IFN-γ-Secreting-Mesenchymal Stem Cells Exert an Antitumor EffectIn Vivovia the TRAIL Pathway

Mesenchymal stem cells (MSCs) can exhibit either prooncogenic or antitumor properties depending on the context. Based on our previous study, we hypothesized that MSCs engineered to deliver IFN-γwould kill cancer cells through persistent activation of the TRAIL pathway. Human bone-marrow (BM-) derived MSCs were isolated, amplified, and transduced with a lentiviral vector encoding the IFN-γgene under the control of the EF1αpromoter. The IFN-γ-modified MSCs effectively secreted functional IFN-γ, which led to long-term expression of TRAIL. More importantly, the IFN-γ-modified MSCs selectively induced apoptosis in lung tumor cells through caspase-3 activation within the target cells. The percentage of activated-caspase-3-positive tumor cells in IFN-γ-modified MSCs cocultures was significantly higher than in control MSCs cocultures. Treatment with anti-TRAIL antibody dramatically suppressed the caspase-3 activation observed in H460 cells. After injection into nude mice, the IFN-γ-modified MSCs inhibited the growth and progression of lung carcinoma compared with control cells. Collectively, our results provide a new strategy for tumor therapy that utilizes IFN-γ-modified MSCs.

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PTPN21 Overexpression Promotes Osteogenic and Adipogenic Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells but Inhibits the Immunosuppressive Function

Stem Cells International ◽

10.1155/2019/4686132 ◽

2019 ◽

Vol 2019 ◽

pp. 1-19 ◽

Cited By ~ 1

Author(s):

Huafang Wang ◽

Xiaohang Ye ◽

Haowen Xiao ◽

Ni Zhu ◽

Cong Wei ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Bone Marrow ◽

Endothelial Cells ◽

Mesenchymal Stem Cells ◽

Tumor Cells ◽

Vascular Endothelial Cells ◽

Adipogenic Differentiation ◽

Target Cells ◽

Vascular Endothelial

Protein tyrosine phosphatases (PTPs) act as key regulators in various cellular processes such as proliferation, differentiation, and migration. Our previous research demonstrated that non-receptor-typed PTP21 (PTPN21), a member of the PTP family, played a critical role in the proliferation, cell cycle, and chemosensitivity of acute lymphoblastic leukemia cells. However, the role of PTPN21 in the bone marrow microenvironment has not yet been elucidated. In the study, we explored the effects of PTPN21 on human bone marrow-derived mesenchymal stem cells (BM-MSCs) via lentiviral-mediated overexpression and knock-down of PTPN21 in vitro. Overexpressing PTPN21 in BM-MSCs inhibited the proliferation through arresting cell cycle at the G0 phase but rendered them a higher osteogenic and adipogenic differentiation potential. In addition, overexpressing PTPN21 in BM-MSCs increased their senescence levels through upregulation of P21 and P53 and dramatically changed the levels of crosstalk with their typical target cells including immunocytes, tumor cells, and vascular endothelial cells. BM-MSCs overexpressing PTPN21 had an impaired immunosuppressive function and an increased capacity of recruiting tumor cells and vascular endothelial cells in a chemotaxis transwell coculture system. Collectively, our data suggested that PTPN21 acted as a pleiotropic factor in modulating the function of human BM-MSCs.

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GDF11 enhances therapeutic functions of mesenchymal stem cells for angiogenesis

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02519-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Chi Zhang ◽

