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1
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Zhu M, Sun X, Fang J, Li X. Deconvolution of cell-type-associated markers predictive of response to neoadjuvant radiotherapy. Comput Biol Chem 2024; 113:108269. [PMID: 39520737 DOI: 10.1016/j.compbiolchem.2024.108269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 09/30/2024] [Accepted: 10/20/2024] [Indexed: 11/16/2024]
Abstract
Tumor microenvironent contains prognostic molecular markers and therapeutic targets from different cellular sources, which are still not fully revealed in the resistance and recurrence after radiotherapy for rectal cancer. By integrating the scRNA-seq data, we deconvoluted the bulk transcriptomics of rectal cancer collected before preoperative neoadjuvant radiotherapy (nRT) into fractions and gene expression of the six cell types. The inferred cell-type-associated DEGs, abbreviated as caDEGs, of myeloid and stromal cells were enriched for overlapping yet unique biological processes including immunity, angiogenesis, and metabolism, respectively. Ecotyper analysis indicates that the caDEGs reflects cell states and ecotypes in association with nRT response. By mapping the caDEGs onto the context-free and newly built ligand-receptor and collagen-integrin lists from scRNA-Seq data, respectively, we inferred 297 cell-type-specific trans- and/or cis-collagen-integrin and 219 heterotypic ligand-receptor interactions potentially associated with nRT response, including interactions between stromal-associated COL1A2/COL6A1/COL6A2 and stromal or CMS1-associated ITGA1/B1, between epithelial-associated JAG1 and stromal-associated NOTCHs, between CMS2 epithelial-associated CCL15 and proliferating myeloid-associated CCR1, between myeloid-associated CCL4/CD86 and lymphatic endothelial-associated ACKR2, and between myeloid-associated TNFS13B and B cell-associated TNFRSF13B/C, etc. Intriguingly, results suggest a greater number of down-regulated cell-type-related markers in resistant cancers to nRT. Favorable myeloid-associated CD14, epithelial-associated DYM, stromal-associated COL1A2 and COL3A1, and unfavorable epithelial-associated CELSR3 and KCNH8 markers were inferred at least from two independent nCRT datasets of GSE119409, GSE35452, and GSE45404. The results provide insights into roles of the stromal and immune cells beside epithelial cells in resistance to radiotherapy for rectal cancers. The proposed approach can be applicable to other diseases as well. Codes and additional data are available at https://github.com/Xueling21/rectalNRT_deconv.
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Affiliation(s)
- Min Zhu
- Hefei Cancer Hospital of CAS; Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences (CAS), Hefei 230031, China; School of Mathematics and Computer Science, Tongling University, Tongling 244061, China
| | - Xiao Sun
- Hefei Cancer Hospital of CAS; Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences (CAS), Hefei 230031, China; School of Electronic and Information Engineering, Anhui Jianzhu University, South Campus: No. 292 Ziyun Road, Shushan District, Hefei 230009, China
| | - Jinman Fang
- Hefei Cancer Hospital of CAS; Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences (CAS), Hefei 230031, China.
| | - Xueling Li
- Hefei Cancer Hospital of CAS; Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences (CAS), Hefei 230031, China; School of Mathematics and Computer Science, Tongling University, Tongling 244061, China.
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Hayashi Y, Hashimoto M, Takaoka K, Takemoto T, Takakura N, Kidoya H. Tumor endothelial cell-derived Sfrp1 supports the maintenance of cancer stem cells via Wnt signaling. In Vitro Cell Dev Biol Anim 2024; 60:1123-1131. [PMID: 38625488 PMCID: PMC11655579 DOI: 10.1007/s11626-024-00899-y] [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: 01/25/2024] [Accepted: 03/15/2024] [Indexed: 04/17/2024]
Abstract
Cancer stem cells (CSCs), which are critical targets for cancer therapy as they are involved in drug resistance to anticancer drugs, and metastasis, are maintained by angiocrine factors produced by particular niches that form within tumor tissue. Secreted frizzled-related protein 1 (Sfrp1) is an extracellular protein that modulates Wnt signaling. However, the cells that produce Sfrp1 in the tumor environment and its function remain unclear. We aimed to elucidate angiocrine factors related to CSC maintenance, focusing on Sfrp1. Although Sfrp1 is a Wnt pathway-related factor, its impact on tumor tissues remains unknown. We investigated the localization of Sfrp1 in tumors and found that it is expressed in some tumor vessels. Analysis of mice lacking Sfrp1 showed that tumor growth was suppressed in Sfrp1-deficient tumor tissues. Flow cytometry analysis indicated that CSCs were maintained in the early tumor growth phase in the Sfrp1 knockout (KO) mouse model of tumor-bearing cancer. However, tumor growth was inhibited in the late tumor growth phase because of the inability to maintain CSCs. Real-time PCR results from tumors of Sfrp1 KO mice showed that the expression of Wnt signaling target genes significantly decreased in the late stage of tumor growth. This suggests that Sfrp1, an angiocrine factor produced by the tumor vascular niche, is involved in Wnt signaling-mediated mechanisms in tumor tissues.
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Affiliation(s)
- Yumiko Hayashi
- Department of Integrative Vascular Biology, Faculty of Medical Science, Fukui University, 23-3 Matsuoka-Shimoaizuki, Eiheiji, Yoshida, Fukui, 910-1193, Japan
- Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Japan
| | - Masakazu Hashimoto
- Laboratory for Embryogenesis, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan
| | - Katsuyoshi Takaoka
- Laboratory for Embryology, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
| | - Tatsuya Takemoto
- Laboratory for Embryology, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
| | - Nobuyuki Takakura
- Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Japan
- World Premier Institute Immunology Frontier Research Center, Integrated Frontier Research for Medical Science Division, Osaka University, Suita, Japan
- Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita, Japan
- Center for Infectious Disease Education and Research, Osaka University, Suita, Japan
| | - Hiroyasu Kidoya
- Department of Integrative Vascular Biology, Faculty of Medical Science, Fukui University, 23-3 Matsuoka-Shimoaizuki, Eiheiji, Yoshida, Fukui, 910-1193, Japan.
- Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
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Tomasina C, Mohren R, Camarero‐Espinosa S, Cillero‐Pastor B, Moroni L. A Proteomic Approach to Determine Stem Cell Skeletal Differentiation Signature on Additive Manufactured Scaffolds. SMALL SCIENCE 2024; 4:2300316. [PMID: 40212118 PMCID: PMC11935236 DOI: 10.1002/smsc.202300316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 04/19/2024] [Indexed: 04/13/2025] Open
Abstract
Understanding how porous biomaterials interact with cells at their surface and how they either promote or inhibit cellular processes has presented several challenges. Additive manufacturing enables the fabrication of scaffolds with distinct compositions and designs for different tissue engineering applications. To evaluate the in vitro performance of multiple printed materials, biochemical assays can be limiting in providing valuable insight and key information to select the best tissue destination. Omics technologies like proteomics are crucial for studying important cellular events and gathering valuable information about cellular processes and mechanisms. However, only few studies focus on proteomics to decipher cell-material interactions and cell differentiation on additive manufactured scaffolds. Here, scaffolds were fabricated using three polymers (polycaprolactone (PCL), poly(ethylene oxide)-poly(butylene terephthalate) (PEOT/PBT), and polylactic acid (PLA)) through additive manufacturing. Their chondrogenic and osteogenic potential were characterized and compared using human bone marrow-derived mesenchymal stem cells (hBMSCs) through proteomics analysis. The 3D scaffolds were all hydrophilic and displayed Young's moduli close to those of bone or cartilage for PLA and PCL and PEOT/PBT, respectively. Biochemical assays indicated that PEOT/PBT and PLA scaffolds have a greater chondrogenic potential by higher glycosaminoglycan (GAG) and collagen deposition compared to PCL. PLA and PEOT/PBT showed to be more effective in promoting bone formation, as evidenced by higher calcium deposits detected by alizarin red staining, and higher alkaline phosphatase (ALP), especially for PLA in osteogenic medium. Proteomics data revealed the most distinct separation between conditions in chondrogenic medium, which had the highest protein identification rates. Pathway analysis showed that PCL did not induce any differentiation-related pathways when compared to PEOT/PBT and PLA in any of the tested media conditions. Analysis of PEOT/PBT proteins showed pathways involved in chondrogenesis in all three media and pathways related to hypertrophic phenotype progression in chondrogenic medium. These data suggests that PEOT/PBT is a valuable candidate for cartilage and osteochondral applications, able to drive hBMSCs differentiation without the need of growth factors. PLA was also a valuable candidate for cartilage and bone applications by upregulating both chondrogenic and osteogenic-related proteins in maintenance and chondrogenic media. In osteogenic and maintenance media, the upregulation of angiogenic proteins makes PLA a better candidate for bone application where vascularization is key.
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Affiliation(s)
- Clarissa Tomasina
- MERLN Institute for Technology‐inspired Regenerative MedicineComplex Tissue Regeneration DepartmentMaastricht UniversityP.O. Box 6166200 MDMaastrichtThe Netherlands
| | - Ronny Mohren
- The Maastricht MultiModal Molecular Imaging Institute (M4i)Division of Imaging Mass SpectrometryMaastricht University6200 MDMaastrichtThe Netherlands
| | - Sandra Camarero‐Espinosa
- MERLN Institute for Technology‐inspired Regenerative MedicineComplex Tissue Regeneration DepartmentMaastricht UniversityP.O. Box 6166200 MDMaastrichtThe Netherlands
- POLYMAT Basque Center for Macromolecular Design and EngineeringJoxe Mari Korta Center ‐ Avda. Tolosa, 7220018Donostia‐San SebastianSpain
- IKERBASQUEBasque Foundation for Science48009BilbaoSpain
| | - Berta Cillero‐Pastor
- MERLN Institute for Technology‐inspired Regenerative MedicineComplex Tissue Regeneration DepartmentMaastricht UniversityP.O. Box 6166200 MDMaastrichtThe Netherlands
- The Maastricht MultiModal Molecular Imaging Institute (M4i)Division of Imaging Mass SpectrometryMaastricht University6200 MDMaastrichtThe Netherlands
| | - Lorenzo Moroni
- MERLN Institute for Technology‐inspired Regenerative MedicineComplex Tissue Regeneration DepartmentMaastricht UniversityP.O. Box 6166200 MDMaastrichtThe Netherlands
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Shaji M, Tamada A, Fujimoto K, Muguruma K, Karsten SL, Yokokawa R. Deciphering potential vascularization factors of on-chip co-cultured hiPSC-derived cerebral organoids. LAB ON A CHIP 2024; 24:680-696. [PMID: 38284292 DOI: 10.1039/d3lc00930k] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2024]
Abstract
The lack of functional vascular system in stem cell-derived cerebral organoids (COs) limits their utility in modeling developmental processes and disease pathologies. Unlike other organs, brain vascularization is poorly understood, which makes it particularly difficult to mimic in vitro. Although several attempts have been made to vascularize COs, complete vascularization leading to functional capillary network development has only been achieved via transplantation into a mouse brain. Understanding the cues governing neurovascular communication is therefore imperative for establishing an efficient in vitro system for vascularized cerebral organoids that can emulate human brain development. Here, we used a multidisciplinary approach combining microfluidics, organoids, and transcriptomics to identify molecular changes in angiogenic programs that impede the successful in vitro vascularization of human induced pluripotent stem cell (iPSC)-derived COs. First, we established a microfluidic cerebral organoid (CO)-vascular bed (VB) co-culture system and conducted transcriptome analysis on the outermost cell layer of COs cultured on the preformed VB. Results revealed coordinated regulation of multiple pro-angiogenic factors and their downstream targets. The VEGF-HIF1A-AKT network was identified as a central pathway involved in the angiogenic response of cerebral organoids to the preformed VB. Among the 324 regulated genes associated with angiogenesis, six transcripts represented significantly regulated growth factors with the capacity to influence angiogenic activity during co-culture. Subsequent on-chip experiments demonstrated the angiogenic and vasculogenic potential of cysteine-rich angiogenic inducer 61 (CYR61) and hepatoma-derived growth factor (HDGF) as potential enhancers of organoid vascularization. Our study provides the first global analysis of cerebral organoid response to three-dimensional microvasculature for in vitro vascularization.
