scholarly journals Characterization of Mesenchymal Stem Cells Derived from Bisphosphonate-Related Osteonecrosis of the Jaw Patients’ Gingiva

2021 ◽  
Author(s):  
Mengyu Li ◽  
Jiajia Wang ◽  
Yejia Yu ◽  
Yuqiong Zhou ◽  
Yueqi Shi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Mesenchymal Stem Cells ◽  
Signaling Pathway ◽  
Critical Role ◽  
Osteonecrosis Of The Jaw ◽  
Skin Model ◽  
Tgf Β1

AbstractBisphosphonate-related osteonecrosis of the jaw (BRONJ) is a clinical condition that specifically occurs in the oral cavity, characterized by retarded wound healing in oral mucosa accelerating the exposure of bone. Moreover, the pathological mechanism remains poorly understood. Gingival mesenchymal stem cells (GMSCs) play a critical role in gingival healing and soft tissue regeneration. Although previous studies have showed that bisphosphonates (BPs) are highly toxic to healthy GMSC, there is overall lack of direct evidence demonstrating the characterization of GMSCs derived from BRONJ patients. In present study, we isolated GMSCs for the first time from the central area of BRONJ patients’ gingiva (center-BRONJ GMSCs) and the peripheral area (peri-BRONJ GMSCs), and found that they exhibited decreased proliferation, adhesion, migration capacities and underwent early apoptosis in vitro compared control GMSCs. Notably, the central and peripheral BRONJ GMSCs transplantation in a mice excisional skin model also displayed lower cell survival rate and poor healing effects than that of controls. Mechanistically, TGF-β1 signaling pathway was suppressed not only in BRONJ patients’ gingival lesions but also in BRONJ GMSCs transplantation animal model. The results above suggested that under the microenvironment of BRONJ patients, the dysfunction of GMSCs and the suppressed TGF-β1 signaling pathway may be the vital factors in impaired gingival healing, thus contributing to persistent exposure of underlying bone and development of BRONJ. This study provides new insights into the prevention for BRONJ by improving the functions of GMSCs and upregulating TGF-β1 in accelerating gingival wound healing. Graphical Abstract Schematic illustration of the dysfunction of BRONJ GMSCs in vitro and BRONJ GMSCs transplantation in a mice skin model delaying cutaneous wound healing mainly via suppressing TGF-β1 signaling pathway.

scholarly journals The Outcome of Bisphosphonate-Related Osteonecrosis of the Jaw Patients’ Gingiva-Derived Mesenchymal Stem Cells on Wound Healing in a Mice Excisional Skin Model.

2021 ◽  
Author(s):  
Mengyu Li ◽  
Yejia Yu ◽  
Jiajia Wang ◽  
Yuqiong Zhou ◽  
Yueqi Shi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Animal Model ◽  
Mesenchymal Stem Cells ◽  
Cell Survival ◽  
Osteonecrosis Of The Jaw ◽  
Skin Model ◽  
Group A ◽  
Tgf Β1

Abstract Background: Retarded gingival healing is the hallmark of bisphosphonate-related osteonecrosis of the jaw (BRONJ) and poses a great challenge to maxillofacial surgeons. Although previous studies have showed that bisphosphonates (BPs) are highly toxic to healthy gingival mesenchymal stem cells (GMSCs) in vitro, there is overall lack of direct evidence demonstrating the regeneration capacity of oral mucosa in BRONJ patients. In present study, we aim to isolate GMSCs from BRONJ patients’ gingiva and assessed their phenotypes and functions in vitro, as well as their therapeutic effects for wound healing in a mice excisional skin model. Methods: BRONJ patients’ gingival samples were used for microarray analysis, histological detection and cell culture. The stem cells isolated from the central gingiva (center-BRONJ GMSCs) and the peripheral lesions (peri-BRONJ GMSCs) were analyzed by Cell Counting Kit-8 (CCK-8), cell adhesion, scratch and flow cytometry. Luciferase/GFP (Green Fluorescent Proteins)-labeled GMSCs combined with Hydrogel were transplanted in a mice excisional skin model, and mice were divided into a hydrogel alone group, a hydrogel/control GMSCs group, a hydrogel/center-BRONJ GMSCs group and a hydrogel/peri-BRONJ GMSCs group. Bioluminescence imaging trace cell survival in vivo. Healing effects were evaluated by wound area measurement, histology, immunohistochemistry (IH) and immunofluorescence (IF). Results: Center-BRONJ GMSCs and peri-BRONJ GMSCs were all fibroblast-like cells, but they became slender and more wrinkled compared control GMSCs. Notably, they exhibited decreased proliferation, adhesion, migration capacities and underwent early apoptosis in vitro. In animal model, BRONJ GMSCs transplantation also displayed lower cell survival rate and poor healing effects than that of control group. Mechanistically, we found that the expression of TGF-β1 signaling pathway was suppressed not only in BRONJ patients’ gingival lesions but also in BRONJ GMSCs transplantation animal model. Conclusions: In BRONJ patients’ microenvironment, the regeneration ability of oral mucosa was dramatically decreased. Our mice skin model demonstrated for the first time that BRONJ GMSCs transplantation displayed poor effects on wound healing mainly via suppressing TGF-β1 signaling pathway. This study provides new insights into the prevention for BRONJ by improving the functions of GMSCs in accelerating gingival wound healing.

