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Zhang L, Qiang W, Li MQ, Wang SJ, Jia W, Wang R, Bai SW, Wang QF, Wang HY. A drug delivery system of HIF-1α siRNA nanoparticles loaded by mesenchymal stem cells on choroidal neovascularization. Nanomedicine (Lond) 2024; 19:2171-2185. [PMID: 39225143 PMCID: PMC11485800 DOI: 10.1080/17435889.2024.2393075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 08/13/2024] [Indexed: 09/04/2024] Open
Abstract
Aim: To assess mesenchymal stem cells (MSCs) as carriers for HIF-1α siRNA-loaded nanoparticles (NPs) for targeted therapy of experimental choroidal neovascularization (CNV).Materials & methods: A poly (lactic-co-glycolic acid) (PLGA)-core/lipid-shell hybrid NP was designed. The transfection efficacy of MSCs with the hybrid NPs was assessed. Mice were intravenously injected with MSCs after laser photocoagulation and CNV was assessed at 7 days post-injection.Results & conclusion: The transfection efficiency of hybrid NPs into MSCs was 72.7%. HIF-1α mRNA expression in 661w cells co-cultured with MSC-hybrid-siRNA NPs was significantly lower. Intravenous delivery of MSC-hybrid-siRNA NPs greatly reduced CNV area and length. Intravenous injection of MSC-hybrid-siRNA NPs achieved therapeutic efficacy in reducing CNV area. The MSC-mediated homing enabled targeted inhibition of ocular angiogenesis.
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Affiliation(s)
- Lei Zhang
- Xi'an Key Laboratory of Digital Medical Technology of Ophthalmologic Imaging, Shaanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, 710004, Shaanxi, China
| | - Wei Qiang
- Xi'an Key Laboratory of Digital Medical Technology of Ophthalmologic Imaging, Shaanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, 710004, Shaanxi, China
| | - Mu-Qiong Li
- Department of Pharmaceutical Chemistry & Analysis Pharmacy, Air Force Medical University, Xi'an, 710032, Shaanxi Province, China
| | - Si-Jia Wang
- Institute of Biomedical Photonics & Sensors, School of Life Science & Technology, Key Laboratory of Biomedical Information Engineering of Ministry of Education, Xi'an Jiaotong University, Xi'an, 710049, Shaanxi Province, China
| | - Wei Jia
- Xi'an Key Laboratory of Digital Medical Technology of Ophthalmologic Imaging, Shaanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, 710004, Shaanxi, China
| | - Ru Wang
- Xi'an Key Laboratory of Digital Medical Technology of Ophthalmologic Imaging, Shaanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, 710004, Shaanxi, China
| | - Shu-Wei Bai
- Xi'an Key Laboratory of Digital Medical Technology of Ophthalmologic Imaging, Shaanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, 710004, Shaanxi, China
| | - Qian-Feng Wang
- Medical College of Optometry & Ophthalmology, Shandong University of Traditional Chinese Medicine, Jinan, 250000, Shandong Province, China
| | - Hai-Yan Wang
- Xi'an Key Laboratory of Digital Medical Technology of Ophthalmologic Imaging, Shaanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, 710004, Shaanxi, China
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Yang Y, Wen W, Chen FL, Zhang YJ, Liu XC, Yang XY, Hu SS, Jiang Y, Yuan J. Expression and significance of pigment epithelium-derived factor and vascular endothelial growth factor in colorectal adenoma and cancer. World J Gastrointest Oncol 2024; 16:670-686. [PMID: 38577437 PMCID: PMC10989378 DOI: 10.4251/wjgo.v16.i3.670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/16/2024] [Accepted: 02/04/2024] [Indexed: 03/12/2024] Open
Abstract
BACKGROUND The incidence and mortality of colorectal cancer (CRC) are among the highest in the world, and its occurrence and development are closely related to tumor neovascularization. When the balance between pigment epithelium-derived factors (PEDF) that inhibit angiogenesis and vascular endothelial growth factors (VEGF) that stimulate angiogenesis is broken, angiogenesis is out of control, resulting in tumor development. Therefore, it is very necessary to find more therapeutic targets for CRC for early intervention and later treatment. AIM To investigate the expression and significance of PEDF, VEGF, and CD31-stained microvessel density values (CD31-MVD) in normal colorectal mucosa, adenoma, and CRC. METHODS In this case-control study, we collected archived wax blocks of specimens from the Digestive Endoscopy Center and the General Surgery Department of Chengdu Second People's Hospital from April 2022 to October 2022. Fifty cases of specimen wax blocks were selected as normal intestinal mucosa confirmed by electronic colonoscopy and concurrent biopsy (normal control group), 50 cases of specimen wax blocks were selected as colorectal adenoma confirmed by electronic colonoscopy and pathological biopsy (adenoma group), and 50 cases of specimen wax blocks were selected as CRC confirmed by postoperative pathological biopsy after inpatient operation of general surgery (CRC group). An immunohistochemical staining experiment was carried out to detect PEDF and VEGF expression in three groups of specimens, analyze their differences, study the relationship between the two and clinicopathological factors in CRC group, record CD31-MVD in the three groups, and analyze the correlation of PEDF, VEGF, and CD31-MVD in the colorectal adenoma group and the CRC group. The F test or adjusted F test is used to analyze measurement data statistically. Kruskal-Wallis rank sum test was used between groups for ranked data. The chi-square test, adjusted chi-square test, or Fisher's exact test were used to compare the rates between groups. All differences between groups were compared using the Bonferroni method for multiple comparisons. Spearman correlation analysis was used to test the correlation of the data. The test level (α) was 0.05, and a two-sided P< 0.05 was considered statistically significant. RESULTS The positive expression rate and expression intensity of PEDF were gradually decreased in the normal control group, adenoma group, and CRC group (100% vs 78% vs 50%, χ2 = 34.430, P < 0.001; ++~++ vs +~++ vs -~+, H = 94.059, P < 0.001), while VEGF increased gradually (0% vs 68% vs 96%, χ2 = 98.35, P < 0.001; - vs -~+ vs ++~+++, H = 107.734, P < 0.001). In the CRC group, the positive expression rate of PEDF decreased with the increase of differentiation degree, invasion depth, lymph node metastasis, distant metastasis, and TNM stage (χ2 = 20.513, 4.160, 5.128, 6.349, 5.128, P < 0.05); the high expression rate of VEGF was the opposite (χ2 = 10.317, 13.134, 17.643, 21.844, 17.643, P < 0.05). In the colorectal adenoma group, the expression intensity of PEDF correlated negatively with CD31-MVD (r = -0.601, P < 0.001), whereas VEGF was not significantly different (r = 0.258, P = 0.07). In the CRC group, the expression intensity of PEDF correlated negatively with the expression intensity of CD31-MVD and VEGF (r = -0.297, P < 0.05; r = -0.548, P < 0.05), while VEGF expression intensity was positively related to CD31-MVD (r = 0.421, P = 0.002). CONCLUSION It is possible that PEDF can be used as a new treatment and prevention target for CRC by upregulating the expression of PEDF while inhibiting the expression of VEGF.
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Affiliation(s)
- Ye Yang
- Digestive Diseases, Chengdu Qingbaijiang District People's Hospital, Chengdu 610300, Sichuan Province, China
| | - Wu Wen
- Digestive Diseases, Chengdu Second People’s Hospital, Chengdu 610000, Sichuan Province, China
| | - Feng-Lin Chen
- Graduate School, Chengdu Medical College, Chengdu 610000, Sichuan Province, China
| | - Ying-Jie Zhang
- Digestive Diseases, Chengdu Second People’s Hospital, Chengdu 610000, Sichuan Province, China
| | - Xiao-Cong Liu
- Digestive Diseases, Chengdu Second People’s Hospital, Chengdu 610000, Sichuan Province, China
| | - Xiao-Yan Yang
- Digestive Diseases, Chengdu Second People’s Hospital, Chengdu 610000, Sichuan Province, China
| | - Shan-Shan Hu
- Digestive Diseases, Chengdu Second People’s Hospital, Chengdu 610000, Sichuan Province, China
| | - Ye Jiang
- Digestive Diseases, Chengdu Second People’s Hospital, Chengdu 610000, Sichuan Province, China
| | - Jing Yuan
- Digestive Diseases, Chengdu Second People’s Hospital, Chengdu 610000, Sichuan Province, China
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Gao P, Luo X, Yin B, Jiao Z, Piao J, Zhao A, Yang P. Effects of Coupled-/soluble-Copper, Generating from Copper-doped Titanium Dioxide Nanotubes on Cell Response. RECENT PATENTS ON NANOTECHNOLOGY 2023; 17:150-158. [PMID: 35034600 DOI: 10.2174/1872210516666220114120412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 08/24/2021] [Accepted: 11/30/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND Endothelialization in vitro is a very common method for surface modification of cardiovascular materials. However, mature endothelial cells are not suitable because of the difficulty in obtaining and immunogenicity. METHODS In this patent work, we determined the appropriate amount of copper by constructing a copper- loaded titanium dioxide nanotube array that can catalyze the release of nitric oxide, compared the effects of coupled-/soluble-copper on stem cells, and then induced stem cells to differentiate into endothelial cells. RESULTS The results showed that it had a strong promotion effect on the differentiation of stem cells into endothelial cells, which might be used for endothelialization in vitro. CONCLUSION SEM and EDS results prove that a high content of copper ions are indeed doped onto the surface of nanotubes with small amounts of Cu release. The release of NO confirms that the release of several samples within a period of time is within the physiological concentration.
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Affiliation(s)
- Pengyu Gao
- Key Lab. for Advanced Technologies of Materials, Ministry of Education, School of Material Sciences and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, P.R. China
| | - Xiao Luo
- Key Lab. for Advanced Technologies of Materials, Ministry of Education, School of Material Sciences and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, P.R. China
| | - Benli Yin
- Key Lab. for Advanced Technologies of Materials, Ministry of Education, School of Material Sciences and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, P.R. China
| | - Zhisha Jiao
- Nanyang Grain and Oil Quality Inspection Center, Nanyang, Henan, P.R. China
| | - JunJi Piao
- Department of Materials Science and Engineering, Chonnam National University, Gwangju, South Korea
| | - Ansha Zhao
- Key Lab. for Advanced Technologies of Materials, Ministry of Education, School of Material Sciences and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, P.R. China
| | - Ping Yang
- Key Lab. for Advanced Technologies of Materials, Ministry of Education, School of Material Sciences and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, P.R. China
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Shahbazi B, Arab SS, Mafakher L, Azadmansh K, Teimoori-Toolabi L. Computational assessment of pigment epithelium-derived factor as an anti-cancer protein during its interaction with the receptors. J Biomol Struct Dyn 2022:1-17. [PMID: 35510592 DOI: 10.1080/07391102.2022.2069863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Pigment epithelium-derived factor (PEDF) is a member of the serine proteinase inhibitor (serpin) with antiangiogenic, anti-tumorigenic, antioxidant, anti-atherosclerosis, antithrombotic, anti-inflammatory, and neuroprotective properties. The PEDF can bind to low-density lipoprotein receptor-related protein 6 (LRP6), laminin (LR), vascular endothelial growth factor receptor 1 (VEGFR1), vascular endothelial growth factor receptor 2 (VEGFR2), and ATP synthase β-subunit receptors. In this study, we aimed to investigate the structural basis of the interaction between PEDF and its receptors using bioinformatics approaches to identify the critical amino acids for designing anticancer peptides. The human ATP synthase β-subunit was predicted by homology modeling. The molecular docking, molecular dynamics (MD) simulation, and Molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) were used to study this protein-receptor complex. The molecular docking showed PEDF could bind to the Laminin and VEGFR2 much stronger than ATP synthase β-subunit, VEGFR1, and LRP6. The PEDF could effectively interact with various receptors during the simulation. The N-terminal of PEDF has an important role in the interaction with the receptors. The MM/PBSA showed the electrostatic (ΔEElec) and van der Waals interactions (ΔEVdW) contributed positively to the binding process of the complexes. The critical amino acids in the binding interaction of PEDF to its receptors in the MD simulation were determined. The interaction mode of 34-mer PEDF to laminin, VEGFR2, and LRP6 were different from VEGFR1, ATP synthase β-subunit. The 34-mer PEDF has an important role in the interaction with different receptors and these critical amino acids can be used for designing peptides for future therapeutic aims.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Behzad Shahbazi
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Seyed Shahriar Arab
- Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ladan Mafakher
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | | | - Ladan Teimoori-Toolabi
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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Kang Y, Xu C, Meng L, Dong X, Qi M, Jiang D. Exosome-functionalized magnesium-organic framework-based scaffolds with osteogenic, angiogenic and anti-inflammatory properties for accelerated bone regeneration. Bioact Mater 2022; 18:26-41. [PMID: 35387167 PMCID: PMC8961306 DOI: 10.1016/j.bioactmat.2022.02.012] [Citation(s) in RCA: 88] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 02/08/2022] [Accepted: 02/08/2022] [Indexed: 12/12/2022] Open
Abstract
Exosomes derived from human adipose-derived stem cells (hADSCs-Exos) have shown potential as an effective therapeutic tool for repairing bone defects. Although metal-organic framework (MOF) scaffolds are promising strategies for bone tissue regeneration, their potential use for exosome loading remains unexplored. In this study, motivated by the potential advantages of hADSCs-Exos and Mg-GA MOF, we designed and synthesized an exosome-functionalized cell-free PLGA/Mg-GA MOF (PLGA/Exo-Mg-GA MOF) scaffold, taking using of the benefits of hADSCs-Exos, Mg2+, and gallic acid (GA) to construct unique nanostructural interfaces to enhance osteogenic, angiogenic and anti-inflammatory capabilities simultaneously. Our in vitro work demonstrated the beneficial effects of PLGA/Exo-Mg-GA MOF composite scaffolds on the osteogenic effects in human bone marrow-derived mesenchymal stem cells (hBMSCs) and angiogenic effects in human umbilical endothelial cells (HUVECs). Slowly released hADSCs-Exos from composite scaffolds were phagocytosed by co-cultured cells, stabilized the bone graft environment, ensured blood supply, promoted osteogenic differentiation, and accelerated bone reconstruction. Furthermore, our in vivo experiments with rat calvarial defect model showed that PLGA/Exo-Mg-GA MOF scaffolds promoted new bone formation and satisfactory osseointegration. Overall, we provide valuable new insights for designing exosome-coated nanocomposite scaffolds with enhanced osteogenesis property.
