M2 Macrophagy-derived Exosomal MiRNA-5106 Induces Bone Mesenchymal Stem Cells towards Osteoblastic Fate by Targeting Salt-inducible Kinase 2 and 3

Abstract Background Osteoblast differentiation is a vital process for fracture healing, and exosomes are nanosized membrane vesicles that can deliver therapeutic drugs easily and safely. Macrophages participate in the regulation of various biological processes in vivo , and macrophage-derived exosomes (MD-Exos) have recently been a topic of increasing research interest. However, few study has explored the link between MD-Exos and osteoblast differentiation. Herein, we sought to identify miRNAs differentially expressed between M1 and M2 macrophage-derived exosomes, and to evaluate their roles in the context of osteoblast differentiation.Results We found that microRNA-5106 (miR-5106) was significantly overexpressed in M2 macrophage-derived exosomes (M2D-Exos), while its expression was decreased in M1 macrophage-derived exosomes (M1D-Exos), and we found that this exosomal miRNA can induce bone mesenchymal stem cell (BMSC) osteogenic differentiation via directly targeting the Salt-inducible kinase 2 and 3 ( SIK2 and SIK3 ) genes. In addition, the local injection of both a miR-5106 agonist or M2D-Exos to fracture sites was sufficient to accelerate healing in vivo.Conclusions Our study demonstrates that miR-5106 is highly enriched in M2D-Exos, and that it can be transferred to BMSCs wherein it targets SIK2 and SIK3 genes to promote osteoblast differentiation.

Download Full-text

M2 Macrophagy-derived Exosomal MiRNA-5106 Induces Bone Mesenchymal Stem Cells towards Osteoblastic Fate by Targeting Salt-inducible Kinase 2 and 3

10.21203/rs.3.rs-18281/v2 ◽

2020 ◽

Author(s):

Yuan Xiong ◽

Lang Chen ◽

Chenchen Yan ◽

Wu Zhou ◽

Tao Yu ◽

...

Keyword(s):

Stem Cells ◽

Osteoblast Differentiation ◽

Membrane Vesicles ◽

M2 Macrophage ◽

Biological Processes ◽

Bone Mesenchymal Stem Cells ◽

Therapeutic Drugs ◽

M1 Macrophage ◽

Exosomal Mirna

Abstract Background Osteoblast differentiation is a vital process for fracture healing, and exosomes are nanosized membrane vesicles that can deliver therapeutic drugs easily and safely. Macrophages participate in the regulation of various biological processes in vivo , and macrophage-derived exosomes (MD-Exos) have recently been a topic of increasing research interest. However, few study has explored the link between MD-Exos and osteoblast differentiation. Herein, we sought to identify miRNAs differentially expressed between M1 and M2 macrophage-derived exosomes, and to evaluate their roles in the context of osteoblast differentiation. Results We found that microRNA-5106 (miR-5106) was significantly overexpressed in M2 macrophage-derived exosomes (M2D-Exos), while its expression was decreased in M1 macrophage-derived exosomes (M1D-Exos), and we found that this exosomal miRNA can induce bone mesenchymal stem cell (BMSC) osteogenic differentiation via directly targeting the Salt-inducible kinase 2 and 3 ( SIK2 and SIK3 ) genes. In addition, the local injection of both a miR-5106 agonist or M2D-Exos to fracture sites was sufficient to accelerate healing in vivo . Conclusions Our study demonstrates that miR-5106 is highly enriched in M2D-Exos, and that it can be transferred to BMSCs wherein it targets SIK2 and SIK3 genes to promote osteoblast differentiation.

Download Full-text

Tenuigenin promotes the osteogenic differentiation of bone mesenchymal stem cells in vitro and in vivo

Cell and Tissue Research ◽

10.1007/s00441-016-2528-1 ◽

2016 ◽

Vol 367 (2) ◽

pp. 257-267 ◽

Cited By ~ 3

Author(s):

Hua-ji Jiang ◽

Xing-gui Tian ◽

Shou-bin Huang ◽

Guo-rong Chen ◽

Min-jun Huang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Osteogenic Differentiation ◽

Bone Mesenchymal Stem Cells

Download Full-text

O9 M1 macrophages evoke an increase in PIGR expression in MDA-MB468 breast cancer cells through interlukin-1β

British Journal of Surgery ◽

10.1093/bjs/znab282.014 ◽

2021 ◽

Vol 108 (Supplement_5) ◽

Author(s):