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Affiliation(s)
- Maneesha Shaji
- Department of Micro Engineering, Graduate School of Engineering, Kyoto University, Kyoto daigaku-Katsura, Nishikyo-ku, Kyoto - 615-8540, Japan.
| | - Atsushi Tamada
- Department of iPS Cell Applied Medicine, Kansai Medical University, 2-5-1 Shin-machi, Hirakata City, Osaka - 573-1010, Japan.
| | - Kazuya Fujimoto
- Department of Micro Engineering, Graduate School of Engineering, Kyoto University, Kyoto daigaku-Katsura, Nishikyo-ku, Kyoto - 615-8540, Japan.
| | - Keiko Muguruma
- Department of iPS Cell Applied Medicine, Kansai Medical University, 2-5-1 Shin-machi, Hirakata City, Osaka - 573-1010, Japan.
| | - Stanislav L Karsten
- Department of Micro Engineering, Graduate School of Engineering, Kyoto University, Kyoto daigaku-Katsura, Nishikyo-ku, Kyoto - 615-8540, Japan.
| | - Ryuji Yokokawa
- Department of Micro Engineering, Graduate School of Engineering, Kyoto University, Kyoto daigaku-Katsura, Nishikyo-ku, Kyoto - 615-8540, Japan.
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Arango-Rodríguez ML, Mateus LC, Sossa CL, Becerra-Bayona SM, Solarte-David VA, Ochoa Vera ME, Viviescas LTG, Berrio AMV, Serrano SE, Vargas O, Isla AC, Benitez A, Rangel G. A novel therapeutic management for diabetes patients with chronic limb-threatening ischemia: comparison of autologous bone marrow mononuclear cells versus allogenic Wharton jelly-derived mesenchymal stem cells. Stem Cell Res Ther 2023; 14:221. [PMID: 37626416 PMCID: PMC10464344 DOI: 10.1186/s13287-023-03427-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 07/24/2023] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND Chronic limb-threatening ischemia (CLTI) represents the final stage of peripheral arterial disease. Approximately one-third of patients with CLTI are not eligible for conventional surgical treatments. Furthermore, patients with advanced stage of CLTI are prone to amputation and death. Thus, an effective therapeutic strategy is urgently needed. In this context, autologous bone marrow mononuclear cell (auto-BM-MNC) and allogeneic mesenchymal stem cells represent a promising therapeutic approach for treating CLTI. In this study, we compared the safety and beneficial therapeutic effect of auto-BM-MNC versus allogeneic Wharton jelly-derived mesenchymal stem cells (allo-WJ-MSCs) in diabetic patients with CLTI. METHODS We performed a randomized, prospective, double-blind and controlled pilot study. Twenty-four diabetic patients in the advanced stage of CLTI (4 or 5 in Rutherford's classification) and a transcutaneous oxygen pressure (TcPO2) below 30 mmHg were randomized to receive 15 injections of (i) auto-BM-MNC (7.197 × 106 ± 2.984 × 106 cells/mL) (n = 7), (ii) allo-WJ-MSCs (1.333 × 106 cells/mL) (n = 7) or (iii) placebo solution (1 mL) (n = 10), which were administered into the periadventitial layer of the arterial walls under eco-Doppler guidance. The follow-up visits were at months 1, 3, 6, and 12 to evaluate the following parameters: (i) Rutherford's classification, (ii) TcPO2, (iii) percentage of wound closure, (iv) pain, (v) pain-free walking distance, (vi) revascularization and limb-survival proportion, and (vii) life quality (EQ-5D questionnaire). RESULTS No adverse events were reported. Patients with CLTI who received auto-BM-MNC and allo-WJ-MSCs presented an improvement in Rutherford's classification, a significant increase in TcPO2 values, a reduction in the lesion size in a shorter time, a decrease in the pain score and an increase in the pain-free walking distance, in comparison with the placebo group. In addition, the participants treated with auto-BM-MNC and allo-WJ-MSCs kept their limbs during the follow-up period, unlike the placebo group, which had a marked increase in amputation. CONCLUSIONS Our results showed that patients with CLTI treated with auto-BM-MNC and allo-WJ-MSCs conserved 100% of their limb during 12 months of the follow-up compared to the placebo group, where 60% of participants underwent limb amputation in different times. Furthermore, we observed a faster improvement in the allo-WJ-MSC group, unlike the auto-BM-MNC group. Trial registration This study was retrospectively registered at ClinicalTrials.gov (NCT05631444).
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Affiliation(s)
- Martha L Arango-Rodríguez
- Banco Multitejidos y Centro de Terapias Avanzadas, Clínica FOSCAL Internacional, 681004, Floridablanca, Colombia.
| | - Ligia C Mateus
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
| | - Claudia L Sossa
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
- Programa para el Tratamiento y Estudio de Enfermedades Hematológicas y Oncológicas de Santander (PROTEHOS), 681004153, Floridablanca, Colombia
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, 681003, Bucaramanga, Colombia
| | - Silvia M Becerra-Bayona
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, 681003, Bucaramanga, Colombia
| | - Víctor Alfonso Solarte-David
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, 681003, Bucaramanga, Colombia
- Facultad de Ingeniería, Universidad Autónoma de Bucaramanga - UNAB, 680003, Bucaramanga, Colombia
| | - Miguel Enrique Ochoa Vera
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, 681003, Bucaramanga, Colombia
| | - Lady T Giratá Viviescas
- Banco Multitejidos y Centro de Terapias Avanzadas, Clínica FOSCAL Internacional, 681004, Floridablanca, Colombia
| | - Ana M Vera Berrio
- Banco Multitejidos y Centro de Terapias Avanzadas, Clínica FOSCAL Internacional, 681004, Floridablanca, Colombia
| | - Sergio Eduardo Serrano
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, 681003, Bucaramanga, Colombia
| | - Oliverio Vargas
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
| | - Andrés Catalá Isla
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
| | - Alape Benitez
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
| | - Germán Rangel
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
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Caiati C, Jirillo E. Transplantation of Mesenchymal Stem Cells as a New Approach for Cardiovascular Diseases: From Bench to Bedside: A Perspective. Endocr Metab Immune Disord Drug Targets 2023; 23:1359-1364. [PMID: 37055907 DOI: 10.2174/1871530323666230411142308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 03/01/2023] [Indexed: 04/15/2023]
Affiliation(s)
- Carlo Caiati
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Emilio Jirillo
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
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Shirbaghaee Z, Hassani M, Heidari Keshel S, Soleimani M. Emerging roles of mesenchymal stem cell therapy in patients with critical limb ischemia. Stem Cell Res Ther 2022; 13:462. [PMID: 36068595 PMCID: PMC9449296 DOI: 10.1186/s13287-022-03148-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/19/2022] [Indexed: 11/25/2022] Open
Abstract
Critical limb ischemia (CLI), the terminal stage of peripheral arterial disease (PAD), is characterized by an extremely high risk of amputation and vascular issues, resulting in severe morbidity and mortality. In patients with severe limb ischemia with no alternative therapy options, such as endovascular angioplasty or bypass surgery, therapeutic angiogenesis utilizing cell-based therapies is vital for increasing blood flow to ischemic regions. Mesenchymal stem cells (MSCs) are currently considered one of the most encouraging cells as a regenerative alternative for the surgical treatment of CLI, including restoring tissue function and repairing ischemic tissue via immunomodulation and angiogenesis. The regenerative treatments for limb ischemia based on MSC therapy are still considered experimental. Despite recent advances in preclinical and clinical research studies, it is not recommended for regular clinical use. In this study, we review the immunomodulatory features of MSC besides the current understanding of different sources of MSC in the angiogenic treatment of CLI subjects and their potential applications as therapeutic agents. Specifically, this paper concentrates on the most current clinical application issues, and several recommendations are provided to improve the efficacy of cell therapy for CLI patients.
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Affiliation(s)
- Zeinab Shirbaghaee
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Hassani
- Department of Vascular and Endovascular Surgery, Ayatollah Taleghani Hospital Research Development Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Heidari Keshel
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoud Soleimani
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Applied Cell Science and Hematology Department, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran.
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Hettler F, Schreck C, Marquez SR, Engleitner T, Vilne B, Landspersky T, Weidner H, Hausinger R, Mishra R, Oellinger R, Rauner M, Naumann R, Peschel C, Bassermann F, Rad R, Istvanffy R, Oostendorp RA. Osteoprogenitor SFRP1 prevents exhaustion of hematopoietic stem cells via PP2A-PR72/130-mediated regulation of p300. Haematologica 2022; 108:490-501. [PMID: 35950533 PMCID: PMC9890018 DOI: 10.3324/haematol.2022.280760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Indexed: 02/03/2023] Open
Abstract
Remodeling of the bone marrow microenvironment in chronic inflammation and in aging reduces hematopoietic stem cell (HSC) function. To assess the mechanisms of this functional decline of HSC and find strategies to counteract it, we established a model in which the Sfrp1 gene was deleted in Osterix+ osteolineage cells (OS1Δ/Δ mice). HSC from these mice showed severely diminished repopulating activity with associated DNA damage, enriched expression of the reactive oxygen species pathway and reduced single-cell proliferation. Interestingly, not only was the protein level of Catenin beta-1 (bcatenin) elevated, but so was its association with the phosphorylated co-activator p300 in the nucleus. Since these two proteins play a key role in promotion of differentiation and senescence, we inhibited in vivo phosphorylation of p300 through PP2A-PR72/130 by administration of IQ-1 in OS1Δ/Δ mice. This treatment not only reduced the b-catenin/phosphop300 association, but also decreased nuclear p300. More importantly, in vivo IQ-1 treatment fully restored HSC repopulating activity of the OS1Δ/Δ mice. Our findings show that the osteoprogenitor Sfrp1 is essential for maintaining HSC function. Furthermore, pharmacological downregulation of the nuclear b-catenin/phospho-p300 association is a new strategy to restore poor HSC function.
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Affiliation(s)
- Franziska Hettler
- Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology/Oncology, Munich, Germany,FH and CS contributed equally as co-first authors
| | - Christina Schreck
- Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology/Oncology, Munich, Germany,FH and CS contributed equally as co-first authors
| | - Sandra Romero Marquez
- Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology/Oncology, Munich, Germany
| | - Thomas Engleitner
- Technical University of Munich, School of Medicine, Center for Translational Cancer Research (TranslaTUM), Munich, Germany: ,Technical University of Munich, School of Medicine, Institute of Molecular Oncology and Functional Genomics, Munich, Germany
| | - Baiba Vilne
- Bioinformatics Research Unit, Riga Stradins University Riga, Riga, Latvia,netOmics, Riga, Latvia
| | - Theresa Landspersky
- Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology/Oncology, Munich, Germany
| | - Heike Weidner
- Bone Lab Dresden, Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Renate Hausinger
- Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology/Oncology, Munich, Germany
| | - Ritu Mishra
- Technical University of Munich, School of Medicine, Center for Translational Cancer Research (TranslaTUM), Munich, Germany: ,School of Medicine, Institute of Clinical Chemistry and Pathobiochemistry, Technical University of Munich, Munich, Germany
| | - Rupert Oellinger
- Technical University of Munich, School of Medicine, Center for Translational Cancer Research (TranslaTUM), Munich, Germany: ,Technical University of Munich, School of Medicine, Institute of Molecular Oncology and Functional Genomics, Munich, Germany
| | - Martina Rauner
- Bone Lab Dresden, Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Ronald Naumann
- Max Planck Institute of Molecular Cell Biology and Genetics, Transgenic Core Facility, Dresden, Germany
| | - Christian Peschel
- Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology/Oncology, Munich, Germany,German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Florian Bassermann
- Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology/Oncology, Munich, Germany,German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Roland Rad
- Technical University of Munich, School of Medicine, Center for Translational Cancer Research (TranslaTUM), Munich, Germany: ,Technical University of Munich, School of Medicine, Institute of Molecular Oncology and Functional Genomics, Munich, Germany,German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Rouzanna Istvanffy
- Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology/Oncology, Munich, Germany,Current afliation: Technical University of Munich, School of Medicine, Surgery Department, Munich, Germany
| | - Robert A.J. Oostendorp
- Technical University of Munich, School of Medicine, Department of Internal Medicine III Hematology/Oncology, Munich, Germany,RI and RAJO contributed equally as co-senior authors
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9
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Sunkara RR, Mehta D, Sarate RM, Waghmare SK. BMP-AKT-GSK3β signalling restores hair follicle stem cells decrease associated with loss of Sfrp1. Stem Cells 2022; 40:802-817. [PMID: 35689817 DOI: 10.1093/stmcls/sxac041] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 04/05/2022] [Indexed: 11/15/2022]
Abstract
Wnt signaling plays a pivotal role in regulating activation, proliferation, stem cell renewal and differentiation of hair follicle stem cells (HFSCs). Secreted frizzled related protein-1 (Sfrp1), a Wnt antagonist is up regulated in the HFSCs; however, its role in the HFSCs regulation is still obscure. Here, we show that Sfrp1 loss showed a depletion of HFSCs, enhanced HFSC proliferation and faster hair follicle cycle at PD21 to PD28, HFSC markers such as Lgr5 and Axin2 were decreased in both the Sfrp1 +/- and Sfrp1 -/- HFSCs. In addition, the second hair follicle cycle was also faster as compared to WT. Importantly, Sfrp1 -/- showed a restoration of HFSC by 2 nd telogen (PD49), while Sfrp1+/- did not show restoration with still having a decreased HFSC. Infact, restoration of HFSCs was due to a pronounced down-regulation of β-CATENIN activity mediated through a cross-talk of BMP-AKT-GSK3β signalling in Sfrp1-/- as compared to Sfrp1+/-, where down regulation was less pronounced. In cultured keratinocytes, Sfrp1 loss resulted in enhanced proliferation and clonogenicity, which were reversed by treating with either BMPR1A or GSK3β inhibitor thereby confirming BMP-AKT-GSK3β signaling involved in β-CATENIN regulation in both the Sfrp1 +/- and Sfrp1 -/- mice. Our study reveals a novel function of Sfrp1 by unravelling an in vivo molecular mechanism that regulate the HFSCs pool mediated through a hitherto unknown cross-talk of BMP-AKT-GSK3β signalling that maintain stem cell pool balance, which in turn maintain skin tissue homeostasis.