PLGA/Exo-Mg-GA MOF scaffolds with nanostructures were synthesized, on which exosomes were densely deposited on the above scaffolds. Composite scaffolds with exosomes can actualize the slow release of exosomes, Mg ions and gallic acid. PLGA/Exo-Mg-GA MOF scaffolds exhibit great biocompatibility and osteogenic differentiation of hBMSCs. PLGA/Exo-Mg-GA MOF scaffolds have excellent osteogenic, pro-angiogenic and anti-inflammatory activity.
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Zhang M, Tombran-Tink J, Yang S, Zhang X, Li X, Barnstable CJ. PEDF is an endogenous inhibitor of VEGF-R2 angiogenesis signaling in endothelial cells. Exp Eye Res 2021; 213:108828. [PMID: 34742690 DOI: 10.1016/j.exer.2021.108828] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 10/20/2021] [Accepted: 11/01/2021] [Indexed: 01/03/2023]
Abstract
Pigment epithelium derived factor (PEDF), an endogenous inhibitor of angiogenesis, targets the growth of aberrant blood vessels in many tissues, including the eye. In this study we show that PEDF prevented early mitogenic signals of vascular endothelial growth factor (VEGF-A) in primate retinal endothelial cells, blocking proliferation, migration and tube formation. PEDF inhibited the phosphorylation and activation of five major downstream VEGF-A signaling partners, namely phosphoinositide-3-OH Kinase (PI3K), AKT, FAK, Src (Y416), and PLC-γ. It did so by binding to the extracellular domain of VEGF-R2, blocking VEGF-A-induced tyrosine phosphorylation (Tyr 951 and Tyr 1175), and inhibiting VEGF-R2 receptor kinase activity. PEDF had no effect on the transcription or translation of VEGF-R2 in cultured HUVECs. PEDF also bound to the extracellular domain of VEGF-R1. We conclude that PEDF blocks the growth of new blood vessels, in part, by reducing VEGF-A activation of its key mitogenic receptor, VEGF-R2, and by preventing its downstream signals in endothelial cells.
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Affiliation(s)
- Mingliang Zhang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, 251 Fukang Road, Tianjin, 300384, China
| | - Joyce Tombran-Tink
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, 251 Fukang Road, Tianjin, 300384, China; Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, 17033, USA.
| | - Songyang Yang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, 251 Fukang Road, Tianjin, 300384, China
| | - Xiaomin Zhang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, 251 Fukang Road, Tianjin, 300384, China.
| | - Xiaorong Li
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, 251 Fukang Road, Tianjin, 300384, China.
| | - Colin J Barnstable
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, 251 Fukang Road, Tianjin, 300384, China; Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, 17033, USA.
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Ko VH, Yu LJ, Secor JD, Pan A, Mitchell PD, Kishikawa H, Puder M. Deficiency in pigment epithelium-derived factor accelerates pulmonary growth and development in a compensatory lung growth model. FASEB J 2021; 35:e21850. [PMID: 34569654 DOI: 10.1096/fj.202002661rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 07/26/2021] [Accepted: 07/28/2021] [Indexed: 01/05/2023]
Abstract
Children with hypoplastic lung disease associated with congenital diaphragmatic hernia (CDH) continue to suffer significant morbidity and mortality secondary to progressive pulmonary disease. Recently published work from our lab demonstrated the potential of Roxadustat (FG-4592), a prolyl hydroxylase inhibitor, as a treatment for CDH-associated pulmonary hypoplasia. Treatment with Roxadustat led to significantly accelerated compensatory lung growth (CLG) through downregulation of pigment epithelium-derived factor (PEDF), an anti-angiogenic factor, rather than upregulation of vascular endothelial growth factor (VEGF). PEDF and its role in pulmonary development is a largely unexplored field. In this study, we sought to further evaluate the role of PEDF in accelerating CLG. PEDF-deficient mice demonstrated significantly increased lung volume, total lung capacity, and alveolarization compared to wild type controls following left pneumonectomy without increased VEGF expression. Furthermore, Roxadustat administration in PEDF-deficient mice did not further accelerate CLG. Human microvascular endothelial lung cells (HMVEC-L) and human pulmonary alveolar epithelial cells (HPAEC) similarly demonstrated decreased PEDF expression with Roxadustat administration. Additionally, downregulation of PEDF in Roxadustat-treated HMVEC-L and HPAEC, a previously unreported finding, speaks to the potential translatability of Roxadustat from small animal studies. Taken together, these findings further suggest that PEDF downregulation is the primary mechanism by which Roxadustat accelerates CLG. More importantly, these data highlight the critical role PEDF may have in pulmonary growth and development, a previously unexplored field.
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Affiliation(s)
- Victoria H Ko
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Lumeng J Yu
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jordan D Secor
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Amy Pan
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Paul D Mitchell
- Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Hiroko Kishikawa
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Mark Puder
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Kreps LM, Addison CL. Targeting Intercellular Communication in the Bone Microenvironment to Prevent Disseminated Tumor Cell Escape from Dormancy and Bone Metastatic Tumor Growth. Int J Mol Sci 2021; 22:ijms22062911. [PMID: 33805598 PMCID: PMC7998601 DOI: 10.3390/ijms22062911] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/06/2021] [Accepted: 03/11/2021] [Indexed: 02/07/2023] Open
Abstract
Metastasis to the bone is a common feature of many cancers including those of the breast, prostate, lung, thyroid and kidney. Once tumors metastasize to the bone, they are essentially incurable. Bone metastasis is a complex process involving not only intravasation of tumor cells from the primary tumor into circulation, but extravasation from circulation into the bone where they meet an environment that is generally suppressive of their growth. The bone microenvironment can inhibit the growth of disseminated tumor cells (DTC) by inducing dormancy of the DTC directly and later on following formation of a micrometastatic tumour mass by inhibiting metastatic processes including angiogenesis, bone remodeling and immunosuppressive cell functions. In this review we will highlight some of the mechanisms mediating DTC dormancy and the complex relationships which occur between tumor cells and bone resident cells in the bone metastatic microenvironment. These inter-cellular interactions may be important targets to consider for development of novel effective therapies for the prevention or treatment of bone metastases.
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Affiliation(s)
- Lauren M. Kreps
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada;
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8L6, Canada
| | - Christina L. Addison
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada;
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8L6, Canada
- Department of Medicine, University of Ottawa, Ottawa, ON K1H 8L6, Canada
- Correspondence: ; Tel.: +1-613-737-7700
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Li J, Zhu Y, Li N, Wu T, Zheng X, Heng BC, Zou D, Xu J. Upregulation of ETV2 Expression Promotes Endothelial Differentiation of Human Dental Pulp Stem Cells. Cell Transplant 2021; 30:963689720978739. [PMID: 33522307 PMCID: PMC7863555 DOI: 10.1177/0963689720978739] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 10/30/2020] [Accepted: 12/12/2020] [Indexed: 11/26/2022] Open
Abstract
The lack of vasculogenesis often hampers the survivability and integration of newly engineered tissue grafts within the host. Autologous endothelial cells (ECs) are an ideal cell source for neovascularization, but they are limited by their scarcity, lack of proliferative capacity, and donor site morbidity upon isolation. The objective of this study was to determine whether differentiation of human dental pulp stem cells (DPSCs) into the endothelial lineage can be enhanced by recombinant ETV2 overexpression. DPSCs were extracted from fresh dental pulp tissues. ETV2 overexpression in DPSCs was achieved by lentiviral infection and cellular morphological changes were evaluated. The mRNA and protein expression levels of endothelial-specific markers were assessed through quantitative real-time polymerase chain reaction, western blot, immunofluorescence staining, and flow cytometry. The tube formation assay and Matrigel plug assay were also performed to evaluate the angiogenic potential of the ETV2-transduced cells in vitro and in vivo, respectively. Additionally, proteomic analysis was performed to analyze global changes in protein expression following ETV2 overexpression. After lentiviral infection, ETV2-overexpressing DPSCs showed endothelial-like morphology. Compared with control DPSCs, significantly higher mRNA and protein expression levels of endothelial-specific genes, including CD31, VE-Cadherin, VEGFR1, and VEGFR2, were detected in ETV2-overexpressing DPSCs. Moreover, ETV2 overexpression enhanced capillary-like tube formation on Matrigel in vitro, as well as neovascularization in vivo. In addition, comparative proteomic profiling showed that ETV2 overexpression upregulated the expression of vascular endothelial growth factor (VEGF) receptors, which was indicative of increased VEGF signaling. Taken together, our results indicate that ETV2 overexpression significantly enhanced the endothelial differentiation of DPSCs. Thus, this study shows that DPSCs can be a promising candidate cell source for tissue engineering applications.
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Affiliation(s)
- Jing Li
- Department of Orthodontics, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, P. R. China
| | - Youming Zhu
- Department of Orthodontics, Stomatologic Hospital & College, Anhui Medical University, Key Lab of Oral Diseases Research of Anhui Province, Hefei, P. R. China
| | - Na Li
- Department of Orthodontics, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, P. R. China
| | - Tao Wu
- Department of Orthodontics, Stomatologic Hospital & College, Anhui Medical University, Key Lab of Oral Diseases Research of Anhui Province, Hefei, P. R. China
| | - Xianyu Zheng
- Department of Orthodontics, Stomatologic Hospital & College, Anhui Medical University, Key Lab of Oral Diseases Research of Anhui Province, Hefei, P. R. China
| | - Boon chin Heng
- Central Laboratories, School of Stomatology, Peking University, Beijing, P. R. China
| | - Duohong Zou
- Department of Oral Surgery, Shanghai Key Laboratory of Stomatology, National Clinical Research Center of Stomatology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China
| | - Jianguang Xu
- Department of Orthodontics, Stomatologic Hospital & College, Anhui Medical University, Key Lab of Oral Diseases Research of Anhui Province, Hefei, P. R. China
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Ding MH, Lozoya EG, Rico RN, Chew SA. The Role of Angiogenesis-Inducing microRNAs in Vascular Tissue Engineering. Tissue Eng Part A 2020; 26:1283-1302. [PMID: 32762306 DOI: 10.1089/ten.tea.2020.0170] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Angiogenesis is an important process in tissue repair and regeneration as blood vessels are integral to supply nutrients to a functioning tissue. In this review, the application of microRNAs (miRNAs) or anti-miRNAs that can induce angiogenesis to aid in blood vessel formation for vascular tissue engineering in ischemic diseases such as peripheral arterial disease and stroke, cardiac diseases, and skin and bone tissue engineering is discussed. Endothelial cells (ECs) form the endothelium of the blood vessel and are recognized as the primary cell type that drives angiogenesis and studied in the applications that were reviewed. Besides ECs, mesenchymal stem cells can also play a pivotal role in these applications, specifically, by secreting growth factors or cytokines for paracrine signaling and/or as constituent cells in the new blood vessel formed. In addition to delivering miRNAs or cells transfected/transduced with miRNAs for angiogenesis and vascular tissue engineering, the utilization of extracellular vesicles (EVs), such as exosomes, microvesicles, and EVs collectively, has been more recently explored. Proangiogenic miRNAs and anti-miRNAs contribute to angiogenesis by targeting the 3'-untranslated region of targets to upregulate proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and hypoxia-inducible factor-1 and increase the transduction of VEGF signaling through the PI3K/AKT and Ras/Raf/MEK/ERK signaling pathways such as phosphatase and tensin homolog or regulating the signaling of other pathways important for angiogenesis such as the Notch signaling pathway and the pathway to produce nitric oxide. In conclusion, angiogenesis-inducing miRNAs and anti-miRNAs are promising tools for vascular tissue engineering for several applications; however, future work should emphasize optimizing the delivery and usage of these therapies as miRNAs can also be associated with the negative implications of cancer.
