Autophagy of umbilical cord mesenchymal stem cells conduces to pro-angiogenic function of conditioned medium

2021 ◽  
Author(s):  
Wenya Wang ◽  
Xiao Li ◽  
Chaochu Cui ◽  
Dongling Liu ◽  
Guotian Yin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Mesenchymal Stem Cells ◽  
Conditioned Medium ◽  
Umbilical Cord ◽  
Tube Formation ◽  
Dependent Manner ◽  
And Control

Abstract BackgroundAngiogenesis is a key prerequisite for wound healing. The conditioned medium following culture of umbilical cord mesenchymal stem cells (UCMSCs) has a potential to promote angiogenesis, but the efficacy is very low. Autophagy is an important process in protein recycling and a contributor for cell exocrine, which maybe stimulate the release of cytokines from UCMSCs to the medium and enhance the pro-angiogenic efficacy of the conditioned medium.MethodsAutophagy in UCMSCs was induced by 100 nM, 1 µM and 10 µM rapamycin for 6-hour and then detected by LC-3 immunofluorescence staining. After induction, the cells were washed with PBS for 3 times and cultured in fresh medium without rapamycin for additional 24-hour. And then, the conditioned medium was collected for the following experiments. The angiogenic effects of different groups of conditioned medium were verified by in vitro and in vivo tube formation assays in the matrigel-coated plates and matrigel plaques injected in mouse inguinal areas. Finally, the expressions of angiogenic factors including VEGF, FGF-1, FGF-2, TGF-α, MMP-3, MMP-9, PDGF-α, PDGF-β, HIF-1α and Ang II in the autophagic and control UCMSCs were measured by q-PCR assay.ResultsRapamycin induced autophagy of UCMSCs in a dose dependent manner, but the conditioned medium in 100 nM rapamycin-induced group was with the best pro-angiogenic efficacy. Thus, this group of medium was viewed as the optimal conditioned medium. The in vivo tube formation assay showed that angiogenesis in matrigel plaques injected daily with the optimal conditioned medium was more obvious than that injected with the control conditioned medium. Further, the expressions of VEGF, FGF-2, PDGF-α, MMP-9 and HIF-1α were markedly increased in UCMSCs following treatment with 100 nM rapamycin.ConclusionAppropriate autophagy improves the pro-angiogenic efficacy of the conditioned medium, which might be utilized to optimize the applications of UCMSCs-derived conditioned medium in wound healing and tissue repair.Trial registrationNot applicable.

scholarly journals Platelet-Rich Plasma Improves the Wound Healing Potential of Mesenchymal Stem Cells through Paracrine and Metabolism Alterations

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Barbara Hersant ◽  
Mounia Sid-Ahmed ◽  
Laura Braud ◽  
Maud Jourdan ◽  
Yasmine Baba-Amer ◽  
...  
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Mesenchymal Stem Cells ◽  
Platelet Rich Plasma ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
Dependent Manner ◽  
Safe Alternative

Chronic and acute nonhealing wounds represent a major public health problem, and replacement of cutaneous lesions by the newly regenerated skin is challenging. Mesenchymal stem cells (MSC) and platelet-rich plasma (PRP) were separately tested in the attempt to regenerate the lost skin. However, these treatments often remained inefficient to achieve complete wound healing. Additional studies suggested that PRP could be used in combination with MSC to improve the cell therapy efficacy for tissue repair. However, systematic studies related to the effects of PRP on MSC properties and their ability to rebuild skin barrier are lacking. We evaluated in a mouse exhibiting 4 full-thickness wounds, the skin repair ability of a treatment combining human adipose-derived MSC and human PRP by comparison to treatment with saline solution, PRP alone, or MSC alone. Wound healing in these animals was measured at day 3, day 7, and day 10. In addition, we examined in vitro and in vivo whether PRP alters in MSC their proangiogenic properties, their survival, and their proliferation. We showed that PRP improved the efficacy of engrafted MSC to replace lost skin in mice by accelerating the wound healing processes and ameliorating the elasticity of the newly regenerated skin. In addition, we found that PRP treatment stimulated in vitro, in a dose-dependent manner, the proangiogenic potential of MSC through enhanced secretion of soluble factors like VEGF and SDF-1. Moreover, PRP treatment ameliorated the survival and activated the proliferation of in vitro cultured MSC and that these effects were accompanied by an alteration of the MSC energetic metabolism including oxygen consumption rate and mitochondrial ATP production. Similar observations were found in vivo following combined administration of PRP and MSC into mouse wounds. In conclusion, our study strengthens that the use of PRP in combination with MSC might be a safe alternative to aid wound healing.