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Affiliation(s)
- Raghava R Sunkara
- Stem Cell Biology Group, Waghmare Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India
| | - Darshan Mehta
- Stem Cell Biology Group, Waghmare Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India
| | - Rahul M Sarate
- Stem Cell Biology Group, Waghmare Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India
| | - Sanjeev K Waghmare
- Stem Cell Biology Group, Waghmare Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.,Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India
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10
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Molnar V, Pavelić E, Vrdoljak K, Čemerin M, Klarić E, Matišić V, Bjelica R, Brlek P, Kovačić I, Tremolada C, Primorac D. Mesenchymal Stem Cell Mechanisms of Action and Clinical Effects in Osteoarthritis: A Narrative Review. Genes (Basel) 2022; 13:genes13060949. [PMID: 35741711 PMCID: PMC9222975 DOI: 10.3390/genes13060949] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/21/2022] [Accepted: 05/24/2022] [Indexed: 02/04/2023] Open
Abstract
With the insufficient satisfaction rates and high cost of operative treatment for osteoarthritis (OA), alternatives have been sought. Furthermore, the inability of current medications to arrest disease progression has led to rapidly growing clinical research relating to mesenchymal stem cells (MSCs). The availability and function of MSCs vary according to tissue source. The three primary sources include the placenta, bone marrow, and adipose tissue, all of which offer excellent safety profiles. The primary mechanisms of action are trophic and immunomodulatory effects, which prevent the further degradation of joints. However, the function and degree to which benefits are observed vary significantly based on the exosomes secreted by MSCs. Paracrine and autocrine mechanisms prevent cell apoptosis and tissue fibrosis, initiate angiogenesis, and stimulate mitosis via growth factors. MSCs have even been shown to exhibit antimicrobial effects. Clinical results incorporating clinical scores and objective radiological imaging have been promising, but a lack of standardization in isolating MSCs prevents their incorporation in current guidelines.
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Affiliation(s)
- Vilim Molnar
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Eduard Pavelić
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | - Kristijan Vrdoljak
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.V.); (M.Č.)
| | - Martin Čemerin
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.V.); (M.Č.)
| | - Emil Klarić
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | - Vid Matišić
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | - Roko Bjelica
- Department of Oral Surgery, School of Dental Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Petar Brlek
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | | | | | - Dragan Primorac
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Medical School, University of Split, 21000 Split, Croatia
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Medical School, University of Rijeka, 51000 Rijeka, Croatia
- Medical School REGIOMED, 96450 Coburg, Germany
- Eberly College of Science, The Pennsylvania State University, University Park, PA 16802, USA
- The Henry C. Lee College of Criminal Justice and Forensic Sciences, University of New Haven, West Haven, CT 06516, USA
- Correspondence:
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11
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Matheakakis A, Batsali A, Papadaki HA, Pontikoglou CG. Therapeutic Implications of Mesenchymal Stromal Cells and Their Extracellular Vesicles in Autoimmune Diseases: From Biology to Clinical Applications. Int J Mol Sci 2021; 22:10132. [PMID: 34576296 PMCID: PMC8468750 DOI: 10.3390/ijms221810132] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/14/2021] [Accepted: 09/15/2021] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are perivascular multipotent stem cells originally identified in the bone marrow (BM) stroma and subsequently in virtually all vascularized tissues. Because of their ability to differentiate into various mesodermal lineages, their trophic properties, homing capacity, and immunomodulatory functions, MSCs have emerged as attractive candidates in tissue repair and treatment of autoimmune disorders. Accumulating evidence suggests that the beneficial effects of MSCs may be primarily mediated via a number of paracrine-acting soluble factors and extracellular vesicles (EVs). EVs are membrane-coated vesicles that are increasingly being acknowledged as playing a key role in intercellular communication via their capacity to carry and deliver their cargo, consisting of proteins, nucleic acids, and lipids to recipient cells. MSC-EVs recapitulate the functions of the cells they originate, including immunoregulatory effects but do not seem to be associated with the limitations and concerns of cell-based therapies, thereby emerging as an appealing alternative therapeutic option in immune-mediated disorders. In the present review, the biology of MSCs will be outlined and an overview of their immunomodulatory functions will be provided. In addition, current knowledge on the features of MSC-EVs and their immunoregulatory potential will be summarized. Finally, therapeutic applications of MSCs and MSC-EVs in autoimmune disorders will be discussed.
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Affiliation(s)
- Angelos Matheakakis
- Department of Hematology, School of Medicine, University of Crete, 71500 Heraklion, Greece; (A.M.); (H.A.P.)
- Haemopoiesis Research Laboratory, School of Medicine, University of Crete, 71500 Heraklion, Greece;
| | - Aristea Batsali
- Haemopoiesis Research Laboratory, School of Medicine, University of Crete, 71500 Heraklion, Greece;
| | - Helen A. Papadaki
- Department of Hematology, School of Medicine, University of Crete, 71500 Heraklion, Greece; (A.M.); (H.A.P.)
- Haemopoiesis Research Laboratory, School of Medicine, University of Crete, 71500 Heraklion, Greece;
| | - Charalampos G. Pontikoglou
- Department of Hematology, School of Medicine, University of Crete, 71500 Heraklion, Greece; (A.M.); (H.A.P.)
- Haemopoiesis Research Laboratory, School of Medicine, University of Crete, 71500 Heraklion, Greece;
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12
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Gong Y, Yang J, Li X, Zhou C, Chen Y, Wang Z, Qiu X, Liu Y, Zhang H, Greenbaum J, Cheng L, Hu Y, Xie J, Yang X, Li Y, Bai Y, Wang YP, Chen Y, Tan LJ, Shen H, Xiao HM, Deng HW. A systematic dissection of human primary osteoblasts in vivo at single-cell resolution. Aging (Albany NY) 2021; 13:20629-20650. [PMID: 34428745 PMCID: PMC8436943 DOI: 10.18632/aging.203452] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 06/19/2021] [Indexed: 12/12/2022]
Abstract
Human osteoblasts are multifunctional bone cells, which play essential roles in bone formation, angiogenesis regulation, as well as maintenance of hematopoiesis. However, the categorization of primary osteoblast subtypes in vivo in humans has not yet been achieved. Here, we used single-cell RNA sequencing (scRNA-seq) to perform a systematic cellular taxonomy dissection of freshly isolated human osteoblasts from one 31-year-old male with osteoarthritis and osteopenia after hip replacement. Based on the gene expression patterns and cell lineage reconstruction, we identified three distinct cell clusters including preosteoblasts, mature osteoblasts, and an undetermined rare osteoblast subpopulation. This novel subtype was found to be the major source of the nuclear receptor subfamily 4 group A member 1 and 2 (NR4A1 and NR4A2) in primary osteoblasts, and the expression of NR4A1 was confirmed by immunofluorescence staining on mouse osteoblasts in vivo. Trajectory inference analysis suggested that the undetermined cluster, together with the preosteoblasts, are involved in the regulation of osteoblastogenesis and also give rise to mature osteoblasts. Investigation of the biological processes and signaling pathways enriched in each subpopulation revealed that in addition to bone formation, preosteoblasts and undetermined osteoblasts may also regulate both angiogenesis and hemopoiesis. Finally, we demonstrated that there are systematic differences between the transcriptional profiles of human and mouse osteoblasts, highlighting the necessity for studying bone physiological processes in humans rather than solely relying on mouse models. Our findings provide novel insights into the cellular heterogeneity and potential biological functions of human primary osteoblasts at the single-cell level.
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MESH Headings
- Adult
- Animals
- Cell Differentiation
- Cells, Cultured
- Humans
- Male
- Mice
- Nuclear Receptor Subfamily 4, Group A, Member 1/genetics
- Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism
- Nuclear Receptor Subfamily 4, Group A, Member 2/genetics
- Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism
- Osteoblasts/cytology
- Osteoblasts/metabolism
- Sequence Analysis, RNA
- Single-Cell Analysis
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Affiliation(s)
- Yun Gong
- Tulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Junxiao Yang
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Xiaohua Li
- Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha 410081, China
| | - Cui Zhou
- Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha 410081, China
| | - Yu Chen
- Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha 410081, China
| | - Zun Wang
- Xiangya Nursing School, Central South University, Changsha 410013, China
| | - Xiang Qiu
- School of Basic Medical Science, Central South University, Changsha 410008, China
| | - Ying Liu
- Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha 410081, China
| | - Huixi Zhang
- Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha 410081, China
| | - Jonathan Greenbaum
- Tulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Liang Cheng
- Department of Orthopedics and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Yihe Hu
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Jie Xie
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Xuecheng Yang
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Yusheng Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Yuntong Bai
- Tulane Center for Bioinformatics and Genomics, Department of Biomedical Engineering, Tulane University, New Orleans, LA 70112, USA
| | - Yu-Ping Wang
- Tulane Center for Bioinformatics and Genomics, Department of Biomedical Engineering, Tulane University, New Orleans, LA 70112, USA
| | - Yiping Chen
- Department of Cell and Molecular Biology, School of Science and Engineering, Tulane University, New Orleans, LA 70112, USA
| | - Li-Jun Tan
- Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha 410081, China
| | - Hui Shen
- Tulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Hong-Mei Xiao
- Center of Reproductive Health, System Biology and Data Information, Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha 410081, China
- School of Basic Medical Science, Central South University, Changsha 410008, China
| | - Hong-Wen Deng
- Tulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, LA 70112, USA
- School of Basic Medical Science, Central South University, Changsha 410008, China
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13
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Zhuang WZ, Lin YH, Su LJ, Wu MS, Jeng HY, Chang HC, Huang YH, Ling TY. Mesenchymal stem/stromal cell-based therapy: mechanism, systemic safety and biodistribution for precision clinical applications. J Biomed Sci 2021; 28:28. [PMID: 33849537 PMCID: PMC8043779 DOI: 10.1186/s12929-021-00725-7] [Citation(s) in RCA: 154] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 04/07/2021] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are a promising resource for cell-based therapy because of their high immunomodulation ability, tropism towards inflamed and injured tissues, and their easy access and isolation. Currently, there are more than 1200 registered MSC clinical trials globally. However, a lack of standardized methods to characterize cell safety, efficacy, and biodistribution dramatically hinders the progress of MSC utility in clinical practice. In this review, we summarize the current state of MSC-based cell therapy, focusing on the systemic safety and biodistribution of MSCs. MSC-associated risks of tumor initiation and promotion and the underlying mechanisms of these risks are discussed. In addition, MSC biodistribution methodology and the pharmacokinetics and pharmacodynamics of cell therapies are addressed. Better understanding of the systemic safety and biodistribution of MSCs will facilitate future clinical applications of precision medicine using stem cells.