scholarly journals Prrx1 promotes stemness and angiogenesis via activating TGF-β/smad pathway and upregulating proangiogenic factors in glioma

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Zetao Chen ◽  
Yihong Chen ◽  
Yan Li ◽  
Weidong Lian ◽  
Kehong Zheng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Therapeutic Strategy ◽  
Critical Role ◽  
Glioma Stem Cells ◽  
Promoter Regions ◽  
Aberrant Expression ◽  
Smad Pathway ◽  
Tgf Β1

AbstractGlioma is one of the most lethal cancers with highly vascularized networks and growing evidences have identified glioma stem cells (GSCs) to account for excessive angiogenesis in glioma. Aberrant expression of paired-related homeobox1 (Prrx1) has been functionally associated with cancer stem cells including GSCs. In this study, Prrx1 was found to be markedly upregulated in glioma specimens and elevated Prrx1 expression was inversely correlated with prognosis of glioma patients. Prrx1 potentiated stemness acquisition in non-stem tumor cells (NSTCs) and stemness maintenance in GSCs, accompanied with increased expression of stemness markers such as SOX2. Prrx1 also promoted glioma angiogenesis by upregulating proangiogenic factors such as VEGF. Consistently, silencing Prrx1 markedly inhibited glioma proliferation, stemness, and angiogenesis in vivo. Using a combination of subcellular proteomics and in vitro analyses, we revealed that Prrx1 directly bound to the promoter regions of TGF-β1 gene, upregulated TGF-β1 expression, and ultimately activated the TGF-β/smad pathway. Silencing TGF-β1 mitigated the malignant behaviors induced by Prrx1. Activation of this pathway cooperates with Prrx1 to upregulate the expression of stemness-related genes and proangiogenic factors. In summary, our findings revealed that Prrx1/TGF-β/smad signal axis exerted a critical role in glioma stemness and angiogeneis. Disrupting the function of this signal axis might represent a new therapeutic strategy in glioma patients.

scholarly journals Chronic senescent human mesenchymal stem cells as possible contributor to the wound healing disorder after exposure to the alkylating agent sulfur mustard

2021 ◽  
Vol 95 (2) ◽  
pp. 727-747
Author(s):  
Simone Rothmiller ◽  
Niklas Jäger ◽  
Nicole Meier ◽  
Thimo Meyer ◽  
Adrian Neu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Mesenchymal Stem Cells ◽  
Alkylating Agent ◽  
Chronic Wounds ◽  
Sulfur Mustard ◽  
Morphological Changes ◽  
Human Mesenchymal Stem Cells ◽  
Age Related

AbstractWound healing is a complex process, and disturbance of even a single mechanism can result in chronic ulcers developing after exposure to the alkylating agent sulfur mustard (SM). A possible contributor may be SM-induced chronic senescent mesenchymal stem cells (MSCs), unable to fulfil their regenerative role, by persisting over long time periods and creating a proinflammatory microenvironment. Here we show that senescence induction in human bone marrow derived MSCs was time- and concentration-dependent, and chronic senescence could be verified 3 weeks after exposure to between 10 and 40 µM SM. Morphological changes, reduced clonogenic and migration potential, longer scratch closure times, differences in senescence, motility and DNA damage response associated genes as well as increased levels of proinflammatory cytokines were revealed. Selective removal of these cells by senolytic drugs, in which ABT-263 showed initial potential in vitro, opens the possibility for an innovative treatment strategy for chronic wounds, but also tumors and age-related diseases.

scholarly journals Positively Correlated CD47 Activation and Autophagy in Umbilical Cord Blood-Derived Mesenchymal Stem Cells during Senescence

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Gee-Hye Kim ◽  
Yun Kyung Bae ◽  
Ji Hye Kwon ◽  
Miyeon Kim ◽  
Soo Jin Choi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Cell Growth ◽  
Cell Therapy ◽  
Critical Role ◽  
Therapeutic Effects ◽  
Stem Cell Maintenance ◽  
Selection Of

Autophagy plays a critical role in stem cell maintenance and is related to cell growth and cellular senescence. It is important to find a quality-control marker for predicting senescent cells. This study verified that CD47 could be a candidate to select efficient mesenchymal stem cells (MSCs) to enhance the therapeutic effects of stem cell therapy by analyzing the antibody surface array. CD47 expression was significantly decreased during the expansion of MSCs in vitro ( p < 0.01 ), with decreased CD47 expression correlated with accelerated senescence phenotype, which affected cell growth. UCB-MSCs transfected with CD47 siRNA significantly triggered the downregulation of pRB and upregulation of pp38, which are senescence-related markers. Additionally, autophagy-related markers, ATG5, ATG12, Beclin1, and LC3B, revealed significant downregulation with CD47 siRNA transfection. Furthermore, autophagy flux following treatment with an autophagy inducer, rapamycin, has shown that CD47 is a key player in autophagy and senescence to maintain and regulate the growth of MSCs, suggesting that CD47 may be a critical key marker for the selection of effective stem cells in cell therapy.