scholarly journals The Healing Effects of Conditioned Medium Derived from Mesenchymal Stem Cells on Radiation-Induced Skin Wounds in Rats

2018 ◽  
Vol 28 (1) ◽  
pp. 105-115 ◽  
Author(s):  
JiaYang Sun ◽  
YunFeng Zhang ◽  
XianJi Song ◽  
Jiajing Zhu ◽  
QingSan Zhu
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Mesenchymal Stem Cells ◽  
Conditioned Medium ◽  
Radiation Dermatitis ◽  
Skin Wounds ◽  
Cutaneous Injury ◽  
Radiation Induced

Radioactive dermatitis is caused by the exposure of skin and mucous membranes to radiation fields. The pathogenesis of radioactive dermatitis is complex and difficult to cure. Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) may serve as a promising candidate for the therapy of cutaneous wounds. The aim of this study was to investigate whether a WJ-MSC-derived conditioned medium (MSC-CM) could be used to treat radiation-induced skin wounds in rats using a radiation-induced cutaneous injury model. The present study was designed to examine MSC-CM therapy in the recovery of radiation-induced skin wounds in vitro and in vivo. Firstly, we prepared the MSC-CM and tested the effects of the MSC-CM on human umbilical vein endothelial cell proliferation in vitro. After that, we used a β-ray beam to make skin wounds in rats and tested the effects of MSC-CM on cutaneous wound healing in vivo. Our results indicated that MSC-CM secreted factors that promoted HUVEC proliferation, regeneration of sebaceous glands, and angiogenesis. Importantly, MSC-CM promoted wound healing in excess of the positive control (epidermal growth factor), with no, or smaller, scar formation. In conclusion, MSC-CM significantly accelerated wound closure and enhanced the wound healing quality. MSC-CM has a beneficial therapeutic effect on radiation-induced cutaneous injury skin in rats and in this way MSC-CM may serve as a basis of a novel cell-free therapeutic approach for radiation dermatitis.

scholarly journals Exosomes Derived from Human Bone Marrow Mesenchymal Stem Cells Stimulated by Deferoxamine Accelerate Cutaneous Wound Healing by Promoting Angiogenesis

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Jianing Ding ◽  
Xin Wang ◽  
Bi Chen ◽  
Jieyuan Zhang ◽  
Jianguang Xu
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Wound Healing ◽  
Mesenchymal Stem Cells ◽  
Wound Repair ◽  
Umbilical Vein ◽  
Tube Formation ◽  
Diabetic Rats

The exosomes are derived from mesenchymal stem cells (MSCs) and may be potentially used as an alternative for cell therapy, for treating diabetic wounds, and aid in angiogenesis. This study, aimed to investigate whether exosomes originated from bone marrow-derived MSCs (BMSCs) preconditioned by deferoxamine (DFO-Exos) exhibited superior proangiogenic property in wound repair and to explore the underlying mechanisms involved. Human umbilical vein endothelial cells (HUVECs) were used for assays involving cell proliferation, scratch wound healing, and tube formation. To test the effects in vivo, streptozotocin-induced diabetic rats were established. Two weeks after the procedure, histological analysis was used to measure wound-healing effects, and the neovascularization was evaluated as well. Our findings demonstrated that DFO-Exos activate the PI3K/AKT signaling pathway via miR-126 mediated PTEN downregulation to stimulate angiogenesis in vitro. This contributed to enhanced wound healing and angiogenesis in streptozotocin-induced diabetic rats in vivo. Our results suggest that, in cell-free therapies, exosomes derived from DFO preconditioned stem cells manifest increased proangiogenic ability.

scholarly journals Exposure to blue light stimulates the proangiogenic capability of exosomes derived from human umbilical cord mesenchymal stem cells

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Kun Yang ◽  
Dong Li ◽  
Meitian Wang ◽  
Zhiliang Xu ◽  
Xiao Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Mesenchymal Stem Cells ◽  
Blue Light ◽  
Umbilical Cord ◽  
Tube Formation ◽  
Human Umbilical Cord ◽  
Light Illumination