Yinuo Lin ◽

Ke Zhang ◽

Luyang Meng ◽

Xinyang Hu ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Growth Factor ◽

Transforming Growth Factor ◽

Lentiviral Vector ◽

Retention Rate ◽

Antibody Array ◽

Mouse Bone Marrow ◽

Control Mscs

Abstract Background The efficacy of stem cell therapy for ischemia repair has been limited by low cell retention rate. Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor-β super family, which has multiple effects on development, physiology and diseases. The objective of the study is to investigate whether GDF11 could affect the efficacy of stem cell transplantation. Methods We explored the effects of GDF11 on proangiogenic activities of mesenchymal stem cells (MSCs) for angiogenic therapy in vitro and in vivo. Results Mouse bone marrow-derived MSCs were transduced with lentiviral vector to overexpress GDF11 (MSCGDF11). After exposed to hypoxia and serum deprivation for 48 h, MSCGDF11 were significantly better in viability than control MSCs (MSCvector). MSCGDF11 also had higher mobility and better angiogenic paracrine effects. The cytokine antibody array showed more angiogenic cytokines in the conditioned medium of MSCGDF11 than that of MSCvector, such as epidermal growth factor, platelet-derived growth factor-BB, placenta growth factor. When MSCs (1 × 106 cells in 50 μl) were injected into ischemic hindlimb of mice after femoral artery ligation, MSCGDF11 had higher retention rate in the muscle than control MSCs. Injection of MSCGDF11 resulted in better blood reperfusion and limb salvage than that of control MSCs after 14 days. Significantly more CD31+ endothelial cells and α-SMA + smooth muscle cells were detected in the ischemic muscles that received MSCGDF11. The effects of GDF11 were through activating TGF-β receptor and PI3K/Akt signaling pathway. Conclusion Our study demonstrated an essential role of GDF11 in promoting therapeutic functions of MSCs for ischemic diseases by enhancing MSC viability, mobility, and angiogenic paracrine functions.

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Puerarin Relieved Compression-Induced Apoptosis and Mitochondrial Dysfunction in Human Nucleus Pulposus Mesenchymal Stem Cells via the PI3K/Akt Pathway

Stem Cells International ◽

10.1155/2020/7126914 ◽

2020 ◽

Vol 2020 ◽

pp. 1-16 ◽

Cited By ~ 3

Author(s):

Donghua Huang ◽

Yizhong Peng ◽

Kaige Ma ◽

Xiangcheng Qing ◽

Xiangyu Deng ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cell Viability ◽

Mitochondrial Dysfunction ◽

Nucleus Pulposus ◽

Caspase 3 ◽

Akt Pathway ◽

Ros Accumulation ◽

Induced Apoptosis ◽

Apoptosis Level

Puerarin (PUR), an 8-C-glucoside of daidzein extracted from Pueraria plants, is closely related to autophagy, reduced reactive oxygen species (ROS) production, and anti-inflammatory effects, but its effects on human nucleus pulposus mesenchymal stem cells (NPMSCs) have not yet been identified. In this study, NPMSCs were cultured in a compression apparatus to simulate the microenvironment of the intervertebral disc under controlled pressure (1.0 MPa), and we found that cell viability was decreased and apoptosis level was gradually increased as compression duration was prolonged. After PUR administration, apoptosis level evaluated by flow cytometry and caspase-3 activity was remitted, and protein levels of Bas as well as cleaved caspase-3 were decreased, while elevated Bcl-2 level was identified. Moreover, ATP production detection, ROS, and JC-1 fluorography as well as quantitative analysis suggested that PUR could attenuate intercellular ROS accumulation and mitochondrial dysfunction. Besides, the rat tail compression model was utilized, which indicated that PUR could restore impaired nucleus pulposus degeneration induced by compression. The PI3K/Akt pathway was identified to be deactivated after compression stimulation by western blot, and PUR could rescue the phosphorylation of Akt, thus reactivating the pathway. The effects of PUR, such as antiapoptosis, cell viability restoration, antioxidation, and mitochondrial maintenance, were all counteracted by application of the PI3K/Akt pathway inhibitor (LY294002). Summarily, PUR could alleviate compression-induced apoptosis and cell death of human NPMSCs in vitro as well as on the rat compression model and maintain intracellular homeostasis by stabilizing mitochondrial membrane potential and attenuating ROS accumulation through activating the PI3K/Akt pathway.