W Asanprakit ◽

D N Lobo ◽

O Eremin ◽

A J Bennett

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Immune Cells ◽

Breast Cancer Cells ◽

Polarization State ◽

M2 Macrophage ◽

M1 Macrophages ◽

M1 Macrophage ◽

Macrophage Cytokine

Abstract Introduction The polymeric immunoglobulin receptor (PIGR) is a transmembrane protein, which transports polymeric immunoglobulin (pIg) across the epithelial cells. High expression of PIGR in breast cancer has been reported to associate with increased 5-year survival rate. In this study, the factors in tumour microenvironment which affected PIGR expression in breast cancer cell lines, were investigated. Method M1, M2 macrophage conditioned media (CM) and recombinant human cytokines were used to determine factors which increased PIGR expression in breast cancer cells. The level of PIGR expression in the cells and secreted PIGR free secretory component (SC) were evaluated by real time quantitative polymerase chain reaction and Western blotting. Results M1 macrophage CM induced a striking dose dependent increase in PIGR mRNA expression in MDA-MB468 cells, up to 20-fold in 100% CM. Interferon gamma (IFNγ) and interleukin (IL)-1β also increased PIGR expression in MDA-MB468 cells. However, IL-1β was demonstrated to increase in M1 macrophages, while IFNγ was not. The role of IL-1β secreted from M1 macrophages in increasing expression of PIGR was confirmed by IL-1 receptor blockade, indicating that IL-1β was the M1 macrophage cytokine that enhanced PIGR expression in breast cancer cells. Conclusions IL-1β was the M1 macrophage cytokine which enhanced PIGR expression in breast cancer cells. IFNγ was also shown to increase PIGR expression in the present study. These imply that elevated PIGR expression in breast cancer in vivo may reflect the polarization state of tumour associated immune cells. Take-home Message IL-1β secreted from M1 macrophage enhances PIGR expression in breast cancer cells. The elevated PIGR expression in breast cancer in vivo may reflect the polarization state of tumour associated immune cells.

Download Full-text

Effects of Magnetically Guided, SPIO-Labeled, and Neurotrophin-3 Gene-Modified Bone Mesenchymal Stem Cells in a Rat Model of Spinal Cord Injury

Stem Cells International ◽

10.1155/2016/2018474 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 6

Author(s):

Rui-Ping Zhang ◽

Ling-Jie Wang ◽

Sheng He ◽

Jun Xie ◽

Jian-Ding Li

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Rat Model ◽

Therapeutic Effects ◽

Magnetic Targeting ◽

Bone Mesenchymal Stem Cells ◽

Cord Injury

Despite advances in our understanding of spinal cord injury (SCI) mechanisms, there are still no effective treatment approaches to restore functionality. Although many studies have demonstrated that transplantingNT3gene-transfected bone marrow-derived mesenchymal stem cells (BMSCs) is an effective approach to treat SCI, the approach is often low efficient in the delivery of engrafted BMSCs to the site of injury. In this study, we investigated the therapeutic effects of magnetic targeting ofNT3gene-transfected BMSCs via lumbar puncture in a rat model of SCI. With the aid of a magnetic targeting cells delivery system, we can not only deliver the engrafted BMSCs to the site of injury more efficiently, but also perform cells imaging in vivo using MR. In addition, we also found that this composite strategy could significantly improve functional recovery and nerve regeneration compared to transplantingNT3gene-transfected BMSCs without magnetic targeting system. Our results suggest that this composite strategy could be promising for clinical applications.

Download Full-text

Hematopoietic stem cells can differentiate into pericytes and myofibroblast in wound healing, not bone Mesenchymal stem cells

10.21203/rs.3.rs-81020/v1 ◽

2020 ◽

Author(s):

Yanan Kong ◽

Liuhanghang Cheng ◽

Min Xuan ◽

Hao Ding ◽

Biao Cheng

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Wound Healing ◽

Mesenchymal Stem Cells ◽

Hematopoietic Stem Cells ◽

Fluorescent Protein ◽

Bone Mesenchymal Stem Cells ◽

Hematopoietic Stem ◽

Green Fluorescent

Abstract Background Hematopoietic stem cells(HSCs) and mesenchymal stem cells(MSCs) can participate in wound healing. However, very few studies had shown HSCs and MSCs could arrive to the wound and differentiate into tissues. In this study, we intend to investigate the role of bone marrow HSCs and MSCs in wound healing. Methods We first removed the bone marrow of mice by irradiation. Furthermore, we injected different colours of fluorescent HSCs and MSCs into the tail vein of irradiated mice to reconstruct bone marrow function. We prepared wound models on the back of these mice. In vivo imaging and immunohistochemical staining were used to track the expression of fluorescent protein. Results HSCs and MSCs have been isolated and cultured. HSCs expressed expressed Sca1, not lineage, CD34 or CD48. MSCs expressed expressed CD29 and CD44,not CD34 or CD45. HSCs labeled with green fluorescent protein reached the wound and co-expressed with desmin and α-SMA. MSCs didn’t stay on the wound. Conclusions The results show HSCs in the bone marrow of mice can directly participate in wound healing and differentiate into pericytes and myofibroblasts.

