were HNA-positive, suggesting that the main role of transplanted cells in MRONJ healing was via paracrine effect. The EPC secretome consists of more than 300 molecules (Bouchentouf et al, 2011;Maki et al, 2018) including VEGF. Our previous results showed that blocking VEGF receptor on gingival fibroblasts and keratinocytes reduced wound healing in vitro.…”

Section: Discussionmentioning

confidence: 99%

Endothelial progenitors increase vascularization and improve fibroblasts function that prevent medication‐related osteonecrosis of the jaw

et al. 2020

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Objectives In a previous rat model, MRONJ occurrence was 50%. Our aim was to investigate the potential of endothelial progenitor cells (EPCs) to improve fibroblasts function and prevent MRONJ. Methods Human gingival fibroblasts were cultured with EPC‐conditioned media (EPC‐CM); endothelial growth media (EGM‐2) or DMEM followed by incubation with 10 µM zoledronic (ZOL) and dexamethasone (DEX). Cell proliferation and migration were assessed by XTT and scratch wound healing assays. In vivo, ten Lewis rats were treated weekly with ZOL and DEX for 11 weeks. After a week, EPCs or EGM‐2 were injected to the gingiva around the molars. At 3 weeks, bilateral molars were extracted. After 8 weeks, wound healing was assessed, and serum VEGF and blood vessels were quantified. Results ZOL/DEX significantly reduced fibroblasts proliferation and wound healing. Treatment with EPC‐CM before ZOL/DEX improved cell proliferation, and scratch healing (p = .007, p = .023). In vivo, local EPC injection before tooth extraction increased serum VEGF (p = .01) and soft tissue vascularization (p = .05). Normal healing was similar (80%) in EPCs and EGM‐2 groups. Conclusion EPC rescued fibroblasts from the cytotoxic effect of ZOL/DEX and elevated serum VEGF and vessel density that might reduce MRONJ occurrence to 20% compared to 50% in a similar model.

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Section: Discussionmentioning

confidence: 99%

Endothelial progenitors increase vascularization and improve fibroblasts function that prevent medication‐related osteonecrosis of the jaw

et al. 2020

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“…The possibility of MV-dependent activity was not discussed at all. A 2018 published investigation analyzed the EPC secretome in the context of oligodendrocyte repair [26]. The authors performed a detailed proteomic study and identified a heterogenous group of proteins excreted by the cells.…”

Section: Discussionmentioning

confidence: 99%

PAC-mediated AKI protection is critically mediated but does not exclusively depend on cell-derived microvesicles

Dihazi¹,

Schwarze²,

Patschan³

et al. 2020

Preprint

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Acute Kidney Injury (AKI) significantly worsens the prognosis of hospitalized patients. In recent years, cell-based strategies have been established as reliable option for improving AKI outcomes in experimental AKI. Own studies focused on so-called Proangiogenic Cells (PACs). Mechanisms that contribute to PAC-mediated AKI protection include production / secretion of extracellular vesicles (MV -microvesicles). In addition, the cells most likely act by paracrinic processes (secretome). The current study evaluated whether AKI may be preventable by the administration of either PAC-derived MV and / or the secretome alone. AKI was induced in male C57/Bl6N mice (8-12 weeks) by bilateral renal ischemia (IRI -40 minutes). Syngeneic murine PACs were stimulated with either melatonine, Angiopoietin-1 or -2, or with Bone Morphogenetic Protein-5 (BMP-5) for one hour, respectively. PACderived MV and the vesicle-depleted supernatant were subsequently collected and i.v. injected postischemia. Mice were analyzed 48 hours later. IRI induced significant kidney excretory dysfunction as reflected by higher serum cystatin C levels. The only measure that improved AKI was the injection of MV, collected from native PACs. The following conditions worsened post-ischemic renal function even further: MV+Ang-1, MV+BMP-5, MV+melatonin, and MV+secretome+Ang-1. Together, our data show that PAC-mediated AKI protection substantially depends on the availability of cell-derived MV. However, since previous data showed improved AKI-protection by PACs after cell preconditioning with certain mediators (Ang-1 and -2, melatonine, BMP-5), other than exclusively vesicle-dependent mechanisms must be involved in PAC-mediated AKI protection.

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“…These data are in line with recent reports in which the EOC secretome has been packaged in nanoparticles or hydrogels to treat acute ischemic diseases. 59,60 Previous studies determined that in the absence of the cholesterol efflux transporters (Abca1 and Abcg1) in myeloid cells of the bone marrow was insufficient to explain the anti-atherogenic effects of LXRs described in whole bone marrow transplant experiments. [9][10][11][12][13][14] Our data support the role of another effector cell (EPC) in contributing to the anti-atherogenic effects of LXR.…”

Section: Discussionmentioning

confidence: 99%

The Secretome of Liver X Receptor Agonist Treated Early Outgrowth Cells Decreases Atherosclerosis inLdlr-/- Mice

Rasheed

Shawky

Tsai

et al. 2019

Preprint

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Objective -Endothelial progenitor cells (EPCs) promote the maintenance of the endothelium by the secretion of vasoreparative factors. A population of EPCs known as early outgrowth cells (EOCs) are currently being investigated as novel cell-based therapies for the treatment of cardiovascular disease. We previously demonstrated that the absence of liver x receptors (LXRs) is detrimental to the formation and function of EOCs under hypercholesterolemic conditions. Here, we investigate whether LXR gain-of-function in EOCs is beneficial for the treatment of atherosclerosis.Approach and Results -EOCs were differentiated from the bone marrow of wildtype (WT) and LXR-knockout (Lxrαβ-/-) mice in the presence of vehicle or LXR agonist (GW3965). WT EOCs treated with GW3965 throughout differentiation showed reduced expression of endothelial lineage markers (Cd144, Vegfr2) compared to WT vehicle and Lxrαβ-/cells. GW3965-treated EOCs produced secreted factors that reduced monocyte adhesion to activated endothelial cells in culture. When injected into atherosclerosis-prone Ldlr-/-mice, GW3965-treated EOCs and concentrated conditioned media (CM) from GW3965-treated EOCs, reduced plaque burden within the aortic sinus. Furthermore, when CM from human EOCs (obtained from patients with established CAD) were treated with GW3965, monocyte to endothelial adhesion was decreased suggesting the translatability of the results.

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Endothelial Progenitor Cell Secretome and Oligovascular Repair in a Mouse Model of Prolonged Cerebral Hypoperfusion

Abstract: Factors secreted by EPCs may ameliorate white matter damage in the brain by boosting oligovascular remodeling.

Cited by 70 publications

References 50 publications

Endothelial progenitors increase vascularization and improve fibroblasts function that prevent medication‐related osteonecrosis of the jaw

Endothelial progenitors increase vascularization and improve fibroblasts function that prevent medication‐related osteonecrosis of the jaw

PAC-mediated AKI protection is critically mediated but does not exclusively depend on cell-derived microvesicles

The Secretome of Liver X Receptor Agonist Treated Early Outgrowth Cells Decreases Atherosclerosis inLdlr-/- Mice

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