Mesenchymal stem cell-conditioned medium facilitates angiogenesis and fracture healing in diabetic rats

Wang, Chien-Yuan; Yang, Haw‐Ching; Hsu, Han‐Shui; Chen, Ling–Lan; Tsai, Chih–Chien; Tsai, Kuo–Shu; Yew, Tu-Lai; Kao, Yi‐Hsuan; Hung, Shih‐Chieh

doi:10.1002/term.461

Cited by 80 publications

(71 citation statements)

References 31 publications

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“…Furthermore, we found that MSC exosomes were uptaken by HUVECs and enhanced endothelial angiogenesis in vitro. This latter finding is in line with several reports demonstrating the angiogenic potential of MSC-conditioned medium [61][62][63], and a recent report by Bian et al that examined the angiogenic effects of MSC exosomes [64].…”

Section: Discussionsupporting

confidence: 91%

Mesenchymal Stem Cell Exosomes Induce Proliferation and Migration of Normal and Chronic Wound Fibroblasts, and Enhance Angiogenesis In Vitro

Shabbir

Cox

Rodriguez-Menocal

et al. 2015

Stem Cells and Development

587

480

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Although chronic wounds are common and continue to be a major cause of morbidity and mortality, treatments for these conditions are lacking and often ineffective. A large body of evidence exists demonstrating the therapeutic potential of mesenchymal stem cells (MSCs) for repair and regeneration of damaged tissue, including acceleration of cutaneous wound healing. However, the exact mechanisms of wound healing mediated by MSCs are unclear. In this study, we examined the role of MSC exosomes in wound healing. We found that MSC exosomes ranged from 30 to 100-nm in diameter and internalization of MSC exosomes resulted in a dosedependent enhancement of proliferation and migration of fibroblasts derived from normal donors and chronic wound patients. Uptake of MSC exosomes by human umbilical vein endothelial cells also resulted in dosedependent increases of tube formation by endothelial cells. MSC exosomes were found to activate several signaling pathways important in wound healing (Akt, ERK, and STAT3) and induce the expression of a number of growth factors [hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF1), nerve growth factor (NGF), and stromal-derived growth factor-1 (SDF1)]. These findings represent a promising opportunity to gain insight into how MSCs may mediate wound healing.

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Section: Discussionsupporting

confidence: 91%

Mesenchymal Stem Cell Exosomes Induce Proliferation and Migration of Normal and Chronic Wound Fibroblasts, and Enhance Angiogenesis In Vitro

Shabbir

Cox

Rodriguez-Menocal

et al. 2015

Stem Cells and Development

587

480

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“…In agreement with our results, Osugi et al reported a higher evaluation of new bone regeneration in the MSC-CM group compared with the control and the MSC transplanted groups after 4, and 8 weeks (24). In another study, Wang et al demonstrated that MSC-CM delivered in gelatin sponge increased angiogenesis and bone regeneration in a diabetic rat model (49). We applied a different approach for quantitative comparison between studied groups using three dimensional stereological analysis to determine more reliable results.…”

Section: Discussionsupporting

confidence: 92%

Adipose Derived Stem Cells Conditioned Media in Combination with Bioceramic-Collagen Scaffolds Improved Calvarial Bone Healing in Hypothyroid Rats