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Affiliation(s)
- Wei-Zhan Zhuang
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan
| | - Yi-Heng Lin
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, 10041, Taiwan.,Department of Obstetrics and Gynecology, National Taiwan University Hospital Yunlin Branch, Yunlin, 64041, Taiwan
| | - Long-Jyun Su
- Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, 106, Taiwan
| | - Meng-Shiue Wu
- Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10617, Taiwan
| | - Han-Yin Jeng
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.,TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan
| | - Huan-Cheng Chang
- Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei, 106, Taiwan.,Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei, 106, Taiwan
| | - Yen-Hua Huang
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. .,Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. .,TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. .,International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan. .,Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei, 11031, Taiwan. .,Comprehensive Cancer Center of Taipei Medical University, Taipei, 11031, Taiwan. .,The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan.
| | - Thai-Yen Ling
- Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10617, Taiwan. .,Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, 100, Taiwan.
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14
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Beldi G, Bahiraii S, Lezin C, Nouri Barkestani M, Abdelgawad ME, Uzan G, Naserian S. TNFR2 Is a Crucial Hub Controlling Mesenchymal Stem Cell Biological and Functional Properties. Front Cell Dev Biol 2020; 8:596831. [PMID: 33344453 PMCID: PMC7746825 DOI: 10.3389/fcell.2020.596831] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 11/03/2020] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have drawn lots of attention as gold standard stem cells in fundamental and clinical researches during the last 20 years. Due to their tissue and vascular repair capacities, MSCs have been used to treat a variety of degenerative disorders. Moreover, MSCs are able to modulate immune cells’ functions, particularly T cells while inducing regulatory T cells (iTregs). MSCs are very sensitive to inflammatory signals. Their biological functions could remarkably vary after exposure to different pro-inflammatory cytokines, notably TNFα. In this article, we have explored the importance of TNFR2 expression in a series of MSCs’ biological and functional properties. Thus, MSCs from wild-type (WT) and TNFR2 knockout (TNFR2 KO) mice were isolated and underwent several ex vivo experiments to investigate the biological significance of TNFR2 molecule in MSC main functions. Hampering in TNFR2 signaling resulted in reduced MSC colony-forming units and proliferation rate and diminished the expression of all MSC characteristic markers such as stem cell antigen-1 (Sca1), CD90, CD105, CD44, and CD73. TNFR2 KO-MSCs produced more pro-inflammatory cytokines like TNFα, IFNγ, and IL-6 and less anti-inflammatory mediators such as IL-10, TGFβ, and NO and induced Tregs with less suppressive effect. Furthermore, the TNFR2 blockade remarkably decreased MSC regenerative functions such as wound healing, complex tube formation, and endothelial pro-angiogenic support. Therefore, our results reveal the TNFα–TNFR2 axis as a crucial regulator of MSC immunological and regenerative functions.
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Affiliation(s)
- Ghada Beldi
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France
| | - Sheyda Bahiraii
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France.,Department of Pharmacognosy, University of Vienna, Vienna, Austria
| | - Chloé Lezin
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France.,Paris-Saclay University, Villejuif, France
| | | | - Mohamed Essameldin Abdelgawad
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France.,Paris-Saclay University, Villejuif, France.,Biochemistry Division, Chemistry Department, Faculty of Science, Helwan University, Cairo, Egypt
| | - Georges Uzan
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France.,Paris-Saclay University, Villejuif, France
| | - Sina Naserian
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France.,Paris-Saclay University, Villejuif, France.,CellMedEx, Saint Maur Des Fossés, France
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15
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Zhang W, Zhang X, Zhang Y, Zhang X, Zou T, Zhao W, Lv Y, Wang J, Dai P, Cui H, Zhang Y, Gao D, Ruan C, Zhang X. Retracted: Cell Fate and Tissue Remodeling in Canine Urethral Repair Using a Bone Marrow Mesenchymal Stem Cell+Endothelial Progenitor Cell Amniotic Patch. Tissue Eng Part A 2020; 26:e1403-e1412. [PMID: 32808578 DOI: 10.1089/ten.tea.2020.0129] [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: 11/12/2022] Open
Abstract
The Editors of Tissue Engineering: Part A retract the article entitled, "Cell Fate and Tissue Remodeling in Canine Urethral Repair Using a Bone Marrow Mesenchymal Stem Cell+Endothelial Progenitor Cell Amniotic Patch," by Wenxin Zhang, Xin Zhang, Yihua Zhang, Xinke Zhang, Tong Zou, Wen Zhao, Yangou Lv, Jinglu Wang, Pengxiu Dai, Hao Cui, Yi Zhang, Dengke Gao, Chenmei Ruan, and Xia Zhang (epub ahead of print September 21, 2020; DOI: http://doi.org/10.1089/ten.tea.2020.0129). After the online publication of the article, the authors have indicated that they "feel that we have not yet studied our work completely and some new great results are discovered. So after carefully thinking, we are going to rearrange this manuscript and try to give more precise model. [sic]" The authors have not explained what those expected results will be, so it remains unclear the direction their work is headed. The authors also indicated that they plan to submit an updated version of the paper to Tissue Engineering in the future. Upon submission the new manuscript will undergo rigorous peer review, and there is no guarantee of acceptance.
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Affiliation(s)
- Wenxin Zhang
- Shaanxi Branch of National Stem Cell Engineering and Technology Center, College of Veterinary Medicine, Northwest A&F University, Shaanxi, China
| | - Xin Zhang
- Shaanxi Branch of National Stem Cell Engineering and Technology Center, College of Veterinary Medicine, Northwest A&F University, Shaanxi, China
| | - Yihua Zhang
- Shaanxi Branch of National Stem Cell Engineering and Technology Center, College of Veterinary Medicine, Northwest A&F University, Shaanxi, China
| | - Xinke Zhang
- Shaanxi Branch of National Stem Cell Engineering and Technology Center, College of Veterinary Medicine, Northwest A&F University, Shaanxi, China
| | - Tong Zou
- Shaanxi Branch of National Stem Cell Engineering and Technology Center, College of Veterinary Medicine, Northwest A&F University, Shaanxi, China
| | - Wen Zhao
- Shaanxi Branch of National Stem Cell Engineering and Technology Center, College of Veterinary Medicine, Northwest A&F University, Shaanxi, China
| | - Yangou Lv
- Shaanxi Branch of National Stem Cell Engineering and Technology Center, College of Veterinary Medicine, Northwest A&F University, Shaanxi, China
| | - Jinglu Wang
- Shaanxi Branch of National Stem Cell Engineering and Technology Center, College of Veterinary Medicine, Northwest A&F University, Shaanxi, China
| | - Pengxiu Dai
- Shaanxi Branch of National Stem Cell Engineering and Technology Center, College of Veterinary Medicine, Northwest A&F University, Shaanxi, China
| | - Hao Cui
- Shaanxi Branch of National Stem Cell Engineering and Technology Center, College of Veterinary Medicine, Northwest A&F University, Shaanxi, China
| | - Yi Zhang
- Shaanxi Branch of National Stem Cell Engineering and Technology Center, College of Veterinary Medicine, Northwest A&F University, Shaanxi, China
| | - Dengke Gao
- Shaanxi Branch of National Stem Cell Engineering and Technology Center, College of Veterinary Medicine, Northwest A&F University, Shaanxi, China
| | - Chenmei Ruan
- Shaanxi Branch of National Stem Cell Engineering and Technology Center, College of Veterinary Medicine, Northwest A&F University, Shaanxi, China
| | - Xia Zhang
- Shaanxi Branch of National Stem Cell Engineering and Technology Center, College of Veterinary Medicine, Northwest A&F University, Shaanxi, China
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16
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Lucciola R, Vrljicak P, Gurung S, Filby C, Darzi S, Muter J, Ott S, Brosens JJ, Gargett CE. Impact of Sustained Transforming Growth Factor-β Receptor Inhibition on Chromatin Accessibility and Gene Expression in Cultured Human Endometrial MSC. Front Cell Dev Biol 2020; 8:567610. [PMID: 32984350 PMCID: PMC7490520 DOI: 10.3389/fcell.2020.567610] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 08/13/2020] [Indexed: 12/18/2022] Open
Abstract
Endometrial mesenchymal stem cells (eMSC) drive the extraordinary regenerative capacity of the human endometrium. Clinical application of eMSC for therapeutic purposes is hampered by spontaneous differentiation and cellular senescence upon large-scale expansion in vitro. A83-01, a selective transforming growth factor-β receptor (TGFβ-R) inhibitor, promotes expansion of eMSC in culture by blocking differentiation and senescence, but the underlying mechanisms are incompletely understood. In this study, we combined RNA-seq and ATAC-seq to study the impact of sustained TGFβ-R inhibition on gene expression and chromatin architecture of eMSC. Treatment of primary eMSC with A83-01 for 5 weeks resulted in differential expression of 1,463 genes. Gene ontology analysis showed enrichment of genes implicated in cell growth whereas extracellular matrix genes and genes involved in cell fate commitment were downregulated. ATAC-seq analysis demonstrated that sustained TGFβ-R inhibition results in opening and closure of 3,555 and 2,412 chromatin loci, respectively. Motif analysis revealed marked enrichment of retinoic acid receptor (RAR) binding sites, which was paralleled by the induction of RARB, encoding retinoic acid receptor beta (RARβ). Selective RARβ inhibition attenuated proliferation and clonogenicity of A83-01 treated eMSC. Taken together, our study provides new insights into the gene networks and genome-wide chromatin changes that underpin maintenance of an undifferentiated phenotype of eMSC in prolonged culture.
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Affiliation(s)
- Raffaella Lucciola
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom
| | - Pavle Vrljicak
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom
- Tommy’s National Centre for Miscarriage Research, Warwick Medical School, University Hospitals Coventry and Warwickshire National Health Service Trust, Coventry, United Kingdom
| | - Shanti Gurung
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
| | - Caitlin Filby
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Saeedeh Darzi
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
| | - Joanne Muter
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom
- Tommy’s National Centre for Miscarriage Research, Warwick Medical School, University Hospitals Coventry and Warwickshire National Health Service Trust, Coventry, United Kingdom
| | - Sascha Ott
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom
- Tommy’s National Centre for Miscarriage Research, Warwick Medical School, University Hospitals Coventry and Warwickshire National Health Service Trust, Coventry, United Kingdom
| | - Jan J. Brosens
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom
- Tommy’s National Centre for Miscarriage Research, Warwick Medical School, University Hospitals Coventry and Warwickshire National Health Service Trust, Coventry, United Kingdom
| | - Caroline E. Gargett
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia
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17
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Summers ME, Richmond BW, Menon S, Sheridan RM, Kropski JA, Majka SA, Taketo MM, Bastarache JA, West JD, De Langhe S, Geraghty P, Klemm DJ, Chu HW, Friedman RS, Tao YK, Foronjy RF, Majka SM. Resident mesenchymal vascular progenitors modulate adaptive angiogenesis and pulmonary remodeling via regulation of canonical Wnt signaling. FASEB J 2020; 34:10267-10285. [PMID: 32533805 PMCID: PMC7496763 DOI: 10.1096/fj.202000629r] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 05/18/2020] [Accepted: 05/20/2020] [Indexed: 12/16/2022]
Abstract
Adaptive angiogenesis is necessary for tissue repair, however, it may also be associated with the exacerbation of injury and development of chronic disease. In these studies, we demonstrate that lung mesenchymal vascular progenitor cells (MVPC) modulate adaptive angiogenesis via lineage trace, depletion of MVPC, and modulation of β-catenin expression. Single cell sequencing confirmed MVPC as multipotential vascular progenitors, thus, genetic depletion resulted in alveolar simplification with reduced adaptive angiogenesis. Following vascular endothelial injury, Wnt activation in MVPC was sufficient to elicit an emphysema-like phenotype characterized by increased MLI, fibrosis, and MVPC driven adaptive angiogenesis. Lastly, activation of Wnt/β-catenin signaling skewed the profile of human and murine MVPC toward an adaptive phenotype. These data suggest that lung MVPC drive angiogenesis in response to injury and regulate the microvascular niche as well as subsequent distal lung tissue architecture via Wnt signaling.