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Affiliation(s)
- May-Hui Ding
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, Texas, USA
| | - Eloy G Lozoya
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, Texas, USA
| | - Rene N Rico
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, Texas, USA
| | - Sue Anne Chew
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, Texas, USA
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11
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Ko VH, Yu LJ, Dao DT, Li X, Secor JD, Anez-Bustillos L, Cho BS, Pan A, Mitchell PD, Kishikawa H, Puder M. Roxadustat (FG-4592) accelerates pulmonary growth, development, and function in a compensatory lung growth model. Angiogenesis 2020; 23:637-649. [PMID: 32666268 DOI: 10.1007/s10456-020-09735-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 07/06/2020] [Indexed: 12/12/2022]
Abstract
Children with hypoplastic lung disease associated with congenital diaphragmatic hernia (CDH) continue to suffer significant morbidity and mortality secondary to progressive pulmonary disease. Current management of CDH is primarily supportive and mortality rates of the most severely affected children have remained unchanged in the last few decades. Previous work in our lab has demonstrated the importance of vascular endothelial growth factor (VEGF)-mediated angiogenesis in accelerating compensatory lung growth. In this study, we evaluated the potential for Roxadustat (FG-4592), a prolyl hydroxylase inhibitor known to increase endogenous VEGF, in accelerating compensatory lung growth. Treatment with Roxadustat increased lung volume, total lung capacity, alveolarization, and exercise tolerance compared to controls following left pneumonectomy. However, this effect was likely modulated not only by increased VEGF, but rather also by decreased pigment epithelium-derived factor (PEDF), an anti-angiogenic factor. Furthermore, this mechanism of action may be specific to Roxadustat. Vadadustat (AKB-6548), a structurally similar prolyl hydroxylase inhibitor, did not demonstrate accelerated compensatory lung growth or decreased PEDF expression following left pneumonectomy. Given that Roxadustat is already in Phase III clinical studies for the treatment of chronic kidney disease-associated anemia with minimal side effects, its use for the treatment of pulmonary hypoplasia could potentially proceed expeditiously.
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Affiliation(s)
- Victoria H Ko
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.,Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA, 02115, USA
| | - Lumeng J Yu
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.,Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA, 02115, USA
| | - Duy T Dao
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.,Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA, 02115, USA
| | - Xiaoran Li
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.,Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA, 02115, USA
| | - Jordan D Secor
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.,Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA, 02115, USA
| | - Lorenzo Anez-Bustillos
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.,Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA, 02115, USA
| | - Bennet S Cho
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.,Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA, 02115, USA
| | - Amy Pan
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.,Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA, 02115, USA
| | - Paul D Mitchell
- Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, MA, 02115, USA
| | - Hiroko Kishikawa
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.,Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA, 02115, USA
| | - Mark Puder
- Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA. .,Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA, 02115, USA.
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12
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Castilla-Casadiego DA, Reyes-Ramos AM, Domenech M, Almodovar J. Effects of Physical, Chemical, and Biological Stimulus on h-MSC Expansion and Their Functional Characteristics. Ann Biomed Eng 2020; 48:519-535. [PMID: 31705365 PMCID: PMC6952531 DOI: 10.1007/s10439-019-02400-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 10/30/2019] [Indexed: 01/10/2023]
Abstract
Human adult mesenchymal stem or stromal cells (h-MSC) therapy has gained considerable attention due to the potential to treat or cure diseases given their immunosuppressive properties and tissue regeneration capabilities. Researchers have explored diverse strategies to promote high h-MSC production without losing functional characteristics or properties. Physical stimulus including stiffness, geometry, and topography, chemical stimulus, like varying the surface chemistry, and biochemical stimuli such as cytokines, hormones, small molecules, and herbal extracts have been studied but have yet to be translated to industrial manufacturing practice. In this review, we describe the role of those stimuli on h-MSC manufacturing, and how these stimuli positively promote h-MSC properties, impacting the cell manufacturing field for cell-based therapies. In addition, we discuss other process considerations such as bioreactor design, good manufacturing practice, and the importance of the cell donor and ethics factors for manufacturing potent h-MSC.
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Affiliation(s)
- David A Castilla-Casadiego
- Ralph E. Martin Department of Chemical Engineering, University of Arkansas, 3202 Bell Engineering Center, Fayetteville, AR, 72701, USA
| | - Ana M Reyes-Ramos
- Department of Chemical Engineering, University of Puerto Rico Mayagüez, Call Box 9000, Mayagüez, PR, 00681-9000, USA
| | - Maribella Domenech
- Department of Chemical Engineering, University of Puerto Rico Mayagüez, Call Box 9000, Mayagüez, PR, 00681-9000, USA
| | - Jorge Almodovar
- Ralph E. Martin Department of Chemical Engineering, University of Arkansas, 3202 Bell Engineering Center, Fayetteville, AR, 72701, USA.
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13
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Bieri M, Said E, Antonini G, Dickerson D, Tuma J, Bartlett CE, Patel AN, Gershman A. Phase I and registry study of autologous bone marrow concentrate evaluated in PDE5 inhibitor refractory erectile dysfunction. J Transl Med 2020; 18:24. [PMID: 31937310 PMCID: PMC6958721 DOI: 10.1186/s12967-019-02195-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 12/24/2019] [Indexed: 01/09/2023] Open
Abstract
Background Bone marrow mononuclear cells have been successfully utilized for numerous regenerative purposes. In the current study, patients suffering from erectile dysfunction (ED) unresponsive to phosphodiesterase 5 inhibitors were administered autologous bone marrow concentrate delivered intracavernously utilizing a point of care FDA cleared medical device. Methods A total of 40 patients were treated in the primary trial and 100 in the clinical registry, with the longest follow up of 12 months. Results Minimal treatment associated adverse effects where observed related to short term bruising at the site of harvest or injection. No long-term adverse events were noted related to the intervention. Mean improvements in IIEF-5 score were 2 in the Caverstem 1.0 low dose group, 3 in the high dose Caverstem 1.0 group and 9 in the Caverstem 2.0 group. Furthermore, improvements peaked by 3 months and maintained at 6 months follow-up. Conclusion These data support the safety and efficacy of point of care, minimally to non-manipulated, non-expanded bone marrow concentrate for the treatment of ED. Trial registration Funded by Creative Medical Health, Inc.; Clinicaltrials.gov number: NCT03699943; https://clinicaltrials.gov/ct2/show/NCT03699943?term=caverstem&rank=1; initially registered December 12, 2015.
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Affiliation(s)
- Mark Bieri
- Regenerative Health LLC, Las Cruces, NM, USA
| | - Elias Said
- Regenerative Health LLC, Las Cruces, NM, USA
| | | | | | - Jorge Tuma
- Monterrico Clinic & San Felipe Clinic, Lima, Peru
| | | | - Amit N Patel
- University of Utah - Bioengineering, Salt Lake City, UT, USA.
| | - Alexander Gershman
- Institute for Advanced Urology LLC/University of California Los Angeles, Los Angeles, CA, USA
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14
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Brook N, Brook E, Dharmarajan A, Chan A, Dass CR. The role of pigment epithelium-derived factor in protecting against cellular stress. Free Radic Res 2019; 53:1166-1180. [PMID: 31760841 DOI: 10.1080/10715762.2019.1697809] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Since its discovery as a neurotrophic factor in retinal pigmented epithelium cells in the late 1980s, there has been an increase in understanding of the role that pigment epithelium-derived factor (PEDF) plays in cellular functions. PEDF plays an important role in mediating cellular protection during exposure to oxidative stress and inflammation by preventing stress-induced angiogenesis and apoptosis. PEDF acts to reduce oxidative stress by promoting mitochondrial stability and by regulating the expression of enzymes involved in ROS accumulation and clearance. PEDF protects against the negative effects of oxidative stress by regulating cell survival pathways and the expression of inflammatory and proangiogenic mediators. PEDF-mediated cellular protection may be of clinical importance in diseases characterised by oxidative stress, chronic inflammation and pathological neovascularization, indicating that targeting PEDF may be a potential focus for therapeutic interventions in chronic diseases. In this review, we provide a historical perspective on the discoveries of PEDF interactions and functions, and discuss recent in vitro, in vivo and clinical findings to provide a current summary of the important protective effects following cellular exposure to stress stimuli and future clinical potential of PEDF.
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Affiliation(s)
- Naomi Brook
- School of Pharmacy and Biomedical Science, Curtin University, Bentley, Australia.,Curtin Health Innovation Research Institute, Bentley, Australia
| | - Emily Brook
- School of Pharmacy and Biomedical Science, Curtin University, Bentley, Australia.,Curtin Health Innovation Research Institute, Bentley, Australia
| | - Arun Dharmarajan
- School of Pharmacy and Biomedical Science, Curtin University, Bentley, Australia.,Curtin Health Innovation Research Institute, Bentley, Australia.,Department of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research, Chennai, India
| | - Arlene Chan
- Curtin Medical School, Curtin University, Bentley, Australia.,Hollywood Private Hospital, Breast Clinical Trials Unit, Breast Cancer Research Centre-Western Australia, Nedlands, Australia
| | - Crispin R Dass
- School of Pharmacy and Biomedical Science, Curtin University, Bentley, Australia.,Curtin Health Innovation Research Institute, Bentley, Australia
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15
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Abstract
Accumulating evidence demonstrates that pre-vascularization of tissue-engineered constructs can significantly enhance their survival and engraftment upon transplantation. Endothelial cells (ECs), the basic component of vasculatures, are indispensable to the entire process of pre-vascularization. However, the source of ECs still poses an issue. Recent studies confirmed that diverse approaches are available in the derivation of ECs for tissue engineering, such as direct isolation of autologous ECs, reprogramming of somatic cells, and induced differentiation of stem cells in typology. Herein, we discussed a variety of human stem cells (i.e., totipotent, pluripotent, multipotent, oligopotent, and unipotent stem cells), which can be induced to differentiate into ECs and reviewed the multifarious approaches for EC generation, such as 3D EB formation for embryonic stem cells (ESCs), stem cell-somatic cell co-culture, and directed endothelial differentiation with growth factors in conventional 2D culture.
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Affiliation(s)
- Min Xu
- Key Laboratory of Oral Diseases Research of Anhui Province, Stomatological Hospital and College, Anhui Medical University, 69 Meishan Road, Hefei, 230032 Anhui Province China
| | - Jiacai He
- Key Laboratory of Oral Diseases Research of Anhui Province, Stomatological Hospital and College, Anhui Medical University, 69 Meishan Road, Hefei, 230032 Anhui Province China
| | - Chengfei Zhang
- Faculty of Dentistry, The University of Hong Kong, Pokfulam, Hong Kong China
| | - Jianguang Xu
- Key Laboratory of Oral Diseases Research of Anhui Province, Stomatological Hospital and College, Anhui Medical University, 69 Meishan Road, Hefei, 230032 Anhui Province China
- Faculty of Dentistry, The University of Hong Kong, Pokfulam, Hong Kong China
| | - Yuanyin Wang
- Key Laboratory of Oral Diseases Research of Anhui Province, Stomatological Hospital and College, Anhui Medical University, 69 Meishan Road, Hefei, 230032 Anhui Province China
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16
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Sagaradze G, Grigorieva O, Nimiritsky P, Basalova N, Kalinina N, Akopyan Z, Efimenko A. Conditioned Medium from Human Mesenchymal Stromal Cells: Towards the Clinical Translation. Int J Mol Sci 2019; 20:ijms20071656. [PMID: 30987106 PMCID: PMC6479925 DOI: 10.3390/ijms20071656] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 03/29/2019] [Accepted: 03/30/2019] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSC) remain a promising tool for regenerative medicine as the efficacy of MSC-based cell therapy has been demonstrated for a broad spectrum of indications. Their therapeutic potency is mainly associated with their ability to secrete multiple factors critical for tissue regeneration. Due to comparable effects along with superior safety MSC conditioned medium (MSC-CM) containing a complex of MSC-secreted products is considered a reasonable alternative to cell therapy. However, the lack of standards regulating bioprocessing, use of proper auxiliary materials, and quality control complicates the development of MSC secretome-based therapeutics. In this study, we suggested several approaches addressing these issues. We manufactured 36 MSC-CM samples based on different xeno-free serum-free chemically defined media (DMEM-LG or MSC NutriStem® XF) using original protocols and considered total concentrations of regeneration-associated paracrine factors secreted by human adipose-derived MSC at each time-point of conditioning. Using regression analysis, we retrospectively predicted associations between concentrations of several components of MSC-CM and its biological activity to stimulate human dermal fibroblast and endothelial cell migration in vitro as routine examples of potency assays for cell-based products. We also demonstrated that the cell culture medium might affect MSC-CM biological activity to varying degrees depending on the potency assay type. Furthermore, we showed that regression analysis might help to overcome donor variability. The suggested approaches might be successfully applied for other cell types if their secretome was shown to be promising for application in regenerative medicine.
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Affiliation(s)
- Georgy Sagaradze
- Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, 27-10, Lomonosovsky av., Moscow 119191, Russia.
- Faculty of Medicine, Lomonosov Moscow State University, 27-1, Lomonosovsky av., Moscow 119192, Russia.
| | - Olga Grigorieva
- Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, 27-10, Lomonosovsky av., Moscow 119191, Russia.
| | - Peter Nimiritsky
- Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, 27-10, Lomonosovsky av., Moscow 119191, Russia.
- Faculty of Medicine, Lomonosov Moscow State University, 27-1, Lomonosovsky av., Moscow 119192, Russia.
| | - Nataliya Basalova
- Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, 27-10, Lomonosovsky av., Moscow 119191, Russia.
- Faculty of Medicine, Lomonosov Moscow State University, 27-1, Lomonosovsky av., Moscow 119192, Russia.
| | - Natalia Kalinina
- Faculty of Medicine, Lomonosov Moscow State University, 27-1, Lomonosovsky av., Moscow 119192, Russia.
| | - Zhanna Akopyan
- Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, 27-10, Lomonosovsky av., Moscow 119191, Russia.