Download Full-text

Ocoxin Modulates Cancer Stem Cells and M2 Macrophage Polarization in Glioblastoma

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/9719730 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 4

Author(s):

Esther Hernández-SanMiguel ◽

Ricardo Gargini ◽

Teresa Cejalvo ◽

Berta Segura-Collar ◽

Paula Núñez-Hervada ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Macrophage Polarization ◽

Antioxidant Properties ◽

Therapy Resistance ◽

Oral Solution ◽

M2 Macrophage ◽

Antioxidant Agents

Glioblastoma (GBM) is the most common and devastating primary brain tumor. The presence of cancer stem cells (CSCs) has been linked to their therapy resistance. Molecular and cellular components of the tumor microenvironment also play a fundamental role in the aggressiveness of these tumors. In particular, high levels of hypoxia and reactive oxygen species participate in several aspects of GBM biology. Moreover, GBM contains a large number of macrophages, which normally behave as immunosuppressive tumor-supportive cells. In fact, the presence of both, hypoxia and M2-like macrophages, correlates with malignancy and poor prognosis in gliomas. Antioxidant agents, as nutritional supplements, might have antitumor activity. Ocoxin® oral solution (OOS), in particular, has anti-inflammatory and antioxidant properties, as well as antitumor properties in several neoplasia, without known side effects. Here, we describe how OOS affects stem cell properties in certain GBMs, slowing down their tumor growth. In parallel, OOS has a direct effect on macrophage polarization in vitro and in vivo, inhibiting the protumoral features of M2 macrophages. Therefore, OOS could be a feasible candidate to be used in combination therapies during GBM treatment because it can target the highly resilient CSCs as well as their supportive immune microenvironment, without adding toxicity to conventional treatments.

Download Full-text

Dynamic effects of Fto in regulating the proliferation and differentiation of adult neural stem cells of mice

Human Molecular Genetics ◽

10.1093/hmg/ddz274 ◽

2019 ◽

Vol 29 (5) ◽

pp. 727-735 ◽

Cited By ~ 1

Author(s):

Yuhang Cao ◽

Yingliang Zhuang ◽

Junchen Chen ◽

Weize Xu ◽

Yikai Shou ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Neuronal Development ◽

Conditional Knockout ◽

Biological Processes ◽

Adult Neural Stem Cells ◽

Proliferation And Differentiation

Abstract N 6-methyladenosine (m6A) modification of RNA is deposited by the methyltransferase complex consisting of Mettl3 and Mettl14 and erased by demethylase Fto and Alkbh5 and is involved in diverse biological processes. However, it remains largely unknown the specific function and mechanism of Fto in regulating adult neural stem cells (aNSCs). In the present study, utilizing a conditional knockout (cKO) mouse model, we show that the specific ablation of Fto in aNSCs transiently increases the proliferation of aNSCs and promotes neuronal differentiation both in vitro and in vivo, but in a long term, the specific ablation of Fto inhibits adult neurogenesis and neuronal development. Mechanistically, Fto deficiency results in a significant increase in m6A modification in Pdgfra and Socs5. The increased expression of Pdgfra and decreased expression of Socs5 synergistically promote the phosphorylation of Stat3. The modulation of Pdgfra and Socs5 can rescue the neurogenic deficits induced by Fto depletion. Our results together reveal an important function of Fto in regulating aNSCs through modulating Pdgfra/Socs5-Stat3 pathway.