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Affiliation(s)
- Megan E. Summers
- Department of MedicineDivision of Pulmonary, Critical Care & Sleep MedicineNational Jewish HealthDenverCOUSA
| | - Bradley W. Richmond
- Department of MedicineDivision of Allergy, Pulmonary and Critical Care Medicine or CardiologyVanderbilt University Medical CenterNashvilleTNUSA
| | - Swapna Menon
- Pulmonary Vascular Research Institute KochiAnalyzeDat Consulting ServicesErnakulamIndia
| | - Ryan M. Sheridan
- Department of Biochemistry and Molecular GeneticsRNA Bioscience InitiativeUniversity of Colorado School of MedicineAuroraCOUSA
| | - Jonathan A. Kropski
- Department of MedicineDivision of Allergy, Pulmonary and Critical Care Medicine or CardiologyVanderbilt University Medical CenterNashvilleTNUSA
| | - Sarah A. Majka
- Department of MedicineDivision of Pulmonary, Critical Care & Sleep MedicineNational Jewish HealthDenverCOUSA
| | - M. Mark Taketo
- Division of Experimental TherapeuticsGraduate School of MedicineKyoto UniversityKyotoJapan
| | - Julie A. Bastarache
- Department of MedicineDivision of Allergy, Pulmonary and Critical Care Medicine or CardiologyVanderbilt University Medical CenterNashvilleTNUSA
| | - James D. West
- Department of MedicineDivision of Allergy, Pulmonary and Critical Care Medicine or CardiologyVanderbilt University Medical CenterNashvilleTNUSA
| | | | - Patrick Geraghty
- Division of Pulmonary and Critical Care MedicineSUNY Downstate Medical CenterBrooklynNYUSA
| | - Dwight J. Klemm
- Department of Medicine, Pulmonary & Critical Care MedicineUniversity of ColoradoAuroraCOUSA
- Gates Center for Regenerative Medicine and Stem Cell BiologyUniversity of ColoradoAuroraCOUSA
| | - Hong Wei Chu
- Department of MedicineDivision of Pulmonary, Critical Care & Sleep MedicineNational Jewish HealthDenverCOUSA
| | | | - Yuankai K. Tao
- Pulmonary Vascular Research Institute KochiAnalyzeDat Consulting ServicesErnakulamIndia
| | - Robert F. Foronjy
- Division of Pulmonary and Critical Care MedicineSUNY Downstate Medical CenterBrooklynNYUSA
| | - Susan M. Majka
- Department of MedicineDivision of Pulmonary, Critical Care & Sleep MedicineNational Jewish HealthDenverCOUSA
- Gates Center for Regenerative Medicine and Stem Cell BiologyUniversity of ColoradoAuroraCOUSA
- Department of Biomedical ResearchNational Jewish HealthDenverCOUSA
- Biomedical EngineeringVanderbilt UniversityNashvilleTNUSA
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18
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Chu DT, Phuong TNT, Tien NLB, Tran DK, Thanh VV, Quang TL, Truong DT, Pham VH, Ngoc VTN, Chu-Dinh T, Kushekhar K. An Update on the Progress of Isolation, Culture, Storage, and Clinical Application of Human Bone Marrow Mesenchymal Stem/Stromal Cells. Int J Mol Sci 2020; 21:E708. [PMID: 31973182 PMCID: PMC7037097 DOI: 10.3390/ijms21030708] [Citation(s) in RCA: 127] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 01/10/2020] [Accepted: 01/14/2020] [Indexed: 12/13/2022] Open
Abstract
Bone marrow mesenchymal stem/stromal cells (BMSCs), which are known as multipotent cells, are widely used in the treatment of various diseases via their self-renewable, differentiation, and immunomodulatory properties. In-vitro and in-vivo studies have supported the understanding mechanisms, safety, and efficacy of BMSCs therapy in clinical applications. The number of clinical trials in phase I/II is accelerating; however, they are limited in the size of subjects, regulations, and standards for the preparation and transportation and administration of BMSCs, leading to inconsistency in the input and outcome of the therapy. Based on the International Society for Cellular Therapy guidelines, the characterization, isolation, cultivation, differentiation, and applications can be optimized and standardized, which are compliant with good manufacturing practice requirements to produce clinical-grade preparation of BMSCs. This review highlights and updates on the progress of production, as well as provides further challenges in the studies of BMSCs, for the approval of BMSCs widely in clinical application.
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Affiliation(s)
- Dinh-Toi Chu
- Faculty of Biology, Hanoi National University of Education, Hanoi 100000, Vietnam
- School of Odonto Stomatology, Hanoi Medical University, Hanoi 100000, Vietnam;
| | - Thuy Nguyen Thi Phuong
- Department of Animal Science, College of Agriculture and Life Science, Chonnam National University, Gwangju 61186, Korea
| | - Nguyen Le Bao Tien
- Institute of Orthopaedics and Trauma Surgery, Viet Duc Hospital, Hanoi 100000, Vietnam; (N.L.B.T.); (V.V.T.)
| | - Dang Khoa Tran
- Department of Anatomy, University of Medicine Pham Ngoc Thach, Ho Chi Minh City 700000, Vietnam;
| | - Vo Van Thanh
- Institute of Orthopaedics and Trauma Surgery, Viet Duc Hospital, Hanoi 100000, Vietnam; (N.L.B.T.); (V.V.T.)
- Department of Surgery, Hanoi Medical University, Hanoi 100000, Vietnam
| | - Thuy Luu Quang
- Center for Anesthesia and Surgical Intensive Care, Viet Duc Hospital, Hanoi 100000, Vietnam;
| | | | - Van Huy Pham
- AI Lab, Faculty of Information Technology, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam
| | - Vo Truong Nhu Ngoc
- School of Odonto Stomatology, Hanoi Medical University, Hanoi 100000, Vietnam;
| | - Thien Chu-Dinh
- Institute for Research and Development, Duy Tan University, Danang 550000, Vietnam
| | - Kushi Kushekhar
- Institute of Cancer Research, Oslo University Hospital, 0310 Oslo, Norway;
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19
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Abdelrazik H, Giordano E, Barbanti Brodano G, Griffoni C, De Falco E, Pelagalli A. Substantial Overview on Mesenchymal Stem Cell Biological and Physical Properties as an Opportunity in Translational Medicine. Int J Mol Sci 2019; 20:5386. [PMID: 31671788 PMCID: PMC6862078 DOI: 10.3390/ijms20215386] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Accepted: 10/25/2019] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stem cells (MSC) have piqued worldwide interest for their extensive potential to treat a large array of clinical indications, their unique and controversial immunogenic and immune modulatory properties allowing ample discussions and debates for their possible applications. Emerging data demonstrating that the interaction of biomaterials and physical cues with MSC can guide their differentiation into specific cell lineages also provide new interesting insights for further MSC manipulation in different clinical applications. Moreover, recent discoveries of some regulatory molecules and signaling pathways in MSC niche that may regulate cell fate to distinct lineage herald breakthroughs in regenerative medicine. Although the advancement and success in the MSC field had led to an enormous increase in the amount of ongoing clinical trials, we still lack defined clinical therapeutic protocols. This review will explore the exciting opportunities offered by human and animal MSC, describing relevant biological properties of these cells in the light of the novel emerging evidence mentioned above while addressing the limitations and challenges MSC are still facing.
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Affiliation(s)
- Heba Abdelrazik
- Department of Clinical Pathology, Cairo University, Cairo 1137, Egypt.
- Department of Diagnosis, central laboratory department, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale Policlinico San Martino, 16131 Genoa, Italy.
| | - Emanuele Giordano
- Department of Electrical, Electronic and Information Engineering "Guglielmo Marconi" (DEI), University of Bologna, 47522 Cesena, Italy.
| | - Giovanni Barbanti Brodano
- Department of Oncological and Degenerative Spine Surgery, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.
| | - Cristiana Griffoni
- Department of Oncological and Degenerative Spine Surgery, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.
| | - Elena De Falco
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy.
- Mediterranea Cardiocentro, 80122 Napoli, Italy.
| | - Alessandra Pelagalli
- Department of Advanced Biomedical Sciences, University of Naples "Federico II", 80131 Naples, Italy.
- Institute of Biostructures and Bioimages (IBB), National Research Council (CNR), 80131 Naples, Italy.
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20
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Majka SM, Rojas M, Petrache I, Foronjy RF. Mesenchymal Regulation of the Microvascular Niche in Chronic Lung Diseases. Compr Physiol 2019; 9:1431-1441. [PMID: 31688970 DOI: 10.1002/cphy.c180043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
The adult lung is comprised of diverse vascular, epithelial, and mesenchymal progenitor cell populations that reside in distinct niches. Mesenchymal progenitor cells (MPCs) are intimately associated with both the epithelium and the vasculature, and new evidence is emerging to describe their functional roles in these niches. Also emerging, following lineage analysis and single cell sequencing, is a new understanding of the diversity of mesenchymal cell subpopulations in the lung. However, several gaps in knowledge remain, including how newly defined MPC lineages interact with cells in the vascular niche and the role of adult lung MPCs during lung repair and regeneration following injury, especially in chronic lung diseases. Here we summarize how the current evidence on MPC regulation of the microvasculature during tissue homeostasis and injury may inform studies on understanding their role in chronic lung disease pathogenesis or repair. © 2019 American Physiological Society. Compr Physiol 9:1431-1441, 2019.
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Affiliation(s)
- Susan M Majka
- Department of Medicine, Division of Pulmonary, Critical Care & Sleep Medicine, National Jewish Health, Denver, Colorado, USA
| | - Mauricio Rojas
- McGowan Institute for Regenerative Medicine, Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Irina Petrache
- Department of Medicine, Division of Pulmonary, Critical Care & Sleep Medicine, National Jewish Health, Denver, Colorado, USA
| | - Robert F Foronjy
- Division of Pulmonary and Critical Care Medicine, SUNY Downstate Medical Center, Brooklyn, New York, USA
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21
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Wu X, Gu Q, Chen X, Mi W, Wu T, Huang H. MiR-27a targets DKK2 and SFRP1 to promote reosseointegration in the regenerative treatment of peri-implantitis. J Bone Miner Res 2019; 34:123-134. [PMID: 30151888 DOI: 10.1002/jbmr.3575] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 08/03/2018] [Accepted: 08/12/2018] [Indexed: 12/20/2022]
Abstract
In the inflamed microenvironment of peri-implantitis, limited osteogenesis on the implant surface impedes well-established reosseointegration using current clinical therapies. MicroRNAs (miRNAs) function as potent molecular managers that may simultaneously regulate multiple endogenous processes such as inflammation and osteogenesis. The delivery of miRNAs may provide a way to effectively treat some diseases. In this study, we showed that miR-27a was differentially downregulated in samples from a canine peri-implantitis model. We found that overexpressing miR-27a positively regulated osteogenesis-angiogenesis coupling by ameliorating the TNF-α inhibition of bone formation in vitro. Mechanistically, we identified Dickkopf2 (DKK2) and secreted frizzled related protein 1 (SFRP1) as two essential direct miR-27a targets that were osteogenic and angiogenic. Furthermore, we constructed a miR-27a-enhanced delivery system to repair the bone defect around implants in a canine peri-implantitis model. The results demonstrated that the miR-27a-treated group could optimize new bone formation and reosseointegration in vivo. Our assay provides evidence that this strategy exerts therapeutic effects on peri-implantitis, suggesting that it represents a feasible method to maintain the stability and masticatory function of dental implants. © 2018 American Society for Bone and Mineral Research.