- Faculty of Medicine, Lomonosov Moscow State University, 27-1, Lomonosovsky av., Moscow 119192, Russia.
| | - Anastasia Efimenko
- Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, 27-10, Lomonosovsky av., Moscow 119191, Russia.
- Faculty of Medicine, Lomonosov Moscow State University, 27-1, Lomonosovsky av., Moscow 119192, Russia.
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17
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Hou H, Gao F, Liang H, Lv Y, Li M, Yao L, Zhang J, Dou G, Wang Y. MicroRNA-188-5p regulates contribution of bone marrow-derived cells to choroidal neovascularization development by targeting MMP-2/13. Exp Eye Res 2018; 175:115-123. [DOI: 10.1016/j.exer.2018.06.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 06/06/2018] [Accepted: 06/13/2018] [Indexed: 12/11/2022]
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18
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Hou B, Cai M, Chen C, Ji W, Ye Z, Ling C, Chen Z, Guo Y. Xenogeneic acellular nerve scaffolds supplemented with autologous bone marrow-derived stem cells promote axonal outgrowth and remyelination but not nerve function. J Biomed Mater Res A 2018; 106:3065-3078. [PMID: 30260554 DOI: 10.1002/jbm.a.36497] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 06/07/2018] [Accepted: 06/27/2018] [Indexed: 12/29/2022]
Abstract
Autologous nerves, artificial scaffolds or acellular nerve scaffolds are commonly used in bridging treatment for peripheral nerve defects. Xenogeneic acellular nerve scaffolds and allogeneic cellular nerve scaffolds have the same structural characteristics. Due to the wider source of raw materials, these latter scaffolds have high-potential value for applications. However, whether their heterogeneity will affect nerve regeneration is unknown. The current study evaluated the efficiency of xenogeneic acellular nerve scaffolds (XANs) combined with 5-ethynyl-2'-deoxyuridine (EdU)-labeling of autologous bone marrow-derived stem cells (BMSCs) for repair of a 1.5 cm gap in rat sciatic nerves. XANs from rabbit tibial nerves were prepared, the structure and components of the scaffolds were evaluated after completely removing the cellular components. Animals were divided into four groups based on graft: the simple XAN group, the XAN + BMSC group, the XAN + Media (from BMSC culture) group, and the autograft group. Serological immune tests showed that XANs induce an immune response in the first 2 weeks after transplantation. Moreover, cell tracking revealed that the proportion of EdU+ cells decreased over time, as shown by the measures at 2 days (70%), 4 days (20%), and 8 days (even <3%) postoperatively. Nerve functional analyses revealed that in contrast to the autograft group results, the XAN-BMSC, XAN + Media, and XAN groups did not exhibit good restoration of the sciatic functional index (SFI) or electrophysiological results (the peak action potential amplitudes) 12 weeks, postoperatively. However, the XAN-BMSC and autograft groups demonstrated greater remyelination and increased axon numbers and myelin thickness than the XAN + Media and XAN groups 12 weeks, postoperatively (p < .05). In conclusion, in the early stage of transplantation, XANs induce a certain degree of inflammation. Although the combination of XANs with autologous BMSCs enhanced the number of regenerated axons and the remyelination, the combination did not effectively improve the recovery of nervous motor function. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3065-3078, 2018.
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Affiliation(s)
- Bo Hou
- Departments of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangdong Province, 510630, Guangzhou, China
| | - Meiqin Cai
- Departments of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangdong Province, 510630, Guangzhou, China
| | - Chuan Chen
- Departments of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangdong Province, 510630, Guangzhou, China
| | - Wanqing Ji
- Department of Obstetrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Province, 510623, Guangzhou, China
| | - Zhuopeng Ye
- Departments of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangdong Province, 510630, Guangzhou, China
| | - Cong Ling
- Departments of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangdong Province, 510630, Guangzhou, China
| | - Zhuopeng Chen
- Departments of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangdong Province, 510630, Guangzhou, China
| | - Ying Guo
- Departments of Neurosurgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangdong Province, 510630, Guangzhou, China
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19
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Zhu L, Xie J, Liu Z, Huang Z, Huang M, Yin H, Qi W, Yang Z, Zhou T, Gao G, Zhang J, Yang X. Pigment epithelium-derived factor/vascular endothelial growth factor ratio plays a crucial role in the spontaneous regression of infant hemangioma and in the therapeutic effect of propranolol. Cancer Sci 2018; 109:1981-1994. [PMID: 29664206 PMCID: PMC5989849 DOI: 10.1111/cas.13611] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Revised: 04/05/2018] [Accepted: 04/09/2018] [Indexed: 12/16/2022] Open
Abstract
Infantile hemangioma (IH) is a benign tumor that is formed by aberrant angiogenesis and that undergoes spontaneous regression over time. Propranolol, the first-line therapy for IH, inhibits angiogenesis by downregulating activation of the vascular endothelial growth factor (VEGF) pathway, which is hyperactivated in IH. However, this treatment is reportedly ineffective for 10% of tumors, and 19% of patients relapse after propranolol treatment. Both pro-angiogenic and anti-angiogenic factors regulate angiogenesis, and pigment epithelium-derived factor (PEDF) is the most effective endogenous anti-angiogenic factor. PEDF/VEGF ratio controls many angiogenic processes, but its role in IH and the relationship between this ratio and propranolol remain unknown. Results of the present study showed that the PEDF/VEGF ratio increased during the involuting phase of IH compared with the proliferating phase. Similarly, in hemangioma-derived endothelial cells (HemEC), which were isolated with magnetic beads, increasing the PEDF/VEGF ratio inhibited proliferation, migration, and tube formation and promoted apoptosis. Mechanistically, the VEGF receptors (VEGFR1 and VEGFR2) and PEDF receptor (laminin receptor, LR) were highly expressed in both IH tissues and HemEC, and PEDF inhibited HemEC function by binding to LR. Interestingly, we found that propranolol increased the PEDF/VEGF ratio but did so by lowering VEGF expression rather than by upregulating PEDF as expected. Furthermore, the combination of PEDF and propranolol had a more suppressive effect on HemEC. Consequently, our results suggested that the PEDF/VEGF ratio played a pivotal role in the spontaneous regression of IH and that the combination of PEDF and propranolol might be a promising treatment strategy for propranolol-resistant IH.
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Affiliation(s)
- Liuqing Zhu
- Department of Biochemistry & Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Jinye Xie
- Department of Biochemistry & Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Zhenyin Liu
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Zhijian Huang
- Department of Biochemistry & Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Mao Huang
- Department of Biochemistry & Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Haofan Yin
- Department of Biochemistry & Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Weiwei Qi
- Department of Biochemistry & Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Zhonghan Yang
- Department of Biochemistry & Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Ti Zhou
- Department of Biochemistry & Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Guoquan Gao
- Department of Biochemistry & Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Guangdong Engineering & Technology Research Center for Gene Manipulation and Biomacromolecular Products (Sun Yat-sen University), Guangzhou, China.,China Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, China
| | - Jing Zhang
- Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Xia Yang
- Department of Biochemistry & Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Guangdong Engineering & Technology Research Center for Gene Manipulation and Biomacromolecular Products (Sun Yat-sen University), Guangzhou, China.,Engineering and Technology Research Center for Disease-Model Animals, Sun Yat-Sen University, Guangzhou, China
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20
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Zhou Y, Han S, Xiao L, Han P, Wang S, He J, Chang J, Wu C, Xiao Y. Accelerated host angiogenesis and immune responses by ion release from mesoporous bioactive glass. J Mater Chem B 2018; 6:3274-3284. [PMID: 32254385 DOI: 10.1039/c8tb00683k] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Angiogenesis represents a major focus for novel therapeutic approaches to the treatment and management of multiple pathological conditions, such as ischemic heart disease and critical-sized bone defect. The complex process of angiogenesis begins when cells within a tissue respond to hypoxia by increasing their production of vascular endothelial growth factor (VEGF). Loading biomaterials with angiogenic therapeutics have emerged as a promising approach for developing superior biomaterials for tissue repair and regeneration due to the possibility of reducing treatment costs and side effects when compared to the use of growth factors or genetic engineering approaches. Trace elements, such as copper (Cu), have been reported to be capable of inhibiting prolyl hydroxylases leading to the accumulation and activation of hypoxia-inducible factor-1α (HIF-1α), a major transcription factor regulating the expression of VEGF. It has also recently been speculated that the artifically induced hypoxic microenvironment may regulate the local immune response, which in turn, further facilitates the tissue repair process. The present study has incorporated ionic Cu2+ into mesoporous bioactive glass (MBG), a promising bioactive material system for regenerative medicine, and investigated its effect on angiogenesis and immune responses both in vitro and in vivo. Our results demonstrated that hypoxia-mimicking materials could induce VEGF secretion of bone marrow-derived mesenchymal stromal cells (BMSCs), which provided a positive feedback loop for early blood vessel formation by stimulating migration and tube formation of human umbilical vein endothelial cells (HUVECs). Furthermore, a tissue-regenerative macrophage subtype was triggered by Cu-MBG, leading to superior angiogenic responses (tube formation and angiogenic gene expression) compared to the traditional MBG material. It is concluded that the addition of inorganic ions leads to enhanced angiogenesis and immune responses, which holds promise for the development of functional tissue-engineered constructs to repair and regenerate damaged tissues and organs.
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Affiliation(s)
- Yinghong Zhou
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland 4059, Australia.
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Shiu HT, Leung PC, Ko CH. The roles of cellular and molecular components of a hematoma at early stage of bone healing. J Tissue Eng Regen Med 2018; 12:e1911-e1925. [PMID: 29207216 DOI: 10.1002/term.2622] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 10/23/2017] [Accepted: 11/22/2017] [Indexed: 12/14/2022]
Abstract
Bone healing is a complex repair process that commences with the formation of a blood clot at the injured bone, termed hematoma. It has evidenced that a lack of a stable hematoma causes delayed bone healing or non-union. The hematoma at the injured bone constitutes the early healing microenvironment. It appears to dictate healing pathways that ends in a regenerative bone. However, the hematoma is often clinically removed from the damaged site. Conversely, blood-derived products have been used in bone tissue engineering for treating critical sized defects, including fibrin gels and platelet-rich plasma. A second generation of platelet concentrate that is based on leukocyte and fibrin content has also been developed and introduced in market. Conflicting effect of these products in bone repair are reported. We propose that the bone healing response becomes dysregulated if the blood response and subsequent formation and properties of a hematoma are altered. This review focuses on the central structural, cellular, and molecular components of a fracture hematoma, with a major emphasis on their roles in regulating bone healing mechanism, and their interactions with mesenchymal stem cells. New angles towards a better understanding of these factors and relevant mechanisms involved at the beginning of bone healing may help to clarify limited or adverse effects of blood-derived products on bone repair. We emphasize that the recreation of an early hematoma niche with critical compositions might emerge as a viable therapeutic strategy for enhanced skeletal tissue engineering.
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Affiliation(s)
- Hoi Ting Shiu
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.,State Key Laboratory of Phytochemistry & Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Ping Chung Leung
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.,State Key Laboratory of Phytochemistry & Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Chun Hay Ko
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.,State Key Laboratory of Phytochemistry & Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
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22
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Comparative Therapeutic Effects of Minocycline Treatment and Bone Marrow Mononuclear Cell Transplantation following Striatal Stroke. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:1976191. [PMID: 28713482 PMCID: PMC5497656 DOI: 10.1155/2017/1976191] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/20/2016] [Revised: 02/27/2017] [Accepted: 03/13/2017] [Indexed: 02/07/2023]
Abstract
We explored the comparative effects of minocycline treatment and intrastriatal BMMC transplantation after experimental striatal stroke in adult rats. Male Wistar adult rats were divided as follows: saline-treated (N = 5), minocycline-treated (N = 5), and BMMC-transplanted (N = 5) animals. Animals received intrastriatal microinjections of 80 pmol of endothelin-1 (ET-1). Behavioral tests were performed at 1, 3, and 7 days postischemia. Animals were treated with minocycline (50 mg/kg, i.p.) or intrastriatal transplants of 106 BMMCs at 24 h postischemia. Animals were perfused at 7 days after ischemic induction. Coronal sections were stained with cresyl violet for gross histopathological analysis and immunolabeled for the identification of neuronal bodies (NeuN), activated microglia/macrophages (ED1), and apoptotic cells (active caspase-3). BMMC transplantation and minocycline reduced the number of ED1+ cells (p < 0.05, ANOVA-Tukey), but BMMC afforded better results. Both treatments afforded comparable levels of neuronal preservation compared to control (p > 0.05). BMMC transplantation induced a higher decrease in the number of apoptotic cells compared to control and minocycline treatment. Both therapeutic approaches improved functional recovery in ischemic animals. The results suggest that BMMC transplantation is more effective in modulating microglial activation and reducing apoptotic cell death than minocycline, although both treatments are equally efficacious on improving neuronal preservation.