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Human Mesenchymal Stem Cells of Diverse Origins Support Persistent Infection with Kaposi’s Sarcoma-Associated Herpesvirus and Manifest Distinct Angiogenic, Invasive, and Transforming Phenotypes

mBio ◽

10.1128/mbio.02109-15 ◽

2016 ◽

Vol 7 (1) ◽

Cited By ~ 12

Author(s):

Myung-Shin Lee ◽

Hongfeng Yuan ◽

Hyungtaek Jeon ◽

Ying Zhu ◽

Seungmin Yoo ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Cells ◽

Malignant Transformation ◽

Kaposi's Sarcoma ◽

Human Mesenchymal Stem Cells ◽

Kaposi’S Sarcoma ◽

Target Cells ◽

Kshv Infection ◽

Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT Kaposi’s sarcoma (KS), a highly angiogenic and invasive tumor often involving different organ sites, including the oral cavity, is caused by infection with Kaposi’s sarcoma-associated herpesvirus (KSHV). Diverse cell markers have been identified on KS tumor cells, but their origin remains an enigma. We previously showed that KSHV could efficiently infect, transform, and reprogram rat primary mesenchymal stem cells (MSCs) into KS-like tumor cells. In this study, we showed that human primary MSCs derived from diverse organs, including bone marrow (MSCbm), adipose tissue (MSCa), dental pulp, gingiva tissue (GMSC), and exfoliated deciduous teeth, were permissive to KSHV infection. We successfully established long-term cultures of KSHV-infected MSCa, MSCbm, and GMSC (LTC-KMSCs). While LTC-KMSCs had lower proliferation rates than the uninfected cells, they expressed mixtures of KS markers and displayed differential angiogenic, invasive, and transforming phenotypes. Genetic analysis identified KSHV-derived microRNAs that mediated KSHV-induced angiogenic activity by activating the AKT pathway. These results indicated that human MSCs could be the KSHV target cells in vivo and established valid models for delineating the mechanism of KSHV infection, replication, and malignant transformation in biologically relevant cell types. IMPORTANCE Kaposi’s sarcoma is the most common cancer in AIDS patients. While KSHV infection is required for the development of Kaposi’s sarcoma, the origin of KSHV target cells remains unclear. We show that KSHV can efficiently infect human primary mesenchymal stem cells of diverse origins and reprogram them to acquire various degrees of Kaposi’s sarcoma-like cell makers and angiogenic, invasive, and transforming phenotypes. These results indicate that human mesenchymal stem cells might be the KSHV target cells and establish models for delineating the mechanism of KSHV-induced malignant transformation.

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Mesenchymal stem cells-conditioned medium protects PC12 cells against 2,5-hexanedione-induced apoptosis via inhibiting mitochondria-dependent caspase 3 pathway

Toxicology and Industrial Health ◽

10.1177/0748233715598267 ◽

2016 ◽

Vol 33 (2) ◽

pp. 107-118 ◽

Cited By ~ 9

Author(s):