Sanchooli

Norouzian

Ardeshirylajimi

et al. 2017

Iran Red Crescent Med J

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Background: Tissue engineering is an available treatment for large bone defects. The therapeutic effects of mesenchymal stem cell (MSC) are mostly attributed to secretion of many cytokines and growth factors. Many factors of MSC secretions accumulate in a conditioned medium and these factors recruit native cells into a defect site to generate new bone tissues. Objectives: The aim of this study was to evaluate the influence of adipose tissue derived MSCs-conditioned medium (ADMSC-CM) on bone repair of rats with critical -size calvarial defect. Methods: This experimental study was performed at Shahid Beheshti University of Medical Sciences, Tehran, Iran, from 2016 to 2017. Conditioned medium was collected from healthy rat adipose tissue derived MSC (ADMSC) at passage four. Calvarial bone defect was created in hypothyroid rats using a dental bur. Sampling was taken by the linear-mono-gram method to determine sample size (n = 6 per group). The rats were divided randomly into four groups based on graft material as follows: empty defect, scaffold (Bio-Oss / type I collagen gel), scaffold / ADMSCs, scaffold /ADMSC-CM. Evaluations were made at 4 and 8 weeks after surgery using stereological analysis. Results: Histological analysis at 8 weeks indicated that the newly regenerated tissue almost covered the defect in the ADMSC-CM group. Stereological analysis showed that ADMSC-CM increased regenerated bone and numbers of osteocytes and osteoblasts compared with the defect and scaffold groups (P < 0.05). Also, bone regeneration was more effective in animals treated with ADMSC-CM than in those received ADMSC. Conclusions: These results suggest an important role for ADMSC-CM in bone regeneration, through trophic impact of its cytokines and growth factors that induce native cell proliferation and migration into the defect. Thus, ADMSC-CM seems to have good potential for application in bone tissue regeneration, in the cases of hypothyroidism.

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“…Angiogenesis also plays an important role in fracture healing [46]. CM contains high levels of angiogenic factors such as VEGF and IL-6 and enhances bone ingrowth and fracture healing by stimulating endothelial cells [47]. However, as we previously reported, although VEGF and IL-6 levels in MSC exosomes are low compared with CM and CM-Exo, MSC exosomes induce angiogenesis to a greater extent [36].…”

Section: /2mentioning

confidence: 77%

Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model

Furuta

Miyaki

Ishitobi

et al. 2016

Stem Cells Translational Medicine

371

362

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Paracrine signaling by bone-marrow-derived mesenchymal stem cells (MSCs) plays a major role in tissue repair. Although the production of regulatory cytokines by MSC transplantation is a critical modulator of tissue regeneration, we focused on exosomes, which are extracellular vesicles that contain proteins and nucleic acids, as a novel additional modulator of cell-to-cell communication and tissue regeneration. To address this, we used radiologic imaging, histological examination, and immunohistochemical analysis to evaluate the role of exosomes isolated from MSC-conditioned medium (CM) in the healing process in a femur fracture model of CD9 2/2 mice, a strain that is known to produce reduced levels of exosomes. We found that the bone union rate in CD9 2/2 mice was significantly lower than wild-type mice because of the retardation of callus formation. The retardation of fracture healing in CD9 2/2 mice was rescued by the injection of exosomes, but this was not the case after the injection of exosomes-free conditioned medium (CM-Exo). The levels of the bone repairrelated cytokines, monocyte chemotactic protein-1 (MCP-1), MCP-3, and stromal cell-derived factor-1 in exosomes were low compared with levels in CM and CM-Exo, suggesting that bone repair may be in part mediated by other exosome components, such as microRNAs. These results suggest that exosomes in CM facilitate the acceleration of fracture healing, and we conclude that exosomes are a novel factor of MSC paracrine signaling with an important role in the tissue repair process. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:1620-1630 SIGNIFICANCEThis work focuses on exosomes, which are extracellular vesicles, as a novel additional modulator of cell-to-cell communication. This study evaluated the role of exosomes isolated from mesenchymal stem cell (MSC)-conditioned medium (MSC-CM) in the fracture-healing process of CD9 2/2 mice, a strain that is known to produce reduced levels of exosomes. Retardation of fracture healing in CD9 2/2 mice was rescued by the injection of MSC exosomes, but this was not the case after the injection of exosome-free CM. This study finds that MSC exosomes are a novel factor of MSC paracrine signaling, with an important role in the tissue repair process.

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Mesenchymal stem cell-conditioned medium facilitates angiogenesis and fracture healing in diabetic rats

Cited by 80 publications

References 31 publications

Mesenchymal Stem Cell Exosomes Induce Proliferation and Migration of Normal and Chronic Wound Fibroblasts, and Enhance Angiogenesis In Vitro

Mesenchymal Stem Cell Exosomes Induce Proliferation and Migration of Normal and Chronic Wound Fibroblasts, and Enhance Angiogenesis In Vitro

Adipose Derived Stem Cells Conditioned Media in Combination with Bioceramic-Collagen Scaffolds Improved Calvarial Bone Healing in Hypothyroid Rats

Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model

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