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23
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Zhou Y, Huang R, Fan W, Prasadam I, Crawford R, Xiao Y. Mesenchymal stromal cells regulate the cell mobility and the immune response during osteogenesis through secretion of vascular endothelial growth factor A. J Tissue Eng Regen Med 2017; 12:e566-e578. [DOI: 10.1002/term.2327] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Revised: 05/16/2016] [Accepted: 09/26/2016] [Indexed: 12/23/2022]
Affiliation(s)
- Yinghong Zhou
- Institute of Health and Biomedical Innovation; Queensland University of Technology; Brisbane Queensland Australia
- Australia-China Centre for Tissue Engineering and Regenerative Medicine (ACCTERM); Queensland University of Technology; Brisbane Queensland Australia
| | - Rong Huang
- Institute of Health and Biomedical Innovation; Queensland University of Technology; Brisbane Queensland Australia
- Australia-China Centre for Tissue Engineering and Regenerative Medicine (ACCTERM); Queensland University of Technology; Brisbane Queensland Australia
| | - Wei Fan
- Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology; Wuhan University; Wuhan China
- Australia-China Centre for Tissue Engineering and Regenerative Medicine (ACCTERM); Queensland University of Technology; Brisbane Queensland Australia
| | - Indira Prasadam
- Institute of Health and Biomedical Innovation; Queensland University of Technology; Brisbane Queensland Australia
- Australia-China Centre for Tissue Engineering and Regenerative Medicine (ACCTERM); Queensland University of Technology; Brisbane Queensland Australia
| | - Ross Crawford
- Institute of Health and Biomedical Innovation; Queensland University of Technology; Brisbane Queensland Australia
- The Prince Charles Hospital; Brisbane Queensland Australia
- Australia-China Centre for Tissue Engineering and Regenerative Medicine (ACCTERM); Queensland University of Technology; Brisbane Queensland Australia
| | - Yin Xiao
- Institute of Health and Biomedical Innovation; Queensland University of Technology; Brisbane Queensland Australia
- Australia-China Centre for Tissue Engineering and Regenerative Medicine (ACCTERM); Queensland University of Technology; Brisbane Queensland Australia
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Li F, Armstrong GB, Tombran-Tink J, Niyibizi C. Pigment epithelium derived factor upregulates expression of vascular endothelial growth factor by human mesenchymal stem cells: Possible role in PEDF regulated matrix mineralization. Biochem Biophys Res Commun 2016; 478:1106-10. [PMID: 27530920 DOI: 10.1016/j.bbrc.2016.08.076] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 08/11/2016] [Indexed: 12/12/2022]
Abstract
Pigment epithelium-derived factor (PEDF) encoded by serpinf1 is a potent antiangiogenic factor found in a wide variety of fetal and adult tissues. Several reports have shown that lack of PEDF leads to osteogenesis imperfecta (OI) type VI whose hallmark is a defect in mineralization that leads to excessive osteoid build up that fails to mineralize. Because PEDF is antiangiogenic factor it would pose serious consequences on bone development and healing of fractures. To understand possible mechanisms by which PEDF plays a role in bone development and regulation of matrix mineralization, we determined the effects of exogenous PEDF on vascular endothelial growth factor (VEGF) expression by human mesenchymal stem cells (hMSCs) and mechanisms of its regulation by PEDF. Human MSCs incubated in normal medium supplemented with exogenous PEDF increased VEGF expression; this increase was also seen when PEDF was added to hMSCs undergoing osteogenic differentiation. MSCs maintained in osteogenic medium increased synthesis of both VEGF and PEDF but both factors were maintained relatively in balance during differentiation. To understand mechanisms by which exogenous PEDF regulated VEGF expression, hMSCs exposed to PEDF activated Erk signaling pathway in MSCs; inhibition of Erk signaling reduced VEGF mRNA expression as well as protein production suggesting that PEDF regulates VEGF expression in MSCs via Erk signaling pathway. In conclusion, PEDF increases VEGF expression by MSCs suggesting that regulation of VEGF by PEDF may be part of the mechanisms by which PEDF regulates osteoblastic mineralization.
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Affiliation(s)
- Feng Li
- Department of Orthopaedics and Rehabilitation, Pennsylvania State University College of Medicine, Division of Musculoskeletal Sciences, Hershey, PA 17033, USA
| | - Gillian B Armstrong
- Department of Orthopaedics and Rehabilitation, Pennsylvania State University College of Medicine, Division of Musculoskeletal Sciences, Hershey, PA 17033, USA
| | - Joyce Tombran-Tink
- Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Christopher Niyibizi
- Department of Orthopaedics and Rehabilitation, Pennsylvania State University College of Medicine, Division of Musculoskeletal Sciences, Hershey, PA 17033, USA; Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
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25
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Amorim BR, Silvério KG, Casati MZ, Sallum EA, Kantovitz KR, Nociti FH. Neuropilin Controls Endothelial Differentiation by Mesenchymal Stem Cells From the Periodontal Ligament. J Periodontol 2016; 87:e138-47. [PMID: 26962679 DOI: 10.1902/jop.2016.150603] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Periodontal ligament (PDL) has been reported to be a source of mesenchymal stem cells (MSCs).New vascular networks from undifferentiated cells are essential for repair/regeneration of specialized tissues, including PDL. The current study aims to determine potential of CD105(+)-enriched cell subsets of periodontal ligament cells (PDLSCs) to differentiate into endothelial cell (EC)-like cells and to give insights into the mechanism involved. METHODS CD105(+)-enriched PDLSCs were induced to EC differentiation by endothelial growth medium 2 (EGM-2) for 3, 7, 14, and 21 days, with mRNA/protein levels and functional activity assessed by: 1) real-time polymerase chain reaction; 2) Western blotting; 3) fluorescence-activated cell sorting; 4) immunohistochemistry; 5) immunofluorescence; 6) matrigel; and 7) small interfering RNA assays. RESULTS Data analyses demonstrated that EGM-2 treated PDLSCs presented increased expression of EC markers, including: 1) CD105; 2) kinase domain-containing receptor; and 3) Ulex europaeus agglutinin 1, and were able to form cord/tube-like structures. Gene and protein expression analysis showed that neuropilin 2 (NRP2), a key factor for vascular development, was significantly downregulated during EC differentiation. NRP2 was constitutively expressed in mouse PDL tissues by immunohistochemistry analysis, and NRP2 knockdown in CD105(+)-enriched PDLSCs resulted in increased cord/tube-like structures in a matrigel assay. CONCLUSION These findings demonstrated the potential of CD105(+)-enriched PDLSCs to support angiogenesis, and NRP2 as a pivotal factor regulating this process.
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Affiliation(s)
- Bruna R Amorim
- Department of Prosthodontics and Periodontics, School of Dentistry, University of Campinas, Piracicaba, São Paulo, Brazil
| | - Karina G Silvério
- Department of Prosthodontics and Periodontics, School of Dentistry, University of Campinas, Piracicaba, São Paulo, Brazil
| | - Márcio Z Casati
- Department of Prosthodontics and Periodontics, School of Dentistry, University of Campinas, Piracicaba, São Paulo, Brazil
| | - Enilson A Sallum
- Department of Prosthodontics and Periodontics, School of Dentistry, University of Campinas, Piracicaba, São Paulo, Brazil
| | | | - Francisco H Nociti
- Department of Prosthodontics and Periodontics, School of Dentistry, University of Campinas, Piracicaba, São Paulo, Brazil
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Zarbakhsh S, Goudarzi N, Shirmohammadi M, Safari M. Histological Study of Bone Marrow and Umbilical Cord Stromal Cell Transplantation in Regenerating Rat Peripheral Nerve. CELL JOURNAL 2016; 17:668-77. [PMID: 26862526 PMCID: PMC4746417 DOI: 10.22074/cellj.2016.3839] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 02/05/2015] [Indexed: 12/15/2022]
Abstract
Objective Bone marrow and umbilical cord stromal cells are multipotential stem cells
that have the ability to produce growth factors that play an important role in survival and
generation of axons. The goal of this study was to evaluate the effects of the two different
mesenchymal stem cells on peripheral nerve regeneration.
Materials and Methods In this experimental study, a 10 mm segment of the left sciatic
nerve of male Wistar rats (250-300 g) was removed with a silicone tube interposed into
this nerve gap. Bone marrow stromal cells (BMSCs) and human umbilical cord stromal
cells (HUCSCs) were respectively obtained from rat and human. The cells were sepa-
rately cultured and transplanted into the nerve gap. The sciatic nerve regeneration was
evaluated by immunohistochemistry, and light and electron microscopy. Moreover, histo-
morphology of the gastrocnemius muscle was observed.
Results The nerve regeneration in the BMSCs and HUCSCs groups that had received
the stem cells was significantly more favorable than the control group. In addition, the BM-
SCs group was significantly more favorable than the HUCSCs group (P<0.05).
Conclusion The results of this study suggest that both homograft BMSCs and het-
erograft HUCSCs may have the potential to regenerate peripheral nerve injury and
transplantation of BMSCs may be more effective than HUCSCs in rat.
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Affiliation(s)
- Sam Zarbakhsh
- Research Center of Nervous System Stem Cells, Department of Anatomy, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Nasim Goudarzi
- Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Shirmohammadi
- Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Manouchehr Safari
- Research Center of Nervous System Stem Cells, Department of Anatomy, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
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27
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The New Role of CD163 in the Differentiation of Bone Marrow Stromal Cells into Vascular Endothelial-Like Cells. Stem Cells Int 2016; 2016:2539781. [PMID: 26880943 PMCID: PMC4736601 DOI: 10.1155/2016/2539781] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2015] [Revised: 10/29/2015] [Accepted: 11/03/2015] [Indexed: 01/22/2023] Open
Abstract
Bone marrow stromal cells (BMSCs) can differentiate into vascular endothelial cells (VECs). It is regarded as an important solution to cure many diseases, such as ischemic diseases and diabetes. However, the mechanisms underlying BMSC differentiation into VECs are not well understood. Recent reports showed that CD163 expression was associated with angiogenesis. In this study, overexpression of CD163 in BMSCs elevated the protein level of the endothelial-associated markers CD31, Flk-1, eNOS, and VE-cadherin, significantly increased the proportion of Alexa Fluor 488-acetylated-LDL-positive VECs, and promoted angiogenesis on Matrigel. Furthermore, we demonstrated that CD163 acted downstream homeobox containing 1 (Hmbox1) and upstream fibroblast growth factor 2 (FGF-2). These data suggested that CD163 was involved in Hmbox1/CD163/FGF-2 signal pathway in BMSC differentiation into vascular endothelial-like cells. We found a new signal pathway and a novel target for further investigating the gene control of BMSC differentiation into a VEC lineage.
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Histological study on the role of bone marrow-derived mesenchymal stem cells on the sciatic nerve and the gastrocnemius muscle in a model of sciatic nerve crush injury in albino rats. ACTA ACUST UNITED AC 2015. [DOI: 10.1097/01.ehx.0000470653.67231.07] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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29
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Pogozhykh O, Pogozhykh D, Neehus AL, Hoffmann A, Blasczyk R, Müller T. Molecular and cellular characteristics of human and non-human primate multipotent stromal cells from the amnion and bone marrow during long term culture. Stem Cell Res Ther 2015; 6:150. [PMID: 26297012 PMCID: PMC4546288 DOI: 10.1186/s13287-015-0146-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 02/24/2015] [Accepted: 08/05/2015] [Indexed: 02/07/2023] Open
Abstract
Introduction Multipotent stromal cells (MSCs) are among the key candidates in regenerative medicine. However variety of MSC sources and general heterogeneity lead to controversial data in functional characterization. Furthermore, despite intensive usage as preclinical animal model, little is known about MSCs of the common marmoset monkey. Methods MSCs derived from placental amnion and bone marrow samples from human and common marmoset were characterized in parallel over 12 passages to monitor similarities and significant differences (p ≤ 0.05, Student’s t-test) in MSC markers and major histocompatibility complex (MHC) class I expression by immunohistochemistry, flow cytometry, real-time PCR, metabolic activity test, with special focus on pluripotency associated genes. Results Human and non-human primate MSCs were characterized for expression of MSC markers and capability of differentiation into mesenchymal lineages. MSCs could be cultured more than 100 days (26 passages), but metabolic activity was significantly enhanced in amnion vs. bone marrow MSCs. Interestingly, MHC class I expression is significantly reduced in amnion MSCs until passage 6 in human and marmoset, but not in bone marrow cells. For MSC markers, CD73 and CD105 levels remain unchanged in amnion MSCs and slightly decline in bone marrow at late passages; CD166 is significantly higher expressed in human MSCs, CD106 significantly lower vs. marmoset. All cultured MSCs showed pluripotency marker expression like Oct-4A at passage 3 significantly decreasing over time (passages 6–12) while Nanog expression was highest in human bone marrow MSCs. Furthermore, human MSCs demonstrated the highest Sox2 levels vs. marmoset, whereas the marmoset exhibited significantly higher Lin28A values. Bisulfite sequencing of the Oct-4 promoter region displayed fewer methylations of CpG islands in the marmoset vs. human. Conclusions Little is known about MSC characteristics from the preclinical animal model common marmoset vs. human during long term culture. Studied human and common marmoset samples share many similar features such as most MSC markers and reduced MHC class I expression in amnion cells vs. bone marrow. Furthermore, pluripotency markers indicate in both species a subpopulation of MSCs with true ‘stemness’, which could explain their high proliferation capacity, though possessing differences between human and marmoset in Lin28A and Sox2 expression.
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Affiliation(s)
- Olena Pogozhykh
- Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.
| | - Denys Pogozhykh
- Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.
| | - Anna-Lena Neehus
- Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.
| | - Andrea Hoffmann
- Department of Orthopaedic Surgery, Hannover Medical School, Anna-von-Borries-Straße 1-7, 30625, Hannover, Germany.
| | - Rainer Blasczyk
- Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.
| | - Thomas Müller
- Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.