Shuang-yue Li ◽

Yuan Qi ◽

Shu-hai Hu ◽

Feng-yuan Piao ◽

Huai Guan ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cytochrome C ◽

Conditioned Medium ◽

Pc12 Cells ◽

Caspase 3 ◽

Transmembrane Potential ◽

Mitochondrial Transmembrane Potential ◽

Neural Cells ◽

Induced Apoptosis

Studies suggested that the conditioned medium of mesenchymal stem cells (MSC-CM) inhibited the increased apoptosis in various cells. However, there are no reports underlying the protection of MSC-CM against 2,5-hexanedione (HD)-induced apoptosis in neural cells. In the present study, the viability was observed in PC12 cells that received HD alone or with MSC-CM by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptosis was estimated by Hoechst 33342 staining and flow cytometry. Mitochondrial transmembrane potential was examined by rhodamine 123. Moreover, we investigated the expression of Bax and Bcl-2, cytochrome c translocation, and caspase 3 activity by real-time polymerase chain reaction, Western blot, and immunochemistry. Nerve growth factor (NGF) was examined in MSCs and MSC-CM. Our results showed that MSC-CM promoted cell survival and reduced apoptosis in HD-exposed PC12 cells. Moreover, MSC-CM significantly reversed disturbance of Bax and Bcl-2, ameliorated disruption of mitochondrial transmembrane potential, and reduced release of cytochrome c and activity of caspase 3 in HD-exposed PC12 cells. In the meantime, NGF was detected in MSCs and MSC-CM. These findings demonstrate that MSC-CM protects against HD-induced apoptosis in PC12 cells via inhibiting mitochondrial pathway. Our results indicate that NGF in MSC-CM may be involved in the protection of MSC-CM against HD-induced apoptosis. Our study clarifies the protection of MSC-CM on HD neurotoxicity and its underlying mechanism.

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2,5-hexanedione induced apoptosis in mesenchymal stem cells from rat bone marrow via mitochondria-dependent caspase-3 pathway

Industrial Health ◽

10.2486/indhealth.2014-0182 ◽

2015 ◽

Vol 53 (3) ◽

pp. 222-235 ◽

Cited By ~ 20

Author(s):

Ruolin CHEN ◽

Shuang LIU ◽

Fengyuan PIAO ◽

Zhemin WANG ◽

Yuan QI ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Caspase 3 ◽

Induced Apoptosis ◽

Rat Bone

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Let-7f miRNA regulates SDF-1α- and hypoxia-promoted migration of mesenchymal stem cells and attenuates mammary tumor growth upon exosomal release

Cell Death and Disease ◽

10.1038/s41419-021-03789-3 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Virginia Egea ◽

Kai Kessenbrock ◽

Devon Lawson ◽

Alexander Bartelt ◽

Christian Weber ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Growth ◽

Molecular Mechanisms ◽

Hypoxia Inducible Factor ◽

Human Mesenchymal Stem Cells ◽

Target Cells ◽

Autophagic Flux ◽

Stromal Cell Derived Factor

AbstractBone marrow-derived human mesenchymal stem cells (hMSCs) are recruited to damaged or inflamed tissues where they contribute to tissue repair. This multi-step process involves chemokine-directed invasion of hMSCs and on-site release of factors that influence target cells or tumor tissues. However, the underlying molecular mechanisms are largely unclear. Previously, we described that microRNA let-7f controls hMSC differentiation. Here, we investigated the role of let-7f in chemotactic invasion and paracrine anti-tumor effects. Incubation with stromal cell-derived factor-1α (SDF-1α) or inflammatory cytokines upregulated let-7f expression in hMSCs. Transfection of hMSCs with let-7f mimics enhanced CXCR4-dependent invasion by augmentation of pericellular proteolysis and release of matrix metalloproteinase-9. Hypoxia-induced stabilization of the hypoxia-inducible factor 1 alpha in hMSCs promoted cell invasion via let-7f and activation of autophagy. Dependent on its endogenous level, let-7f facilitated hMSC motility and invasion through regulation of the autophagic flux in these cells. In addition, secreted let-7f encapsulated in exosomes was increased upon upregulation of endogenous let-7f by treatment of the cells with SDF-1α, hypoxia, or induction of autophagy. In recipient 4T1 tumor cells, hMSC-derived exosomal let-7f attenuated proliferation and invasion. Moreover, implantation of 3D spheroids composed of hMSCs and 4T1 cells into a breast cancer mouse model demonstrated that hMSCs overexpressing let-7f inhibited tumor growth in vivo. Our findings provide evidence that let-7f is pivotal in the regulation of hMSC invasion in response to inflammation and hypoxia, suggesting that exosomal let-7f exhibits paracrine anti-tumor effects.

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