Download Full-text

Angelica polysaccharide promotes proliferation and osteoblast differentiation of mesenchymal stem cells by regulation of long non-coding RNA H19

Bone and Joint Research ◽

10.1302/2046-3758.87.bjr-2018-0223.r2 ◽

2019 ◽

Vol 8 (7) ◽

pp. 323-332 ◽

Cited By ~ 8

Author(s):

Xiaoyan Xie ◽

Miao Liu ◽

Qiang Meng

Keyword(s):

Stem Cells ◽

Cell Proliferation ◽

Mesenchymal Stem Cells ◽

Western Blot ◽

Cell Viability ◽

Osteoblast Differentiation ◽

Signalling Pathways ◽

Non Coding Rna ◽

Long Non Coding Rna

Objectives Osteoporosis is a systemic bone metabolic disease, which often occurs among the elderly. Angelica polysaccharide (AP) is the main component of angelica sinensis, and is widely used for treating various diseases. However, the effects of AP on osteoporosis have not been investigated. This study aimed to uncover the functions of AP in mesenchymal stem cell (MSC) proliferation and osteoblast differentiation. Methods MSCs were treated with different concentrations of AP, and then cell viability, Cyclin D1 protein level, and the osteogenic markers of runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), alkaline phosphatase (ALP), bone morphogenetic protein 2 (BMP-2) were examined by Cell Counting Kit-8 (CCK-8) and western blot assays, respectively. The effect of AP on the main signalling pathways of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and Wnt/β-catenin was determined by western blot. Following this, si-H19#1 and si-H19#2 were transfected into MSCs, and the effects of H19 on cell proliferation and osteoblast differentiation in MSCs were studied. Finally, in vivo experimentation explored bone mineral density, bone mineral content, and the ash weight and dry weight of femoral bone. Results The results revealed that AP significantly promoted cell viability, upregulated cyclin D1 and increased RUNX2, OCN, ALP, and BMP-2 protein levels in MSCs. Moreover, we found that AP notably activated PI3K/AKT and Wnt/β-catenin signalling pathways in MSCs. Additionally, the relative expression level of H19 was upregulated by AP in a dose-dependent manner. The promoting effects of AP on cell proliferation and osteoblast differentiation were reversed by H19 knockdown. Moreover, in vivo experimentation further confirmed the promoting effect of AP on bone formation. Conclusion These data indicate that AP could promote MSC proliferation and osteoblast differentiation by regulating H19. Cite this article: X. Xie, M. Liu, Q. Meng. Angelica polysaccharide promotes proliferation and osteoblast differentiation of mesenchymal stem cells by regulation of long non-coding RNA H19: An animal study. Bone Joint Res 2019;8:323–332. DOI: 10.1302/2046-3758.87.BJR-2018-0223.R2.

Download Full-text

Bone mesenchymal stem cells derived extracellular vesicles promotes TRAIL-related apoptosis of hepatocellular carcinoma cells via the delivery of microRNA-20a-3p

Cancer Biomarkers ◽

10.3233/cbm-201633 ◽

2020 ◽

pp. 1-13

Author(s):

Lu Deng ◽

Chang Wang ◽

Chao He ◽

Li Chen

Keyword(s):

Hepatocellular Carcinoma ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Conditioned Medium ◽

Extracellular Vesicles ◽

Cell Apoptosis ◽

Bone Mesenchymal Stem Cells ◽

Hcc Cells

OBJECTIVE: Bone mesenchymal stem cells (BMSCs) have been widely researched in cancer treatment, including hepatocellular carcinoma (HCC). This study intended to discuss the mechanism of miR-20a-3p in BMSCs-extracellular vesicles (EVs) in HCC apoptosis. METHODS: BMSCs were isolated and identified. EVs derived from BMSCs were extracted and identified. After overexpressing or inhibiting miR-20a-3p expression in BMSCs, EVs were extracted and acted on HCC cells and transplanted tumors. HCC cell apoptosis in the treatment of BMSCs-conditioned medium, BMSCs-EVs and/or miR-20a-3p mimic/inhibitor were evaluated, with the detection of levels of TRAIL and TRAIL-related proteins. A functional rescue experiment about c-FLIP was carried out in HCC cells. The target binding relationship between miR-20a-3p and c-FLIP was detected. The subcutaneous tumorigenesis model of mice was established and injected with BMSCs-EVs to estimate the effect of BMSCs-EVs-miR-20a-3p on HCC growth. RESULTS: EVs isolated from BMSCs conditioned medium promoted the apoptosis of HCC cells. After BMSCs-EVs treatment, TRAIL levels, downstream proteins and miR-20a-3p were increased significantly, but the expression of c-FLIP was decreased. miR-20a-3p could target c-FLIP. BMSCs-EVs inhibited the growth of HCC cells, decreased c-FLIP expression, increased TRAIL levels, and promote the of HCC cell apoptosis. BMSCs-EVs with overexpressing miR-20a-3p further enhanced the apoptotic effect of HCC cells in vitro and in vivo. CONCLUSION: BMSCs-EVs-carried miR-20a-3p targets c-FLIP and increases TRAIL levels in HCC cells, thus promoting TRAIL-related apoptosis.

Download Full-text