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Ren J, Wang H, Tran K, Civini S, Jin P, Castiello L, Feng J, Kuznetsov SA, Robey PG, Sabatino M, Stroncek DF. Human bone marrow stromal cell confluence: effects on cell characteristics and methods of assessment. Cytotherapy 2015; 17:897-911. [PMID: 25882666 DOI: 10.1016/j.jcyt.2015.03.607] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Accepted: 03/09/2015] [Indexed: 01/05/2023]
Abstract
BACKGROUND AIMS Ex vivo expansion and serial passage of human bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) is required to obtain sufficient quantities for clinical therapy. The BMSC confluence criteria used to determine passage and harvest timing vary widely, and the impact of confluence on BMSC properties remains controversial. The effects of confluence on BMSC properties were studied and confluence-associated markers were identified. METHODS BMSC characteristics were analyzed as they grew from 50% to 100% confluence, including viability, population doubling time, apoptosis, colony formation, immunosuppression, surface marker expression, global gene expression and microRNA expression. In addition, culture supernatant protein, glucose, lactate and pH levels were analyzed. RESULTS Confluence-dependent changes were detected in the expression of several cell surface markers: 39 culture supernatant proteins, 26 microRNAs and 2078 genes. Many of these surface markers, proteins, microRNAs and genes have been reported to be important in BMSC function. The pigment epithelium-derived factor/vascular endothelial growth factor ratio increased with confluence, but 80% and 100% confluent BMSCs demonstrated a similar level of immunosuppression of mixed lymphocyte reactions. In addition, changes in lactate and glucose levels correlated with BMSC density. CONCLUSIONS BMSC characteristics change as confluence increases. 100% confluent BMSCs may have compromised pro-angiogenesis properties but may retain their immunomodulatory properties. Supernatant lactate and glucose levels can be used to estimate confluence and ensure consistency in passage and harvest timing. Flow cytometry or microRNA expression can be used to confirm that the BMSCs have been harvested at the appropriate confluence.
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Affiliation(s)
- Jiaqiang Ren
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Huan Wang
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Katherine Tran
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Sara Civini
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Ping Jin
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Luciano Castiello
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Ji Feng
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Sergei A Kuznetsov
- Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA
| | - Pamela G Robey
- Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA
| | - Marianna Sabatino
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - David F Stroncek
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
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Jeng KS, Chang CF, Jeng WJ, Sheen IS, Jeng CJ. Heterogeneity of hepatocellular carcinoma contributes to cancer progression. Crit Rev Oncol Hematol 2015; 94:337-47. [PMID: 25680939 DOI: 10.1016/j.critrevonc.2015.01.009] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Revised: 10/24/2014] [Accepted: 01/21/2015] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous disease displaying differences in angiogenesis, extracellular matrix proteins, the immune microenvironment and tumor cell populations. Additionally, genetic variations and epigenetic changes of HCC cells could lead to aberrant signaling pathways, induce cancer stem cells and enhance tumor progression. Thus, the heterogeneity in HCC contributes to disease progression and a better understanding of its heterogeneity will greatly aid in the development of strategies for the HCC treatment.
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Affiliation(s)
- Kuo-Shyang Jeng
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
| | - Chiung-Fang Chang
- Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Wen-Juei Jeng
- Department of Hepato-Gastroenterology, Chang-Gung Memorial Hospital, LinKou Medical Center, Chang Gung University, Taiwan
| | - I-Shyan Sheen
- Department of Hepato-Gastroenterology, Chang-Gung Memorial Hospital, LinKou Medical Center, Chang Gung University, Taiwan
| | - Chi-Juei Jeng
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
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Sagaradze G, Grigorieva O, Efimenko A, Chaplenko A, Suslina S, Sysoeva V, Kalinina N, Akopyan Z, Tkachuk V. Therapeutic potential of human mesenchymal stromal cells secreted components: a problem with standartization. ACTA ACUST UNITED AC 2015; 61:750-9. [DOI: 10.18097/pbmc20156106750] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Regenerative medicine approaches, such as replacement of damaged tissue by ex vivo manufactured constructions or stimulation of endogenous reparative and regenerative processes to treat different diseases, are actively developing. One of the major tools for regenerative medicine are stem and progenitor cells, including multipotent mesenchymal stem/stromal cells (MSC). Because the paracrine action of bioactive factors secreted by MSC is considered as a main mechanism underlying MSC regenerative effects, application of MSC extracellular secreted products could be a promising approach to stimulate tissue regeneration; it also has some advantages compared to the injection of the cells themselves. However, because of the complexity of composition and multiplicity of mechanisms of action distinguished the medicinal products based on bioactive factors secreted by human MSC from the most of pharmaceuticals, it is important to develop the approaches to their standardization and quality control. In the current study, based on the literature data and guidelines as well as on our own experimental results, we provided rationalization for nomenclature and methods of quality control for the complex of extracellular products secreted by human adipose-derived MSC on key indicators, such as “Identification”, “Specific activity” and “Biological safety”. Developed approaches were tested on the samples of conditioned media contained products secreted by MSC isolated from subcutaneous adipose tissue of 30 donors. This strategy for the standardization of innovative medicinal products and biomaterials based on the bioactive extracellular factors secreted by human MSC could be applicable for a wide range of bioactive complex products, produced using the different types of stem and progenitor cells.
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Affiliation(s)
- G.D. Sagaradze
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia; OOO “Gene and Cell Therapy”, Moscow, Russia
| | | | - A.Yu. Efimenko
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia; Medical Education and Research Center, Lomonosov Moscow State University, Moscow, Russia
| | | | - S.N. Suslina
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia; Faculty of Medicine, Peoples’ Friendship University of Russia, Moscow, Russia
| | - V.Yu. Sysoeva
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - N.I. Kalinina
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Zh.A. Akopyan
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia; Medical Education and Research Center, Lomonosov Moscow State University, Moscow, Russia
| | - V.A. Tkachuk
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia; Medical Education and Research Center, Lomonosov Moscow State University, Moscow, Russia
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Yi JW, Lee WS, Kim SB, Heo YM, Chae DS. Effect of zoledronate on the expression of vascular endothelial growth factor-a by articular chondrocytes and synovial cells: an in vitro study. J Bone Metab 2014; 21:249-55. [PMID: 25489573 PMCID: PMC4255045 DOI: 10.11005/jbm.2014.21.4.249] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 11/20/2014] [Accepted: 11/21/2014] [Indexed: 11/11/2022] Open
Abstract
Background The aim of this in vitro study was to determine the effect of zoledronate, which is frequently used to treat osteoporosis, on osteoarthritis by analyzing zoledronate-induced expression of vascular endothelial growth factor-A (VEGF-A) in chondrocytes and synovial cells. Methods After chondrocytes and synovial cells were separated and cultured, zoledronate was added, and VEGF-A and pigment epithelium-derived factor (PEDF) expression were quantified by real-time polymerase chain reaction and Western blotting. Results There was no significant difference in the expression of VEGF-A mRNA in chondrocytes between the zoledronate group and the control group on the 8th day of culture. The expression of both VEGF-A and PEDF mRNA in synovial cells was significantly decreased in the zoledronate group (P<0.05). Conclusions Zoledronate decreases the expression of VEGF-A in synovial cells and may affect the development and progression of osteoarthritis.
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Affiliation(s)
- Jin Woong Yi
- Department of Orthopedic Surgery, Konyang University Hospital, Daejeon, Korea
| | - Woo-Suk Lee
- Department of Orthopedic Surgery, Yonsei University Gangnam Severance Hospital, Seoul, Korea
| | - Sang-Bum Kim
- Department of Orthopedic Surgery, Konyang University Hospital, Daejeon, Korea
| | - Youn-Moo Heo
- Department of Orthopedic Surgery, Konyang University Hospital, Daejeon, Korea
| | - Dong-Sik Chae
- Department of Orthopedic Surgery, International St. Mary's Hospital, Catholic Kwandong University College of Medicine, Incheon, Korea
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Roson-Burgo B, Sanchez-Guijo F, Del Cañizo C, De Las Rivas J. Transcriptomic portrait of human Mesenchymal Stromal/Stem Cells isolated from bone marrow and placenta. BMC Genomics 2014; 15:910. [PMID: 25326687 PMCID: PMC4287589 DOI: 10.1186/1471-2164-15-910] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Accepted: 09/24/2014] [Indexed: 02/08/2023] Open
Abstract
Background Human Mesenchymal Stromal/Stem Cells (MSCs) are adult multipotent cells that behave in a highly plastic manner, inhabiting the stroma of several tissues. The potential utility of MSCs is nowadays strongly investigated in the field of regenerative medicine and cell therapy, although many questions about their molecular identity remain uncertain. Results MSC primary cultures from human bone marrow (BM) and placenta (PL) were derived and verified by their immunophenotype standard pattern and trilineage differentiation potential. Then, a broad characterization of the transcriptome of these MSCs was performed using RNA deep sequencing (RNA-Seq). Quantitative analysis of these data rendered an extensive expression footprint that includes 5,271 protein-coding genes. Flow cytometry assays of canonical MSC CD-markers were congruent with their expression levels detected by the RNA-Seq. Expression of other recently proposed MSC markers (CD146, Nestin and CD271) was tested in the placenta samples, finding only CD146 and Nestin. Functional analysis revealed enrichment in stem cell related genes and mesenchymal regulatory transcription factors (TFs). Analysis of TF binding sites (TFBSs) identified 11 meta-regulators, including factors KLF4 and MYC among them. Epigenetically, hypomethylated promoter patterns supported the active expression of the MSC TFs found. An interaction network of these TFs was built to show up their links and relations. Assessment of dissimilarities between cell origins (BM versus PL) disclosed two hundred differentially expressed genes enrolled in microenvironment processes related to the cellular niche, as regulation of bone formation and blood vessel morphogenesis for the case of BM-MSCs. By contrast genes overexpressed in PL-MSCs showed functional enrichment on mitosis, negative regulation of cell-death and embryonic morphogenesis that supported the higher growth rates observed in the cultures of these fetal cells and their closer links with development processes. Conclusions The results present a transcriptomic portrait of the human MSCs isolated from bone marrow and placenta. The data are released as a cell-specific resource, providing a comprehensive expression footprint of the MSCs useful to better understand their cellular and molecular biology and for further investigations on the isolation and biomedical use of these multipotent cells. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-910) contains supplementary material, which is available to authorized users.
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Affiliation(s)
| | | | | | - Javier De Las Rivas
- Bioinformatics and Functional Genomics Group, Cancer Research Center (IBMCC, CSIC/USAL/IBSAL), Consejo Superior de Investigaciones Cientificas (CSIC), Salamanca, Spain.
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Shiu HT, Goss B, Lutton C, Crawford R, Xiao Y. Formation of blood clot on biomaterial implants influences bone healing. TISSUE ENGINEERING PART B-REVIEWS 2014; 20:697-712. [PMID: 24906469 DOI: 10.1089/ten.teb.2013.0709] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The first step in bone healing is forming a blood clot at injured bones. During bone implantation, biomaterials unavoidably come into direct contact with blood, leading to a blood clot formation on its surface prior to bone regeneration. Despite both situations being similar in forming a blood clot at the defect site, most research in bone tissue engineering virtually ignores the important role of a blood clot in supporting healing. Dental implantology has long demonstrated that the fibrin structure and cellular content of a peri-implant clot can greatly affect osteoconduction and de novo bone formation on implant surfaces. This article reviews the formation of a blood clot during bone healing in relation to the use of platelet-rich plasma (PRP) gels. It is implicated that PRP gels are dramatically altered from a normal clot in healing, resulting in conflicting effect on bone regeneration. These results indicate that the effect of clots on bone regeneration depends on how the clots are formed. Factors that influence blood clot structure and properties in relation to bone healing are also highlighted. Such knowledge is essential for developing strategies to optimally control blood clot formation, which ultimately alter the healing microenvironment of bone. Of particular interest are modification of surface chemistry of biomaterials, which displays functional groups at varied composition for the purpose of tailoring blood coagulation activation, resultant clot fibrin architecture, rigidity, susceptibility to lysis, and growth factor release. This opens new scope of in situ blood clot modification as a promising approach in accelerating and controlling bone regeneration.
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Affiliation(s)
- Hoi Ting Shiu
- 1 Science and Engineering Faculty, Institute of Health and Biomedical Innovation, Queensland University of Technology , Brisbane, Australia
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Murthy KR, Goel R, Subbannayya Y, Jacob HK, Murthy PR, Manda SS, Patil AH, Sharma R, Sahasrabuddhe NA, Parashar A, Nair BG, Krishna V, Prasad TK, Gowda H, Pandey A. Proteomic analysis of human vitreous humor. Clin Proteomics 2014; 11:29. [PMID: 25097467 PMCID: PMC4106660 DOI: 10.1186/1559-0275-11-29] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Accepted: 05/16/2014] [Indexed: 12/11/2022] Open
Abstract
Background The vitreous humor is a transparent, gelatinous mass whose main constituent is water. It plays an important role in providing metabolic nutrient requirements of the lens, coordinating eye growth and providing support to the retina. It is in close proximity to the retina and reflects many of the changes occurring in this tissue. The biochemical changes occurring in the vitreous could provide a better understanding about the pathophysiological processes that occur in vitreoretinopathy. In this study, we investigated the proteome of normal human vitreous humor using high resolution Fourier transform mass spectrometry. Results The vitreous humor was subjected to multiple fractionation techniques followed by LC-MS/MS analysis. We identified 1,205 proteins, 682 of which have not been described previously in the vitreous humor. Most proteins were localized to the extracellular space (24%), cytoplasm (20%) or plasma membrane (14%). Classification based on molecular function showed that 27% had catalytic activity, 10% structural activity, 10% binding activity, 4% cell and 4% transporter activity. Categorization for biological processes showed 28% participate in metabolism, 20% in cell communication and 13% in cell growth. The data have been deposited to the ProteomeXchange with identifier PXD000957. Conclusion This large catalog of vitreous proteins should facilitate biomedical research into pathological conditions of the eye including diabetic retinopathy, retinal detachment and cataract.