Hypoxia promotes tenocyte differentiation of mesenchymal stem cells

2020 ◽  
Author(s):  
Guanyin Chen ◽  
wangqian zhang ◽  
Jintao Gu ◽  
Yuan Gao ◽  
Lei He ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Patellar Tendon ◽  
Tendon Repair ◽  
Clinical Results ◽  
Tendon Injury ◽  
Tenogenic Differentiation ◽  
Tgf Β1

Abstract Background: Tendon injury is a common but tough medical problem. Unsatisfactory clinical results have been reported in tendon repair using mesenchymal stem cells (MSCs) therapy, creating a need for a better strategy to induce MSCs to tenogenic differentiation. This study was designed to investigate the role of hypoxia in the tenogenic differentiation of MSCs in vitro and in vivo and to compare the tenogenic differentiation capacities of different MSCs under hypoxia condition in vitro. Methods: Adipose tissue-derived MSCs (AMSCs) and bone marrow-derived MSCs (BMSCs) were isolated and characterized by the expression of MSC-specific markers and tri-lineage differentiation. The expression of hypoxia induced factor-1 alpha (Hif-1α) and the proliferation of AMSCs and BMSCs were examined in order to confirm the establishment of hypoxia condition. qRT-PCR, western blot, and immunofluorescence staining were used to evaluate the expression of tendon-associated marker Col-1a1, Col-3a1, Dcn, and Tnmd in AMSCs and BMSCs under hypoxia and/or Tgf-β1 condition. In vivo, a patellar tendon injury model was established. Normoxic and hypoxic BMSCs were cultured and implanted. Histological, biomechanical and transmission electron microscopy analyses were performed to assess the improved healing effect of hypoxic BMSCs on tendon injury. Results: Hypoxia remarkably increased the expression of Hif-1α and the proliferation of AMSCs and BMSCs. Our in vitro results detected that hypoxia not only promoted a significant increase in tenogenic markers in both AMSCs and BMSCs compared with the normoxia group, but also showed higher inductility compared with Tgf-β1. In addition, hypoxic BMSCs exhibited higher potential of tenogenic differentiation than hypoxic AMSCs. Our in vivo results demonstrated that hypoxic BMSCs possessed better histological and biomechanical properties than those of normoxic BMSCs, as evidenced by histological scores, quantitative analysis of immunohistochemical staining for Col-1a1 and Tnmd, the range and average of collagen fibril diameters and patellar tendon biomechanical tests. Conclusions: These findings suggested that hypoxia may be a practical and reliable strategy to induce tenogenic differentiation of BMSCs for tendon repair and could enhance the effectiveness of MSCs therapy in treating tendon injury.

Bone Marrow-Derived Mesenchymal Stem Cells Combined With Simvastatin Accelerates Burn Wound Healing by Activation of the Akt/mTOR Pathway

2020 ◽  
Vol 41 (5) ◽  
pp. 1069-1078
Author(s):  
Parisa Ramhormozi ◽  
Javad Mohajer Ansari ◽  
Sara Simorgh ◽  
Maliheh Nobakht
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Wound Healing ◽  
Mesenchymal Stem Cells ◽  
Combination Therapy ◽  
Signaling Pathway ◽  
Mtor Signaling Pathway ◽  
Burn Wound ◽  
Qrt Pcr ◽  
Burn Wound Healing

Abstract Burn wound healing is one of the most important problems in the field of medical science. Promising results have recently been reported by researchers who used bone marrow mesenchymal stem cells (BMSCs) to treat burn wounds. In this study, we investigated the effects of BMSC therapy in combination with simvastatin (SMV) on angiogenesis as well as on the activity of the Akt/mTOR signaling pathway during burn wound healing in rats. After creating second-degree burn wounds, 40 adult male Wistar rats were randomly divided into four treatment groups: the control, SMV, BMSCs, and the combination therapy group (BMSCs+SMV). Animals were killed 14 days after treatment initiation, and the wounds were removed for histological and molecular analyses. All in all, combination therapy produced better outcomes than individual therapy in terms of the wound closure area, epidermal regeneration level, collagen deposition intensity, and reepithelialization rate. In addition, the elevations of expression levels of Akt and mTOR genes, at both mRNA and protein levels, were more pronounced in the BMSCs+SMV group (P &lt; .05, at least, for both qRT-PCR and western blot assessments). qRT-PCR findings also demonstrated that the wounds treated with the combination of BMSCs and SMV had the highest expression levels of CD31 and VEGF genes (P &lt; .01 for all comparisons). These data suggest that the combined administration of BMSCs transplantation and topical SMV has a great potential in burn wound healing. According to the findings, the beneficial effects of the combination therapy are caused, at least in part, through stimulating Akt/mTOR signaling pathway.

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.

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