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Affiliation(s)
- Xiaolin Wu
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University, School of Medicine; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China
| | - Qinhua Gu
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University, School of Medicine; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China
| | - Xipeng Chen
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University, School of Medicine; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China
| | - Wenxiang Mi
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University, School of Medicine; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China
| | - Tingting Wu
- Department of Orthodontics, Shanghai Key Laboratory of Stomatology, Ninth People's Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China.,College & Hospital of Stomatology, Anhui Medical University, Anhui Key Laboratory of Oral Diseases Research, Hefei, China
| | - Hui Huang
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University, School of Medicine; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China
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22
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Gurung S, Williams S, Deane JA, Werkmeister JA, Gargett CE. The Transcriptome of Human Endometrial Mesenchymal Stem Cells Under TGFβR Inhibition Reveals Improved Potential for Cell-Based Therapies. Front Cell Dev Biol 2018; 6:164. [PMID: 30564575 PMCID: PMC6288489 DOI: 10.3389/fcell.2018.00164] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 11/15/2018] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are multipotent cells with favorable properties for cell therapies and regenerative medicine. Human endometrium harbors a small population of perivascular, clonogenic MSCs (eMSCs) identified by the SUSD2 marker. As for other MSCs, eMSCs require extensive in vitro expansion to generate clinically relevant numbers of cells, resulting in spontaneous differentiation, replicative senescence and cell death, decreasing therapeutic potency. We previously demonstrated that A83-01, a TGF-β receptor inhibitor, maintained eMSC clonogenicity, promoted proliferation, prevented apoptosis and maintained MSC function in vitro. Here we compare the transcriptome of passaged eMSCs from six women cultured with and without A83-01 for 7 days. We identified 1206 differentially expressed genes (DEG) using a false discovery rate cut-off at 0.01 and fold change >2. Significant enrichment of genes involved in anti-inflammatory responses, angiogenesis, cell migration and proliferation, and collagen fibril and extracellular matrix organization were revealed. TGF-β, Wnt and Akt signaling pathways were decreased. Anti-fibrotic and anti-apoptotic genes were induced, and fibroblast proliferation and myofibroblast related genes were downregulated. We found increased MSC potency genes (TWIST1, TWIST2, JAG1, LIFR, and SLIT2) validating the enhanced potency of A83-01-treated eMSCs, and importantly no pluripotency gene expression. We also identified eMSCs’ potential for secreting exosomes, possibly explaining their paracrine properties. Angiogenic and cytokine protein arrays confirmed the angiogenic, anti-fibrotic and immunomodulatory phenotype of A83-01-treated eMSCs, and increased angiogenic activity was functionally demonstrated in vitro. eMSCs culture expanded with A83-01 have enhanced clinically relevant properties, suggesting their potential for cell-therapies and regenerative medicine applications.
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Affiliation(s)
- Shanti Gurung
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia.,Department of Obstetrics and Gynaecology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia
| | - Sarah Williams
- Monash Bioinformatics Platform, Monash University, Melbourne, VIC, Australia
| | - James A Deane
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia.,Department of Obstetrics and Gynaecology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia
| | - Jerome A Werkmeister
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia.,Department of Obstetrics and Gynaecology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia
| | - Caroline E Gargett
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia.,Department of Obstetrics and Gynaecology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia
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23
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Fu Y, Karbaat L, Wu L, Leijten J, Both SK, Karperien M. Trophic Effects of Mesenchymal Stem Cells in Tissue Regeneration. TISSUE ENGINEERING PART B-REVIEWS 2018; 23:515-528. [PMID: 28490258 DOI: 10.1089/ten.teb.2016.0365] [Citation(s) in RCA: 189] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Mesenchymal stem cells (MSCs) are considered to hold great therapeutic value for cell-based therapy and for tissue regeneration in particular. Recent evidence indicates that the main underlying mechanism for MSCs' beneficial effects in tissue regeneration is based on their capability to produce a large variety of bioactive trophic factors that stimulate neighboring parenchymal cells to start repairing damaged tissues. These new findings could potentially replace the classical paradigm of MSC differentiation and cell replacement. These bioactive factors have diverse actions like modulating the local immune system, enhancing angiogenesis, preventing cell apoptosis, and stimulating survival, proliferation, and differentiation of resident tissue specific cells. Therefore, MSCs are referred to as conductors of tissue repair and regeneration by secreting trophic mediators. In this review article, we have summarized the studies that focused on the trophic effects of MSC within the context of tissue regeneration. We will also highlight the various underlying mechanisms used by MSCs to act as trophic mediators. Besides the secretion of growth factors, we discuss two additional mechanisms that are likely to mediate MSC's beneficial effects in tissue regeneration, namely the production of extracellular vesicles and the formation of membrane nanotubes, which can both connect different cells and transfer a variety of trophic factors varying from proteins to mRNAs and miRNAs. Furthermore, we postulate that apoptosis of the MSCs is an integral part of the trophic effect during tissue repair.
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Affiliation(s)
- Yao Fu
- 1 Developmental BioEngineering, MIRA Institute for Biomedical Technology & Technical Medicine, University of Twente , Enschede, Netherlands
| | - Lisanne Karbaat
- 1 Developmental BioEngineering, MIRA Institute for Biomedical Technology & Technical Medicine, University of Twente , Enschede, Netherlands
| | - Ling Wu
- 2 Center for Craniofacial Molecular Biology, University of Southern California , Los Angeles, Los Angeles, California
| | - Jeroen Leijten
- 1 Developmental BioEngineering, MIRA Institute for Biomedical Technology & Technical Medicine, University of Twente , Enschede, Netherlands
| | - Sanne K Both
- 1 Developmental BioEngineering, MIRA Institute for Biomedical Technology & Technical Medicine, University of Twente , Enschede, Netherlands
| | - Marcel Karperien
- 1 Developmental BioEngineering, MIRA Institute for Biomedical Technology & Technical Medicine, University of Twente , Enschede, Netherlands
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24
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Yamaguchi S, Horie N, Satoh K, Ishikawa T, Mori T, Maeda H, Fukuda Y, Ishizaka S, Hiu T, Morofuji Y, Izumo T, Nishida N, Matsuo T. Age of donor of human mesenchymal stem cells affects structural and functional recovery after cell therapy following ischaemic stroke. J Cereb Blood Flow Metab 2018; 38:1199-1212. [PMID: 28914133 PMCID: PMC6434451 DOI: 10.1177/0271678x17731964] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Cell transplantation therapy offers great potential to improve impairments after stroke. However, the importance of donor age on therapeutic efficacy is unclear. We investigated the regenerative capacity of transplanted cells focusing on donor age (young vs. old) for ischaemic stroke. The quantities of human mesenchymal stem cell (hMSC) secreted brain-derived neurotrophic factor in vitro and of monocyte chemotactic protein-1 at day 7 in vivo were both significantly higher for young hMSC compared with old hMSC. Male Sprague-Dawley rats subjected to transient middle cerebral artery occlusion that received young hMSC (trans-arterially at 24 h after stroke) showed better behavioural recovery with prevention of brain atrophy compared with rats that received old hMSC. Histological analysis of the peri-infarct cortex showed that rats treated with young hMSC had significantly fewer microglia and more vessels covered with pericytes. Interestingly, migration of neural stem/progenitor cells expressing Musashi-1 positively correlated with astrocyte process alignment, which was more pronounced for young hMSC. Aging of hMSC may be a critical factor that affects cell therapy outcomes, and transplantation of young hMSC appears to provide better functional recovery through anti-inflammatory effects, vessel maturation, and neurogenesis potentially by the dominance of trophic factor secretion.
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Affiliation(s)
- Susumu Yamaguchi
- 1 Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Nobutaka Horie
- 1 Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Katsuya Satoh
- 2 Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Takeshi Ishikawa
- 2 Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Tsuyoshi Mori
- 2 Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Hajime Maeda
- 1 Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Yuhtaka Fukuda
- 1 Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Shunsuke Ishizaka
- 1 Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Takeshi Hiu
- 1 Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Yoichi Morofuji
- 1 Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Tsuyoshi Izumo
- 1 Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Noriyuki Nishida
- 2 Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Takayuki Matsuo
- 1 Department of Neurosurgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
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25
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Wang L, Zhu LX, Wang Z, Lou AJ, Yang YX, Guo Y, Liu S, Zhang C, Zhang Z, Hu HS, Yang B, Zhang P, Ouyang HW, Zhang ZY. Development of a centrally vascularized tissue engineering bone graft with the unique core-shell composite structure for large femoral bone defect treatment. Biomaterials 2018; 175:44-60. [PMID: 29800757 DOI: 10.1016/j.biomaterials.2018.05.017] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 05/10/2018] [Accepted: 05/12/2018] [Indexed: 01/09/2023]
Abstract
Great effort has been spent to promote the vascularization of tissue engineering bone grafts (TEBG) for improved therapeutic outcome. However, the thorough vascularization especially in the central region still remained as a major challenge for the clinical translation of TEBG. Here, we developed a new strategy to construct a centrally vascularized TEBG (CV-TEBG) with unique core-shell composite structure, which is consisted of an angiogenic core and an osteogenic shell. The in vivo evaluation in rabbit critical sized femoral defect was conducted to meticulously compare CV-TEBG to other TEBG designs (TEBG with osteogenic shell alone, or angiogenic core alone or angiogenic core+shell). Microfil-enhanced micro-CT analysis has been shown that CV-TEBG could outperform TEBG with pure osteogenic or angiogenic component for neo-vascularization. CV-TEBG achieved a much higher and more homogenous vascularization throughout the whole scaffold (1.52-38.91 folds, p < 0.01), and generated a unique burrito-like vascular network structure to perfuse both the central and peripheral regions of TEBG, indicating a potential synergistic effect between the osteogenic shell and angiogenic core in CV-TEBG to enhance neo-vascularization. Moreover, CV-TEBG has generated more new bone tissue than other groups (1.99-83.50 folds, p < 0.01), achieved successful bridging defect with the formation of both cortical bone like tissue externally and cancellous bone like tissue internally, and restored approximately 80% of the stiffness of the defected femur (benchmarked to the intact femur). It has been further observed that different bone regeneration patterns occurred in different TEBG implants and closely related to their vascularization patterns, revealing the potential profound influence of vascularization patterns on the osteogenesis pattern during defect healing.
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Affiliation(s)
- Le Wang
- Department of Orthopaedic Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China; Translational Research Centre of Regenerative Medicine and 3D Printing Technologies, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China.
| | - Li-Xin Zhu
- Department of Orthopaedic Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, China
| | - Zhao Wang
- Department of Orthopaedic Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China; Translational Research Centre of Regenerative Medicine and 3D Printing Technologies, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China
| | - Ai-Ju Lou
- Translational Research Centre of Regenerative Medicine and 3D Printing Technologies, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China; Department of Rheumatology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China
| | - Yi-Xi Yang
- Department of Orthopaedic Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China; Translational Research Centre of Regenerative Medicine and 3D Printing Technologies, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China
| | - Yuan Guo
- Translational Research Centre of Regenerative Medicine and 3D Printing Technologies, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China
| | - Song Liu
- Department of Orthopaedic Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China; Translational Research Centre of Regenerative Medicine and 3D Printing Technologies, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China
| | - Chi Zhang
- Department of Orthopaedic Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China; Translational Research Centre of Regenerative Medicine and 3D Printing Technologies, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China
| | - Zheng Zhang
- Department of Cardiology, The General Hospital of the PLA Rocket Force, Beijing 100088, China
| | - Han-Sheng Hu
- Department of Orthopaedic Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China
| | - Bo Yang
- Department of Orthopaedic Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China
| | - Ping Zhang
- Department of Orthopaedic Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China
| | - Hong-Wei Ouyang
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University-University of Edinburgh Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China; China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, 310058, China
| | - Zhi-Yong Zhang
- Department of Orthopaedic Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China; Translational Research Centre of Regenerative Medicine and 3D Printing Technologies, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China; China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, 310058, China.
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Lu W, Li X. Vascular stem/progenitor cells: functions and signaling pathways. Cell Mol Life Sci 2018; 75:859-869. [PMID: 28956069 PMCID: PMC11105279 DOI: 10.1007/s00018-017-2662-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 09/05/2017] [Accepted: 09/20/2017] [Indexed: 12/17/2022]
Abstract
Vascular stem/progenitor cells (VSCs) are an important source of all types of vascular cells needed to build, maintain, repair, and remodel blood vessels. VSCs, therefore, play critical roles in the development, normal physiology, and pathophysiology of numerous diseases. There are four major types of VSCs, including endothelial progenitor cells (EPCs), smooth muscle progenitor cells (SMPCs), pericytes, and mesenchymal stem cells (MSCs). VSCs can be found in bone marrow, circulating blood, vessel walls, and other extravascular tissues. During the past two decades, considerable progress has been achieved in the understanding of the derivation, surface markers, and differentiation of VSCs. Yet, the mechanisms regulating their functions and maintenance under normal and pathological conditions, such as in eye diseases, remain to be further elucidated. Owing to the essential roles of blood vessels in human tissues and organs, understanding the functional properties and the underlying molecular basis of VSCs is of critical importance for both basic and translational research.
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Affiliation(s)
- Weisi Lu
- The State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China
| | - Xuri Li
- The State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China.