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Affiliation(s)
- Krishna R Murthy
- Institute of Bioinformatics, International Technology Park, Bangalore 560 066, India.,Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam, Kerala 690 525, India.,Vittala International Institute Of Ophthalmology, Bangalore, Karnataka 560085, India
| | - Renu Goel
- Institute of Bioinformatics, International Technology Park, Bangalore 560 066, India.,Department of Biotechnology, Kuvempu University, Shankaraghatta, Karnataka 577 451, India
| | - Yashwanth Subbannayya
- Institute of Bioinformatics, International Technology Park, Bangalore 560 066, India
| | - Harrys Kc Jacob
- Institute of Bioinformatics, International Technology Park, Bangalore 560 066, India
| | - Praveen R Murthy
- Vittala International Institute Of Ophthalmology, Bangalore, Karnataka 560085, India
| | - Srikanth Srinivas Manda
- Institute of Bioinformatics, International Technology Park, Bangalore 560 066, India.,Centre of Excellence in Bioinformatics, Bioinformatics Centre, School of Life Sciences, Pondicherry University, Puducherry 605 014, India
| | - Arun H Patil
- Institute of Bioinformatics, International Technology Park, Bangalore 560 066, India
| | - Rakesh Sharma
- Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore 560 006, India
| | | | | | - Bipin G Nair
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam, Kerala 690 525, India
| | | | - Ts Keshava Prasad
- Institute of Bioinformatics, International Technology Park, Bangalore 560 066, India.,Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam, Kerala 690 525, India.,Centre of Excellence in Bioinformatics, Bioinformatics Centre, School of Life Sciences, Pondicherry University, Puducherry 605 014, India
| | - Harsha Gowda
- Institute of Bioinformatics, International Technology Park, Bangalore 560 066, India
| | - Akhilesh Pandey
- Department of Biological Chemistry, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore 21205 MD, USA.,Department of Oncology and Pathology, Johns Hopkins University School of Medicine, Baltimore 21205 MD, USA
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Abstract
INTRODUCTION OR BACKGROUND The incidence of chronic lung disease is increasing worldwide due to the spread of risk factors and ageing population. An important advance in treatment would be the development of a bioartificial lung where the blood-gas exchange surface is manufactured from a synthetic or natural scaffold material that is seeded with the appropriate stem or progenitor cells to mimic the functional tissue of the natural lung. SOURCES OF DATA Articles relating to bioartificial lungs were sourced through PubMed and ISI Web of Knowledge. AREAS OF AGREEMENT There is a consensus that advances in bioartificial lung engineering will be beneficial to patients with chronic lung failure. Ultimate success will require the concerted efforts of researchers drawn from a broad range of disciplines, including clinicians, cell biologists, materials scientists and engineers. AREAS OF CONTROVERSY As a source of cells for use in bioartificial lungs it is proposed to use human embryonic stem cells; however, there are ethical and safety concerns regarding the use of these cells. GROWING POINTS There is a need to identify the optimum strategies for differentiating progenitor cells into functional lung cells; a need to better understand cell-biomaterial/ECM interactions and a need to understand how to harness the body's natural capacity to regenerate the lung. AREAS TIMELY FOR DEVELOPING RESEARCH Biomaterial technologies for recreating the natural lung ECM and architecture need further development. Mathematical modelling techniques should be developed for determining optimal scaffold seeding strategies and predicting gas exchange performance.
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Affiliation(s)
- Greg Lemon
- Department of Clinical Science, Intervention and Technology (CLINTEC), Advanced Center for Translational Regenerative Medicine (ACTREM), Karolinska Institutet, Stockholm, Sweden
| | - Mei Ling Lim
- Department of Clinical Science, Intervention and Technology (CLINTEC), Advanced Center for Translational Regenerative Medicine (ACTREM), Karolinska Institutet, Stockholm, Sweden Division of Ear, Nose and Throat, Karolinska University Hospital, Stockholm, Sweden
| | - Fatemeh Ajalloueian
- Department of Clinical Science, Intervention and Technology (CLINTEC), Advanced Center for Translational Regenerative Medicine (ACTREM), Karolinska Institutet, Stockholm, Sweden
| | - Paolo Macchiarini
- Department of Clinical Science, Intervention and Technology (CLINTEC), Advanced Center for Translational Regenerative Medicine (ACTREM), Karolinska Institutet, Stockholm, Sweden Division of Ear, Nose and Throat, Karolinska University Hospital, Stockholm, Sweden
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Pacini S, Petrini I. Are MSCs angiogenic cells? New insights on human nestin-positive bone marrow-derived multipotent cells. Front Cell Dev Biol 2014; 2:20. [PMID: 25364727 PMCID: PMC4207020 DOI: 10.3389/fcell.2014.00020] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Accepted: 04/30/2014] [Indexed: 01/09/2023] Open
Abstract
Recent investigations have made considerable progress in the understanding of tissue regeneration driven by mesenchymal stromal cells (MSCs). Data indicate the anatomical location of MSC as residing in the “perivascular” space of blood vessels dispersed across the whole body. This histological localization suggests that MSCs contribute to the formation of new blood vessels in vivo. Indeed, MSCs can release angiogenic factors and protease to facilitate blood vessel formation and in vitro are able to promote/support angiogenesis. However, the direct differentiation of MCSs into endothelial cells is still matter of debate. Most of the conflicting data might arise from the presence of multiple subtypes of cells with heterogeneous morpho functional features within the MSC cultures. According to this scenario, we hypothesize that the presence of the recently described Mesodermal Progenitor Cells (MPCs) within the MSCs cultures is responsible for their variable angiogenic potential. Indeed, MPCs are Nestin-positive CD31-positive cells exhibiting angiogenic potential that differentiate in MSC upon proper stimuli. The ISCT criteria do not account for the presence of MPC within MSC culture generating confusion in the interpretation of MSC angiogenic potential. In conclusion, the discovery of MPC gives new insight in defining MSC ancestors in human bone marrow, and indicates the tunica intima as a further, and previously overlooked, possible additional source of MSC.
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Affiliation(s)
- Simone Pacini
- Department of Clinical and Experimental Medicine, University of Pisa Pisa, Italy
| | - Iacopo Petrini
- Department of Clinical and Experimental Medicine, University of Pisa Pisa, Italy
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Liu Y, Liu T, Han J, Yang Z, Xue X, Jiang H, Wang H. Advanced age impairs cardioprotective function of mesenchymal stem cell transplantation from patients to myocardially infarcted rats. Cardiology 2014; 128:209-19. [PMID: 24818643 DOI: 10.1159/000360393] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Accepted: 02/05/2014] [Indexed: 11/19/2022]
Abstract
OBJECTIVES Mesenchymal stem cells (MSCs) have limited clinical therapeutic effects in older myocardial infarction (MI) patients. Thus, whether younger MSCs might confer greater protection is worth investigating. METHODS Human MSCs (hMSCs) were isolated before coronary artery bypass graft surgery and growth characteristics of hMSCs at passage 3 were observed. Vascular endothelial growth factor (VEGF) and Bcl-2 mRNA and protein expression from hMSCs were measured. In vivo, 45 adult male rats with MI were randomized to receive one of three treatments: old hMSCs, young hMSCs or culture medium (control) transplanted into infarcted myocardium. Echocardiography, TUNEL, immunohistochemistry and Western blot were used to assess results. RESULTS hMSC proliferation in the old group was significantly lower than the young group. VEGF decreased 35% and Bcl-2 decreased more than 60% at the mRNA level; VEGF and Bcl-2 protein were decreased in the old versus the young group. hMSC transplantation may improve cardiac function, but MSC source may affect therapeutic efficacy. Similar data were obtained from TUNEL, immunohistochemistry and Western blot. CONCLUSION Transplantation of hMSCs improves heart function, but proliferative ability and myocardial protection decrease with older MSCs, likely due to differences between VEGF and Bcl-2 expression and reduced anti-apoptosis.
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Affiliation(s)
- Yu Liu
- Department of Cardiovascular Surgery, Shenyang Northern Hospital, Shenyang, PR China
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40
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Mesenchymal stromal cells from the human placenta promote neovascularization in a mouse model in vivo. Placenta 2014; 35:517-9. [PMID: 24814611 DOI: 10.1016/j.placenta.2014.04.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Revised: 04/10/2014] [Accepted: 04/15/2014] [Indexed: 01/14/2023]
Abstract
Cell transplantation is a promising strategy in regenerative medicine for revascularization of ischemic tissues. Based on our observation that placental mesenchymal stromal cells (PMSC) enhance endothelial cell viability in vitro via secretion of angiogenic factors, we asked whether PMSC support vascular growth in vivo. PMSC were isolated from amnion and placental endothelial cells (PLEC) from chorion and either separately or co-transplanted subcutaneously into immune-deficient mice. Co-transplantation resulted in a higher number of perfused human vessels (CD31+/vimentin+) containing mouse glycophorin A+ erythrocytes. Results indicate positive effects of PMSC on neovascularization in vivo, making them attractive candidates to create autologous PMSC/PLEC pairs for research and transplantation.
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Bronckaers A, Hilkens P, Martens W, Gervois P, Ratajczak J, Struys T, Lambrichts I. Mesenchymal stem/stromal cells as a pharmacological and therapeutic approach to accelerate angiogenesis. Pharmacol Ther 2014; 143:181-96. [PMID: 24594234 DOI: 10.1016/j.pharmthera.2014.02.013] [Citation(s) in RCA: 261] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2013] [Accepted: 12/30/2013] [Indexed: 12/16/2022]
Abstract
Mesenchymal stem cells or multipotent stromal cells (MSCs) have initially captured attention in the scientific world because of their differentiation potential into osteoblasts, chondroblasts and adipocytes and possible transdifferentiation into neurons, glial cells and endothelial cells. This broad plasticity was originally hypothesized as the key mechanism of their demonstrated efficacy in numerous animal models of disease as well as in clinical settings. However, there is accumulating evidence suggesting that the beneficial effects of MSCs are predominantly caused by the multitude of bioactive molecules secreted by these remarkable cells. Numerous angiogenic factors, growth factors and cytokines have been discovered in the MSC secretome, all have been demonstrated to alter endothelial cell behavior in vitro and induce angiogenesis in vivo. As a consequence, MSCs have been widely explored as a promising treatment strategy in disorders caused by insufficient angiogenesis such as chronic wounds, stroke and myocardial infarction. In this review, we will summarize into detail the angiogenic factors found in the MSC secretome and their therapeutic mode of action in pathologies caused by limited blood vessel formation. Also the application of MSC as a vehicle to deliver drugs and/or genes in (anti-)angiogenesis will be discussed. Furthermore, the literature describing MSC transdifferentiation into endothelial cells will be evaluated critically.
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Affiliation(s)
- Annelies Bronckaers
- Group of Morphology, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium.
| | - Petra Hilkens
- Group of Morphology, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Wendy Martens
- Group of Morphology, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Pascal Gervois
- Group of Morphology, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Jessica Ratajczak
- Group of Morphology, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Tom Struys
- Group of Morphology, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Ivo Lambrichts
- Group of Morphology, Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
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Ichim TE, Warbington T, Cristea O, Chin JL, Patel AN. Intracavernous administration of bone marrow mononuclear cells: a new method of treating erectile dysfunction? J Transl Med 2013; 11:139. [PMID: 23758954 PMCID: PMC3718667 DOI: 10.1186/1479-5876-11-139] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 04/23/2013] [Indexed: 02/06/2023] Open
Abstract
While PDE5 inhibitors have revolutionized treatment of ED, approximately 30% of patients are non-responsive. A significant cause of this is vascular and smooth muscle dysfunction, as well as nerve atrophy. Autologous administration of bone marrow mononuclear cells (BMMC) has been performed in over 2000 cardiac patients without adverse effects, for stimulation of angiogenesis/regeneration. Despite its ease of access, and dependence on effective vasculature for function, comparatively little has been perform in terms of BMMC therapy for ED. Here we outline the rationale for use of autologous BMMC in patients with ED, as well as provide early safety data on the first use of this procedure clinically.
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Affiliation(s)
- Thomas E Ichim
- Institute for Molecular Medicine, Huntington Beach, CA, USA.