Abstract Background The therapeutic potential of mesenchymal stem cells (MSCs) may be attributed partly to the secreted paracrine factors, which comprise exosomes. Exosomes are small, saucer-shaped vesicles containing miRNAs, mRNAs, and proteins. Exosomes derived from human umbilical cord mesenchymal stem cells (hUC-MSCs) have been reported to promote angiogenesis. However, the efficacy of exosome-based therapies is still limited both in vitro and in vivo. The present study aimed to develop a new optical manipulation approach to stimulate the proangiogenic potential of exosomes and characterize its mechanism underlying tissue regeneration. Methods We used blue (455 nm) and red (638 nm) monochromatic light exposure to investigate the processing of stimuli. Exosomes were prepared by QIAGEN exoEasy Maxi kit and confirmed to be present by transmission electron microscopy and immunoblotting analyses. The proangiogenic activity of blue light-treated human umbilical vein endothelial cells (HUVECs), when co-cultured with hUC-MSCs, was assessed by EdU (5-ethynyl-2′-deoxyuridine) incorporation, wound closure, and endothelial tube formation assays. The in vivo angiogenic activity of blue light-treated MSC-derived exosomes (MSC-Exs) was evaluated using both murine matrigel plug and skin wound models. Results We found that 455-nm blue light is effective for promoting proliferation, migration, and tube formation of HUVECs co-cultured with MSCs. Furthermore, MSC-Exs stimulated in vivo angiogenesis and their proangiogenic potential were enhanced significantly upon blue light illumination. Finally, activation of the endothelial cells in response to stimulation by blue light-treated exosomes was demonstrated by upregulation of two miRNAs, miR-135b-5p, and miR-499a-3p. Conclusions Blue (455 nm) light illumination improved the therapeutic effects of hUC-MSC exosomes by enhancing their proangiogenic ability in vitro and in vivo with the upregulation of the following two miRNAs: miR-135b-5p and miR-499a-3p. Graphical abstract

scholarly journals Exosomes from Human Umbilical Cord Mesenchymal Stem Cells Facilitate Diabetic Wound Healing through miR-221-3p-mediated Enhancement of Angiogenesis

2021 ◽  
Author(s):  
Qian Wei ◽  
Yaxi Wang ◽  
Kui Ma ◽  
Xiaowei Bian ◽  
Qiankun Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Mesenchymal Stem Cells ◽  
Tube Formation ◽  
Human Umbilical Cord ◽  
Diabetic Wound ◽  
Diabetic Wound Healing ◽  
Diabetic Wounds

Abstract Background: Endothelial dysfunction caused by persistent hyperglycemia in diabetes is responsible for impaired angiogenesis in diabetic wounds. Exosomes are considered potential therapeutic tools to promote diabetic wound healing. The aim of this study was to investigate the effects of exosomes secreted by human umbilical cord mesenchymal stem cells (hucMSC-Exos) on angiogenesis under high glucose (HG) conditions in vivo and in vitro and to explore the underlying mechanisms.Methods: HucMSC-Exos were used to treat diabetic wounds and human umbilical vascular endothelial cells (HUVECs) exposed to HG. Wound healing and angiogenesis were assessed in vivo. The biological characteristics of HUVECs were examined in vitro. Expression of pro-angiogenesis genes in HUVECs was also examined by western blotting. The miRNAs contained within hucMSC-Exos were identified using miRNA microarrays and qRT-PCR. The roles of selected miRNAs in angiogenesis were assessed using specific agomirs and inhibitors.Results: In vivo, local application of hucMSC-Exos enhanced wound healing and angiogenesis. In vitro, hucMSC-Exos reduced senescence of HG-treated HUVECs and promoted proliferation, migration, and tube formation by inhibiting phosphatase and tensin homolog (PTEN) expression and activating the AKT/HIF-1α/VEGF pathways. MiR-221-3p was enriched in hucMSC-Exos. In vitro, MiR-221-3p downregulated PTEN and activated the AKT/HIF-1α/VEGF pathway to promote proliferation, migration, and tube formation in HG-treated HUVECs. In vivo, miR-221-3p agomirs mimicked the effects of hucMSC-Exos on wound healing and angiogenesis, whereas miR-221-3p inhibitors reversed their effects.Conclusions: Our findings suggest that hucMSC-Exos have regenerative and protective effects on HG-induced senescence in endothelial cells via transfer of miR-221-3p, thereby accelerating diabetic wound healing. Thus, hucMSC-Exos may be promising therapeutic candidates for improving diabetic wound angiogenesis.