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Wnt Signaling in Hematological Malignancies. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2018; 153:321-341. [PMID: 29389522 DOI: 10.1016/bs.pmbts.2017.11.002] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Leukemia and lymphoma are a wide encompassing term for a diverse set of blood malignancies that affect people of all ages and result in approximately 23,000 deaths in the United States per year (Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30.). Hematopoietic stem cells (HSCs) are tissue-specific stem cells at the apex of the hierarchy that gives rise to all of the terminally differentiated blood cells, through progressively restricted progenitor populations, a process that is known to be Wnt-responsive. In particular, the progenitor populations are subject to uncontrolled expansion during oncogenic processes, namely the common myeloid progenitor and common lymphoid progenitor, as well as the myeloblast and lymphoblast. Unregulated growth of these cell-types leads to mainly three types of blood cancers (i.e., leukemia, lymphoma, and myeloma), which frequently exhibit deregulation of the Wnt signaling pathway. Generally, leukemia is caused by the expansion of myeloid progenitors, leading to an overproduction of white blood cells; as such, patients are unable to make sufficient numbers of red blood cells and platelets. Likewise, an overproduction of lymphocytes leads to clogging of the lymph system and impairment of the immune system in lymphomas. Finally, cancer of the plasma cells in the blood is called myeloma, which also leads to immune system failure. Within each of these three types of blood cancers, there are multiple subtypes, usually characterized by their timeline of onset and their cell type of origin. Of these, 85% of leukemias are encompassed by the four most common diseases, that is, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL); AML accounts for the majority of leukemia-related deaths (Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30.). Through understanding how HSCs are normally developed and maintained, we can understand how the normal functions of these pathways are disrupted during blood cancer progression; the Wnt pathway is important in regulation of both normal and malignant hematopoiesis. In this chapter, we will discuss the role of Wnt signaling in normal and aberrant hematopoiesis. Our understanding the relationship between Wnt and HSCs will provide novel insights into therapeutic targets.
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Medeiros Tavares Marques JC, Cornélio DA, Nogueira Silbiger V, Ducati Luchessi A, de Souza S, Batistuzzo de Medeiros SR. Identification of new genes associated to senescent and tumorigenic phenotypes in mesenchymal stem cells. Sci Rep 2017; 7:17837. [PMID: 29259202 PMCID: PMC5736717 DOI: 10.1038/s41598-017-16224-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 11/08/2017] [Indexed: 02/06/2023] Open
Abstract
Although human mesenchymal stem cells (hMSCs) are a powerful tool for cell therapy, prolonged culture times result in replicative senescence or acquisition of tumorigenic features. To identify a molecular signature for senescence, we compared the transcriptome of senescent and young hMSCs with normal karyotype (hMSCs/n) and with a constitutional inversion of chromosome 3 (hMSC/inv). Senescent and young cells from both lineages showed differentially expressed genes (DEGs), with higher levels in senescent hMSCs/inv. Among the 30 DEGs in senescent hMSC/inv, 11 are new candidates for biomarkers of cellular senescence. The functional categories most represented in senescent hMSCs were related to cellular development, cell growth/proliferation, cell death, cell signaling/interaction, and cell movement. Mapping of DEGs onto biological networks revealed matrix metalloproteinase-1, thrombospondin 1, and epidermal growth factor acting as topological bottlenecks. In the comparison between senescent hMSCs/n and senescent hMSCs/inv, other functional annotations such as segregation of chromosomes, mitotic spindle formation, and mitosis and proliferation of tumor lines were most represented. We found that many genes categorized into functional annotations related to tumors in both comparisons, with relation to tumors being highest in senescent hMSCs/inv. The data presented here improves our understanding of the molecular mechanisms underlying the onset of cellular senescence as well as tumorigenesis.
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Affiliation(s)
- Joana Cristina Medeiros Tavares Marques
- Faculdade de Ciências da Saúde do Trairi (FACISA), Universidade Federal do Rio Grande do Norte (UFRN), Rua Traíri, S/N, Centro, Santa Cruz, Rio Grande do Norte (RN), 59200-000, Brazil
| | - Déborah Afonso Cornélio
- Laboratório de Biologia Molecular e Genômica, Centro de Biociências, UFRN, Campus Universitário, Avenida Senador Salgado Filho, 3000, Lagoa nova, Natal, RN, 59078-900, Brazil
| | - Vivian Nogueira Silbiger
- Departamento de Análises Clínicas e Toxicológicas, Centro de Ciências da Saúde, CCS/UFRN, Av General Cordeiro de Farias S/N, Petropolis, Natal, 59010-115, RN, Brazil
| | - André Ducati Luchessi
- Departamento de Análises Clínicas e Toxicológicas, Centro de Ciências da Saúde, CCS/UFRN, Av General Cordeiro de Farias S/N, Petropolis, Natal, 59010-115, RN, Brazil
| | - Sandro de Souza
- Instituto do Cérebro, Instituto de Metrópole Digital, UFRN, Av. Nascimento de Castro, 2155, UFRN, 59056-450, RN, Brazil
| | - Silvia Regina Batistuzzo de Medeiros
- Laboratório de Biologia Molecular e Genômica, Centro de Biociências, UFRN, Campus Universitário, Avenida Senador Salgado Filho, 3000, Lagoa nova, Natal, RN, 59078-900, Brazil.
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[Effects of bone marrow mesenchymal stem cell transplantation on retinal neovascularization in neonatal rats with oxygen-induced retinopathy]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2017. [PMID: 29132470 PMCID: PMC7389327 DOI: 10.7499/j.issn.1008-8830.2017.11.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
OBJECTIVE To explore the effects of rat bone mesenchymal stem cell (BMSC) transplantation on retinal neovascularization, and to observe the changes of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factors (VEGF) in rats with oxygen-induced retinopathy (OIR). METHODS Seventy-two seven-day-old Sprague-Dawley rats were randomly divided into three groups: normal control (CON), model (OIR) and BMSC transplantation. In the BMSC transplantation group, BMSCs were transplanted 5 days after oxygen conditioning. The phosphate buffered saline of the same volume was injected in the CON and OIR groups. The OIR model was prerpared according to the classic hyperoxygen method. At seven days after transplantation, retinal neovascularization was examined by retinal flat-mount staining and hematoxylin eosin (HE) staining. The expression of HIF-1α and VEGF proteins was examined by immunohistochemistry staining and Western blot analysis. RESULTS The retinal flat-mount staining results showed that the vessels were well organized in the CON group, but the vessels were irregularly organized, and lots of nonperfusion areas were observed in the OIR group. The large vessels were a bit circuitous, the retinal vessels were relatively organized, and less nonperfusion areas were noted in the BMSC transplantation group. The HE staining results showed that many neovessels and preretinal neovascular (pre-RNC) cells were observed on the internal limiting membrane in the OIR group. There were less pre-RNC cells in the BMSC transplantation group compared with the OIR group (P<0.01). The immunohistochemistry analysis showed that more HIF-1α+ and VEGF+ cells were observed in the OIR group compared with the CON group, and less HIF-1α+ and VEGF+ cells were observed in the BMSC transplantation group compared with OIR group (P<0.05). The Western blot analysis showed the expression of HIF-1α and VEGF proteins in the OIR group was significantly higher than that in the CON group. The expression of HIF-1α and VEGF proteins in the BMSC transplantation group was lower than that in the OIR group (P<0.01). CONCLUSIONS BMSC transplantation therapy could alleviate retinal neovascularization in OIR rats, and its mechanisms might be associated with the inhibition of the expression of HIF-1α and VEGF proteins.
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Abstract
INTRODUCTION In specific forms of congenital heart defects and pulmonary hypertension, the right ventricle (RV) is exposed to systemic levels of pressure overload. The RV is prone to failure in these patients because of its vulnerability to chronic pressure overload. As patients with a systemic RV reach adulthood, an emerging epidemic of RV failure has become evident. Medical therapies proven for LV failure are ineffective in treating RV failure. Areas covered: In this review, the pathophysiology of the failing RV under pressure overload is discussed, with specific emphasis on the pivotal roles of angiogenesis and oxidative stress. Studies investigating the ability of stem cell therapy to improve angiogenesis and mitigate oxidative stress in the setting of pressure overload are then reviewed. Finally, clinical trials utilizing stem cell therapy to prevent RV failure under pressure overload in congenital heart disease will be discussed. Expert commentary: Although considerable hurdles remain before their mainstream clinical implementation, stem cell therapy possesses revolutionary potential in the treatment of patients with failing systemic RVs who currently have very limited long-term treatment options. Rigorous clinical trials of stem cell therapy for RV failure that target well-defined mechanisms will ensure success adoption of this therapeutic strategy.
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Affiliation(s)
- Ming-Sing Si
- a Department of Cardiac Surgery, Section of Pediatric Cardiovascular Surgery , University of Michigan Medical School , Ann Arbor , MI , USA
| | - Richard G Ohye
- a Department of Cardiac Surgery, Section of Pediatric Cardiovascular Surgery , University of Michigan Medical School , Ann Arbor , MI , USA
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Chen C, Zheng S, Zhang X, Dai P, Gao Y, Nan L, Zhang Y. Transplantation of Amniotic Scaffold-Seeded Mesenchymal Stem Cells and/or Endothelial Progenitor Cells From Bone Marrow to Efficiently Repair 3-cm Circumferential Urethral Defect in Model Dogs. Tissue Eng Part A 2017; 24:47-56. [PMID: 28363256 DOI: 10.1089/ten.tea.2016.0518] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The treatment options for patients with a urethral defect are limited by the availability of autologous tissues. We hypothesized that transplantation of decellularized human amniotic scaffolds (dHAS) seeded with allogeneic bone marrow mesenchymal cells (BMSCs) and/or endothelial progenitor cells (EPCs) may serve as a promising repair strategy for long segment of circumferential urethral defect. To verify the hypothesis, with urinary catheterization, a 3-cm segment of whole urethra in 25 male mongrel dogs was excised and replaced by dHAS seeded with allogeneic BMSCs and/or EPCs. Postoperative observation and ascending urethrogram found that dHAS+BMSCs+EPCs and dHAS+EPCs groups demonstrated unhindered urination and capacious urethral caliber, which were similar to the normal group, while urethrostenosis was revealed in dHAS+BMSCs, dHAS, and sham-operated groups, with the shortest narrow section in dHAS+BMSCs group and the longest in sham-operated group. Urethral anatomy check and histological analyses showed that new urethral mucosa composed of stratified columnar epithelium completely covered on the inner surface of the graft site in dHAS+BMSCs+EPCs and dHAS+EPCs groups, but the middle epithelium was thin in dHAS+EPCs group, while incompletely covered in dHAS+BMSCs, dHAS, and sham-operated groups, and there were monolayer epithelial cells at the urethrostenosis in dHAS+BMSCs and dHAS groups. In addition, abundant new vessel and blood sinus showed at submucosa in dHAS+BMSCs+EPCs and dHAS+EPCs groups, instead of the scar tissue of collagen deposition and structural distortion at the urethrostenosis in dHAS+BMSCs, dHAS, and sham-operated groups. This study demonstrates that dHAS seeded with BMSCs+EPCs or EPCs can successfully repair a 3-cm circumferential urethral defect in model dogs, but the former works best. This technology may provide some references for human clinical trials on long segment of circumferential urethral defect repair.
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Affiliation(s)
- Chen Chen
- College of Veterinary Medicine, Northwest A & F University , Yangling, China
| | - Shuxin Zheng
- College of Veterinary Medicine, Northwest A & F University , Yangling, China
| | - Xinke Zhang
- College of Veterinary Medicine, Northwest A & F University , Yangling, China
| | - Pengxiu Dai
- College of Veterinary Medicine, Northwest A & F University , Yangling, China
| | - Yongping Gao
- College of Veterinary Medicine, Northwest A & F University , Yangling, China
| | - Liangliang Nan
- College of Veterinary Medicine, Northwest A & F University , Yangling, China
| | - Yihua Zhang
- College of Veterinary Medicine, Northwest A & F University , Yangling, China
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Golpanian S, Wolf A, Hatzistergos KE, Hare JM. Rebuilding the Damaged Heart: Mesenchymal Stem Cells, Cell-Based Therapy, and Engineered Heart Tissue. Physiol Rev 2016; 96:1127-68. [PMID: 27335447 PMCID: PMC6345247 DOI: 10.1152/physrev.00019.2015] [Citation(s) in RCA: 249] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are broadly distributed cells that retain postnatal capacity for self-renewal and multilineage differentiation. MSCs evade immune detection, secrete an array of anti-inflammatory and anti-fibrotic mediators, and very importantly activate resident precursors. These properties form the basis for the strategy of clinical application of cell-based therapeutics for inflammatory and fibrotic conditions. In cardiovascular medicine, administration of autologous or allogeneic MSCs in patients with ischemic and nonischemic cardiomyopathy holds significant promise. Numerous preclinical studies of ischemic and nonischemic cardiomyopathy employing MSC-based therapy have demonstrated that the properties of reducing fibrosis, stimulating angiogenesis, and cardiomyogenesis have led to improvements in the structure and function of remodeled ventricles. Further attempts have been made to augment MSCs' effects through genetic modification and cell preconditioning. Progression of MSC therapy to early clinical trials has supported their role in improving cardiac structure and function, functional capacity, and patient quality of life. Emerging data have supported larger clinical trials that have been either completed or are currently underway. Mechanistically, MSC therapy is thought to benefit the heart by stimulating innate anti-fibrotic and regenerative responses. The mechanisms of action involve paracrine signaling, cell-cell interactions, and fusion with resident cells. Trans-differentiation of MSCs to bona fide cardiomyocytes and coronary vessels is also thought to occur, although at a nonphysiological level. Recently, MSC-based tissue engineering for cardiovascular disease has been examined with quite encouraging results. This review discusses MSCs from their basic biological characteristics to their role as a promising therapeutic strategy for clinical cardiovascular disease.