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Wang Y, Wang H, Ye Q, Ye J, Xu C, Lin L, Deng H, Hu R. Co-regulation of LPS and tensile strain downregulating osteogenicity via c-fos expression. Life Sci 2013; 93:38-43. [PMID: 23727355 DOI: 10.1016/j.lfs.2013.05.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Revised: 04/04/2013] [Accepted: 05/17/2013] [Indexed: 11/27/2022]
Abstract
AIMS Orthodontic forces are known to aggravate inflammation-induced destruction of the periodontium, but the underlying mechanism has not been elucidated. The present study investigates how inflammation and forces co-regulate periodontium damage. MAIN METHODS Cultures of MC3T3-E1 osteoblasts were pre-treated with conditioned medium from RAW264.7 macrophages exposed to 100ng/ml Porphyromonas gingivalis (Pg)-LPS. Conditioned medium was analyzed by ELISA for interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Osteoblasts were then subjected to tensile strain (0.5Hz; 1000μ or 3000μ) for 0min, 5min, 15min, 30min, 1h, 3h, and 6h. The cultures were analyzed for mRNA and protein levels of c-fos. Cells were also analyzed for alkaline phosphatase (ALP) activity. KEY FINDINGS (Pg)-LPS stimulated the secretion of all three cytokines from RAW264.7 cells in a dose- and time-dependent manner. Medium from (Pg)-LPS stimulated cells induced a 10-fold increase in c-fos expression, which decreased to a 4-fold plateau after 3h. In contrast, ALP activity of control osteoblasts decreased during the first 60min, then recovered over the next 4h. Pretreatment with conditioned medium generated the same initial decrease during tensile strain but prevented the recovery. SIGNIFICANCE Our study showed, for the first time, that the inhibitory effect of inflammation and tensile strain on osteogenicity is associated with the upregulation in c-fos expression. In addition, inflammation may reduce the ability of osteoblasts to restore their osteogenic capacity during sustained tensile stress and contribute to periodontium damage.
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Affiliation(s)
- Yi Wang
- Orthodontic Department, School of Stomatology, Wenzhou Medical College, China
| | - Haiyan Wang
- Orthodontic Department, School of Stomatology, Wenzhou Medical College, China
| | - Qingsong Ye
- Department of Orthodontics, James Cook University, Australia
| | - Jie Ye
- Orthodontic Department, School of Stomatology, Wenzhou Medical College, China
| | - Chunyan Xu
- Orthodontic Department, Yiwu Central Hospital, China
| | - Leilei Lin
- Orthodontic Department, School of Stomatology, Wenzhou Medical College, China
| | - Hui Deng
- Periodontal Department, School of Stomatology, Wenzhou Medical College, China.
| | - Rongdang Hu
- Orthodontic Department, School of Stomatology, Wenzhou Medical College, China.
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Craword SE, Fitchev P, Veliceasa D, Volpert OV. The many facets of PEDF in drug discovery and disease: a diamond in the rough or split personality disorder? Expert Opin Drug Discov 2013; 8:769-92. [PMID: 23642051 DOI: 10.1517/17460441.2013.794781] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Pigment epithelium-derived factor (PEDF) was discovered as a neurotrophic factor secreted by retinal pigment epithelial cells. A decade later, it re-emerged as a powerful angiogenesis inhibitor guarding ocular function. Since then, significant advances were made identifying PEDF's mechanisms, targets and biomedical applications. AREAS COVERED The authors review several methodologies that have generated significant new information about the potential of PEDF as a drug. Furthermore, the authors review and discuss mechanistic and structure-function analyses combined with the functional mapping of active fragments, which have yielded several short bioactive PEDF peptides. Additionally, the authors present functional studies in knockout animals and human correlates that have provided important information about conditions amenable to PEDF-based therapies. EXPERT OPINION Through its four known receptors, PEDF causes a wide range of cellular events vitally important for the organism, which include survival and differentiation, migration and invasion, lipid metabolism and stem cell maintenance. These processes are deregulated in multiple pathological conditions, including cancer, metabolic and cardiovascular disease. PEDF has been successfully used in countless preclinical models of these conditions and human correlates suggest a wide utility of PEDF-based drugs. The most significant clinical application of PEDF, to date, is its potential therapeutic use for age-related macular degeneration. Moreover, PEDF-based gene therapy has advanced to early stage clinical trials. PEDF active fragments have been mapped and used to design short peptide mimetics conferring distinct functions of PEDF, which may address specific clinical problems and become prototype drugs.
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Affiliation(s)
- Susan E Craword
- St. Louis University School of Medicine, Department of Pathology, St. Louis, Missouri, USA
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Tong N, Zhang Z, Zhang W, Qiu Y, Gong Y, Yin L, Qiu Q, Wu X. Diosmin alleviates retinal edema by protecting the blood-retinal barrier and reducing retinal vascular permeability during ischemia/reperfusion injury. PLoS One 2013; 8:e61794. [PMID: 23637907 PMCID: PMC3634841 DOI: 10.1371/journal.pone.0061794] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Accepted: 03/13/2013] [Indexed: 11/24/2022] Open
Abstract
Background and Purpose Retinal swelling, leading to irreversible visual impairment, is an important early complication in retinal ischemia/reperfusion (I/R) injury. Diosmin, a naturally occurring flavonoid glycoside, has been shown to have antioxidative and anti-inflammatory effects against I/R injury. The present study was performed to evaluate the retinal microvascular protective effect of diosmin in a model of I/R injury. Methods Unilateral retinal I/R was induced by increasing intraocular pressure to 110 mm Hg for 60 min followed by reperfusion. Diosmin (100 mg/kg) or vehicle solution was administered intragastrically 30 min before the onset of ischemia and then daily after I/R injury until the animals were sacrificed. Rats were evaluated for retinal functional injury by electroretinogram (ERG) just before sacrifice. Retinas were harvested for HE staining, immunohistochemistry assay, ELISA, and western blotting analysis. Evans blue (EB) extravasation was determined to assess blood–retinal barrier (BRB) disruption and the structure of tight junctions (TJ) was examined by transmission electron microscopy. Results Diosmin significantly ameliorated the reduction of b-wave, a-wave, and b/a ratio in ERG, alleviated retinal edema, protected the TJ structure, and reduced EB extravasation. All of these effects of diosmin were associated with increased zonular occluden-1 (ZO-1) and occludin protein expression and decreased VEGF/PEDF ratio. Conclusions Maintenance of TJ integrity and reduced permeability of capillaries as well as improvements in retinal edema were observed with diosmin treatment, which may contribute to preservation of retinal function. This protective effect of diosmin may be at least partly attributed to its ability to regulate the VEGF/PEDF ratio.
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Affiliation(s)
- Nianting Tong
- Department of Ophthalmology, Shanghai Jiaotong University Affiliated Shanghai First People’s Hospital, Shanghai, China
| | - Zhenzhen Zhang
- Department of Ophthalmology, Shanghai Jiaotong University Affiliated Shanghai First People’s Hospital, Shanghai, China
| | - Wei Zhang
- Department of Ophthalmology, Shanghai Jiaotong University Affiliated Shanghai First People’s Hospital, Shanghai, China
| | - Yating Qiu
- Department of Ophthalmology, Shanghai Jiaotong University Affiliated Shanghai First People’s Hospital, Shanghai, China
| | - Yuanyuan Gong
- Department of Ophthalmology, Shanghai Jiaotong University Affiliated Shanghai First People’s Hospital, Shanghai, China
| | - Lili Yin
- Department of Ophthalmology, Shanghai Jiaotong University Affiliated Shanghai First People’s Hospital, Shanghai, China
| | - Qinghua Qiu
- Department of Ophthalmology, Shanghai Jiaotong University Affiliated Shanghai First People’s Hospital, Shanghai, China
| | - Xingwei Wu
- Department of Ophthalmology, Shanghai Jiaotong University Affiliated Shanghai First People’s Hospital, Shanghai, China
- * E-mail:
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Vittorio O, Jacchetti E, Pacini S, Cecchini M. Endothelial differentiation of mesenchymal stromal cells: when traditional biology meets mechanotransduction. Integr Biol (Camb) 2013; 5:291-9. [DOI: 10.1039/c2ib20152f] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Mamidi MK, Pal R, Dey S, Bin Abdullah BJJ, Zakaria Z, Rao MS, Das AK. Cell therapy in critical limb ischemia: current developments and future progress. Cytotherapy 2012; 14:902-16. [DOI: 10.3109/14653249.2012.693156] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Shi D, Guo W, Chen W, Fu L, Wang J, Tian Y, Xiao X, Kang T, Huang W, Deng W. Nicotine promotes proliferation of human nasopharyngeal carcinoma cells by regulating α7AChR, ERK, HIF-1α and VEGF/PEDF signaling. PLoS One 2012; 7:e43898. [PMID: 22952803 PMCID: PMC3432052 DOI: 10.1371/journal.pone.0043898] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2012] [Accepted: 07/30/2012] [Indexed: 01/28/2023] Open
Abstract
Nicotine, the major component in cigarette smoke, can promote tumor growth and angiogenesis, but the precise mechanisms involved remain largely unknown. Here, we investigated the mechanism of action of nicotine in human nasopharyngeal carcinoma (NPC) cells. Nicotine significantly promoted cell proliferation in a dose and time-dependent manner in human NPC cells. The mechanism studies showed that the observed stimulation of proliferation was accompanied by the nicotine-mediated simultaneous modulation of α7AChR, HIF-1α, ERK and VEGF/PEDF signaling. Treatment of NPC cells with nicotine markedly upregulated the expression of α7AChR and HIF-1α proteins. Transfection with a α7AChR or HIF-1α-specific siRNA or a α7AChR-selective inhibitor significantly attenuated the nicotine-mediated promotion of NPC cell proliferation. Nicotine also promoted the phosphorylation of ERK1/2 but not JNK and p38 proteins, thereby induced the activation of ERK/MAPK signaling pathway. Pretreatment with an ERK-selective inhibitor effectively reduced the nicotine-induced proliferation of NPC cells. Moreover, nicotine upregulated the expression of VEGF but suppressed the expression of PEDF at mRNA and protein levels, leading to a significant increase of the ratio of VEGF/PEDF in NPC cells. Pretreatment with a α7AChR or ERK-selective inhibitor or transfection with a HIF-1α-specific siRNA in NPC cells significantly inhibited the nicotine-induced HIF-1α expression and VEGF/PEDF ratio. These results therefore indicate that nicotine promotes proliferation of human NPC cells in vitro through simultaneous modulation of α7AChR, HIF-1α, ERK and VEGF/PEDF signaling and suggest that the related molecules such as HIF-1α might be the potential therapeutic targets for tobacco-associated diseases such as nasopharyngeal carcinomas.
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Affiliation(s)
- Dingbo Shi
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Wei Guo
- Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China
| | - Wangbin Chen
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Lingyi Fu
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Jingshu Wang
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yung Tian
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xiangsheng Xiao
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Tiebang Kang
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Wenlin Huang
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Targeted Therapy Drug of Guangdong, Guangzhou, China
| | - Wuguo Deng
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Targeted Therapy Drug of Guangdong, Guangzhou, China
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Burns JS, Safwat A, Grisendi G, Kassem M, Dominici M. Sarcomas as a mise en abyme of mesenchymal stem cells: exploiting interrelationships for cell mediated anticancer therapy. Cancer Lett 2012; 325:1-10. [PMID: 22659735 DOI: 10.1016/j.canlet.2012.05.027] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2012] [Revised: 05/22/2012] [Accepted: 05/24/2012] [Indexed: 12/24/2022]
Abstract
Mise en abyme meaning "placed into abyss or infinite recurrence" is an apt paradigm for the relentless growth of sarcoma cells. Its alternative meaning, "self-reflexive embedding" fits the central role attributed to cancer stem cells (CSCs). Diversely sourced and defined, mesenchymal stem cells (MSCs) may be the cells of sarcoma origin, evolve a CSC phenotype and/or contribute to tumor growth through inherent qualities for homing, neovascularization, paracrine cross-feeding, microvesicle secretion, cell fusion, entosis and immune modulation. Exploiting these qualities, MSC expressing modified forms of the TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) are being developed to complement more conventional radiation and chemotherapy.
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Affiliation(s)
- Jorge S Burns
- Laboratory of Cell Biology and Advanced Cancer Therapies, Department of Oncology, Hematology and Respiratory Disease, University Hospital of Modena and Reggio Emilia, Modena, Italy.
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Role of pigment epithelium-derived factor in stem/progenitor cell-associated neovascularization. J Biomed Biotechnol 2012; 2012:871272. [PMID: 22685380 PMCID: PMC3364713 DOI: 10.1155/2012/871272] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2011] [Accepted: 03/26/2012] [Indexed: 11/18/2022] Open
Abstract
Pigment epithelium-derived factor (PEDF) was first identified in retinal pigment epithelium cells. It is an endogenously produced protein that is widely expressed throughout the human body such as in the eyes, liver, heart, and adipose tissue; it exhibits multiple and varied biological activities. PEDF is a multifunctional protein with antiangiogenic, antitumorigenic, antioxidant, anti-inflammatory, antithrombotic, neurotrophic, and neuroprotective properties. More recently, PEDF has been shown to be the most potent inhibitor of stem/progenitor cell-associated neovascularization. Neovascularization is a complex process regulated by a large, interacting network of molecules from stem/progenitor cells. PEDF is also involved in the pathogenesis of angiogenic eye disease, tumor growth, and cardiovascular disease. Novel antiangiogenic agents with tolerable side effects are desired for the treatment of patients with various diseases. Here, we review the value of PEDF as an important endogenous antiangiogenic molecule; we focus on the recently identified role of PEDF as a possible new target molecule to influence stem/progenitor cell-related neovascularization.
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