Conditioned medium from the human umbilical cord-mesenchymal stem cells stimulate the proliferation of human keratinocytes

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Sushmitha Sriramulu ◽  
Antara Banerjee ◽  
Ganesan Jothimani ◽  
Surajit Pathak
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Wound Healing ◽  
Mesenchymal Stem Cells ◽  
Conditioned Medium ◽  
Umbilical Cord ◽  
Human Keratinocytes ◽  
Human Umbilical Cord ◽  
Hacat Cells ◽  
And Migration

AbstractObjectivesWound healing is a complex process with a sequence of restoring and inhibition events such as cell proliferation, differentiation, migration as well as adhesion. Mesenchymal stem cells (MSC) derived conditioned medium (CM) has potent therapeutic functions and promotes cell proliferation, anti-oxidant, immunosuppressive, and anti-apoptotic effects. The main aim of this research is to study the role of human umbilical cord-mesenchymal stem cells (UC-MSCs) derived CM in stimulating the proliferation of human keratinocytes (HaCaT).MethodsFirstly, MSC were isolated from human umbilical cords (UC) and the cells were then cultured in proliferative medium. We prepared and collected the CM after 72 h. Morphological changes were observed after the treatment of HaCaT cells with CM. To validate the findings, proliferation rate, clonal efficiency and also gene expression studies were performed.ResultsIncreased proliferation rate was observed and confirmed with the expression of Proliferating Cell Nuclear Antigen (PCNA) after treatment with HaCaT cells. Cell-cell strap formation was also observed when HaCaT cells were treated with CM for a period of 5–6 days which was confirmed by the increased expression of Collagen Type 1 Alpha 1 chain (Col1A1).ConclusionsOur results from present study depicts that the secretory components in the CM might play a significant role by interacting with keratinocytes to promote proliferation and migration. Thus, the CM stimulates cellular proliferation, epithelialization and migration of skin cells which might be the future promising application in wound healing.

scholarly journals Microvesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Stimulated by Hypoxia Promote Angiogenesis Both In Vitro and In Vivo

2012 ◽  
Vol 21 (18) ◽  
pp. 3289-3297 ◽  
Author(s):  
Hong-Chao Zhang ◽  
Xin-Bin Liu ◽  
Shu Huang ◽  
Xiao-Yun Bi ◽  
Heng-Xiang Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Umbilical Cord ◽  
Human Umbilical Cord

Overexpression of FOXQ1 enhances anti-senescence and migration effects of human umbilical cord mesenchymal stem cells in vitro and in vivo

2018 ◽  
Vol 373 (2) ◽  
pp. 379-393 ◽  
Author(s):  
Tao Zhang ◽  
Pan Wang ◽  
Yanxia Liu ◽  
Jiankang Zhou ◽  
Zhenqing Shi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Umbilical Cord ◽  
Human Umbilical Cord ◽  
And Migration

scholarly journals Adipose-Derived Mesenchymal Stem Cells Migrate and Rescue RPE in the Setting of Oxidative Stress

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Aya Barzelay ◽  
Shira Weisthal Algor ◽  
Anat Niztan ◽  
Sebastian Katz ◽  
Moshe Benhamou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Cell Death ◽  
Mesenchymal Stem Cells ◽  
Conditioned Medium ◽  
Early Passage ◽  
Systemic Injection ◽  
Rpe Cells

Oxidative stress leads to the degeneration of retinal pigment epithelial (RPE) and photoreceptor cells. We evaluated the potential of adipose-derived mesenchymal stem cells (ASCs) as a therapeutic tool by studying the migration capacity of ASCs in vitro and their protective effect against RPE cell death under oxidative stress in vitro and in vivo. ASCs exhibited enhanced migration when exposed to conditioned medium of oxidative stressed RPE cells obtained by hydrogen peroxide. Migration-related axis SDF-1/CXCR4 was studied, and upregulation of SDF-1 in stressed RPE and of CXCR4 in ASCs was detected. Moreover, ASCs’ conditioned medium prevented H2O2-induced cell death of RPE cells. Early passage ASCs had high expression level of HGF, low VEGF levels, and unmodulated IL-1β levels, compared to late passage ASCs. Thus, early passage ASCs show the potential to migrate towards damaged RPE cells and protect them in a paracrine manner from cell death induced by oxidative stress. In vivo, mice received systemic injection of NaIO3, and 72 h later, ASCs were transplanted in the subretinal space. Seven days after ASC transplantation, the eyes were enucleated fixed and frozen for immunohistochemical analysis. Under such conditions, ASC-treated mice showed preservation of nuclear layers in the outer nuclear layer and stronger staining of RPE and photoreceptor layer, compared to PBS-treated mice. Taken together, our results indicate that ASCs are able to home in on damaged RPE cells and protect against damage to the RPE and PR layers caused by oxidative stress. These data imply the potential that ASCs have in regenerating RPE under oxidative stress, providing the basis for a therapeutic approach to retinal degeneration diseases related to oxidative stress that could help save the eyesight of millions of people worldwide.

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