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Affiliation(s)
- Samuel Golpanian
- Interdisciplinary Stem Cell Institute, Department of Medicine, and Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Ariel Wolf
- Interdisciplinary Stem Cell Institute, Department of Medicine, and Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Konstantinos E Hatzistergos
- Interdisciplinary Stem Cell Institute, Department of Medicine, and Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Joshua M Hare
- Interdisciplinary Stem Cell Institute, Department of Medicine, and Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
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Chery J, Wong J, Huang S, Wang S, Si MS. Regenerative Medicine Strategies for Hypoplastic Left Heart Syndrome. TISSUE ENGINEERING PART B-REVIEWS 2016; 22:459-469. [PMID: 27245633 DOI: 10.1089/ten.teb.2016.0136] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hypoplastic left heart syndrome (HLHS), the most severe and common form of single ventricle congenital heart lesions, is characterized by hypoplasia of the mitral valve, left ventricle (LV), and all LV outflow structures. While advances in surgical technique and medical management have allowed survival into adulthood, HLHS patients have severe morbidities, decreased quality of life, and a shortened lifespan. The single right ventricle (RV) is especially prone to early failure because of its vulnerability to chronic pressure overload, a mode of failure distinct from ischemic cardiomyopathy encountered in acquired heart disease. As these patients enter early adulthood, an emerging epidemic of RV failure has become evident. Regenerative medicine strategies may help preserve or boost RV function in children and adults with HLHS by promoting angiogenesis and mitigating oxidative stress. Rescuing a RV in decompensated failure may also require the creation of new, functional myocardium. Although considerable hurdles remain before their clinical translation, stem cell therapy and cardiac tissue engineering possess revolutionary potential in the treatment of pediatric and adult patients with HLHS who currently have very limited long-term treatment options.
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Affiliation(s)
- Josue Chery
- 1 Department of Cardiac Surgery, University of Michigan , Ann Arbor, Michigan
| | - Joshua Wong
- 2 Department of Pediatric Cardiology, University of Michigan , Ann Arbor, Michigan
| | - Shan Huang
- 1 Department of Cardiac Surgery, University of Michigan , Ann Arbor, Michigan
| | - Shuyun Wang
- 1 Department of Cardiac Surgery, University of Michigan , Ann Arbor, Michigan
| | - Ming-Sing Si
- 1 Department of Cardiac Surgery, University of Michigan , Ann Arbor, Michigan
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Yu G, Wang J, Lin X, Diao S, Cao Y, Dong R, Wang L, Wang S, Fan Z. Demethylation of SFRP2 by histone demethylase KDM2A regulated osteo‐/dentinogenic differentiation of stem cells of the apical papilla. Cell Prolif 2016; 49:330-340. [DOI: 20.doi: 10.1111/cpr.12256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/19/2025] Open
Abstract
AbstractObjectivesDental mesenchymal stem cells (MSCs) are easily obtained; however, mechanisms underlying directed differentiation of these cells remains unclear. Wnt/β‐catenin signalling is essential for mesenchymal cell commitment and differentiation, and Wnt inhibition is linked to stem cell maintenance and function. Secreted frizzled‐related protein 2 (SFRP2) competes with the Frizzled receptor for direct binding to Wnt and blocks activation of Wnt signalling. Here, we used stem cells derived from apical papillae (SCAPs) to study the functions of SFRP2.Materials and methodsSCAPs were isolated from apical papillae of immature third molars. The cells were analysed using alkaline phosphatase activity assays, Alizarin red staining and quantitative calcium measurements. In addition, we evaluated expression profile of genes associated with osteogenesis and dentinogenesis (osteo‐/dentinogenesis), and conducted in vivo transplantation experiments to determine osteo‐/dentinogenic differentiation potential of SCAPs. ChIP assays were used to detect histone methylation at the SFRP2 promoter.ResultsWe found that SFRP2 enhanced osteo‐/dentinogenic differentiation via Osterix, a key transcription factor in SCAPs. Furthermore, silencing SFRP2 induced SCAP cell death in osteogenic‐inducing medium, indicating that SFRP2 is a key factor in maintaining SCAP survival following osteo‐/dentinogenic commitment. Moreover, we found that silencing KDM2A, a histone demethylase and BCL6 co‐repressor, de‐repressed SFRP2 transcription by increasing histone H3K4 and H3K36 methylation at the SFRP2 promoter.ConclusionsOur results have identified a new function of SFRP2 and shed new light on the molecular mechanism underlying directed differentiation of stem cells of dental origin.
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Affiliation(s)
- Guoxia Yu
- Laboratory of Molecular Signaling and Stem Cells Therapy Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Beijing 100050 China
- Molecular Laboratory for Gene Therapy and Tooth Regeneration Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Beijing 100050 China
- Department of Stomatology Beijing Children's Hospital Capital Medical University Beijing 100045 China
| | - Jinsong Wang
- Molecular Laboratory for Gene Therapy and Tooth Regeneration Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Beijing 100050 China
- Department of Biochemistry and Molecular Biology Capital Medical University School of Basic Medical Sciences Beijing 100069 China
| | - Xiao Lin
- Laboratory of Molecular Signaling and Stem Cells Therapy Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Beijing 100050 China
- Department of Implant Dentistry Capital Medical University School of Stomatology Beijing 100050 China
| | - Shu Diao
- Laboratory of Molecular Signaling and Stem Cells Therapy Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Beijing 100050 China
| | - Yu Cao
- Laboratory of Molecular Signaling and Stem Cells Therapy Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Beijing 100050 China
- Molecular Laboratory for Gene Therapy and Tooth Regeneration Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Beijing 100050 China
| | - Rui Dong
- Laboratory of Molecular Signaling and Stem Cells Therapy Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Beijing 100050 China
| | - Liping Wang
- Laboratory of Molecular Signaling and Stem Cells Therapy Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Beijing 100050 China
| | - Songlin Wang
- Molecular Laboratory for Gene Therapy and Tooth Regeneration Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Beijing 100050 China
- Department of Biochemistry and Molecular Biology Capital Medical University School of Basic Medical Sciences Beijing 100069 China
| | - Zhipeng Fan
- Laboratory of Molecular Signaling and Stem Cells Therapy Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Beijing 100050 China
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Martinez L, Gomez C, Vazquez-Padron RI. Age-related changes in monocytes exacerbate neointimal hyperplasia after vascular injury. Oncotarget 2016; 6:17054-64. [PMID: 25965835 PMCID: PMC4627291 DOI: 10.18632/oncotarget.3881] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2015] [Accepted: 03/31/2015] [Indexed: 01/09/2023] Open
Abstract
Neointimal hyperplasia is the leading cause of restenosis after endovascular interventions. It is characterized by the accumulation of myofibroblast-like cells and extracellular matrix in the innermost layer of the wall and is exacerbated by inflammation. Monocytes from either young or aged rats were applied perivascularly to injured vascular walls of young recipient animals. Monocytes from aged rats, but not young donors, increased neointima thickness. Accordingly, the gene expression profiles of CD11b+ monocytes from aged rats showed significant up-regulation of genes involved in cellular adhesion, lipid degradation, cytotoxicity, differentiation, and inflammation. These included cadherin 13 (Cdh13), colony stimulating factor 1 (Csf1), chemokine C-X-C motif ligand 1 (Cxcl1), endothelial cell-selective adhesion molecule (Esam), and interferon gamma (Ifng). In conclusion, our results suggest that the increased inflammatory and adhesive profile of monocytes contributes to pathological wall remodeling in aged-related vascular diseases.
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Affiliation(s)
- Laisel Martinez
- Department of Surgery and Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Camilo Gomez
- Department of Surgery and Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Roberto I Vazquez-Padron
- Department of Surgery and Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, FL, USA
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Yu G, Wang J, Lin X, Diao S, Cao Y, Dong R, Wang L, Wang S, Fan Z. Demethylation of SFRP2 by histone demethylase KDM2A regulated osteo-/dentinogenic differentiation of stem cells of the apical papilla. Cell Prolif 2016; 49:330-40. [PMID: 27074224 DOI: 10.1111/cpr.12256] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 03/08/2016] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVES Dental mesenchymal stem cells (MSCs) are easily obtained; however, mechanisms underlying directed differentiation of these cells remains unclear. Wnt/β-catenin signalling is essential for mesenchymal cell commitment and differentiation, and Wnt inhibition is linked to stem cell maintenance and function. Secreted frizzled-related protein 2 (SFRP2) competes with the Frizzled receptor for direct binding to Wnt and blocks activation of Wnt signalling. Here, we used stem cells derived from apical papillae (SCAPs) to study the functions of SFRP2. MATERIALS AND METHODS SCAPs were isolated from apical papillae of immature third molars. The cells were analysed using alkaline phosphatase activity assays, Alizarin red staining and quantitative calcium measurements. In addition, we evaluated expression profile of genes associated with osteogenesis and dentinogenesis (osteo-/dentinogenesis), and conducted in vivo transplantation experiments to determine osteo-/dentinogenic differentiation potential of SCAPs. ChIP assays were used to detect histone methylation at the SFRP2 promoter. RESULTS We found that SFRP2 enhanced osteo-/dentinogenic differentiation via Osterix, a key transcription factor in SCAPs. Furthermore, silencing SFRP2 induced SCAP cell death in osteogenic-inducing medium, indicating that SFRP2 is a key factor in maintaining SCAP survival following osteo-/dentinogenic commitment. Moreover, we found that silencing KDM2A, a histone demethylase and BCL6 co-repressor, de-repressed SFRP2 transcription by increasing histone H3K4 and H3K36 methylation at the SFRP2 promoter. CONCLUSIONS Our results have identified a new function of SFRP2 and shed new light on the molecular mechanism underlying directed differentiation of stem cells of dental origin.
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Affiliation(s)
- Guoxia Yu
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, 100050, China.,Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, 100050, China.,Department of Stomatology, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China
| | - Jinsong Wang
- Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, 100050, China.,Department of Biochemistry and Molecular Biology, Capital Medical University School of Basic Medical Sciences, Beijing, 100069, China
| | - Xiao Lin
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, 100050, China.,Department of Implant Dentistry, Capital Medical University School of Stomatology, Beijing, 100050, China
| | - Shu Diao
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, 100050, China
| | - Yu Cao
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, 100050, China.,Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, 100050, China
| | - Rui Dong
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, 100050, China
| | - Liping Wang
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, 100050, China
| | - Songlin Wang
- Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, 100050, China.,Department of Biochemistry and Molecular Biology, Capital Medical University School of Basic Medical Sciences, Beijing, 100069, China
| | - Zhipeng Fan
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, 100050, China
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Bischoff DS, Zhu JH, Makhijani NS, Yamaguchi DT. Induction of CXC chemokines in human mesenchymal stem cells by stimulation with secreted frizzled-related proteins through non-canonical Wnt signaling. World J Stem Cells 2015; 7:1262-1273. [PMID: 26730270 PMCID: PMC4691694 DOI: 10.4252/wjsc.v7.i11.1262] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 10/03/2015] [Accepted: 11/25/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of secreted frizzled-related proteins (sFRPs) on CXC chemokine expression in human mesenchymal stem cells (hMSCs).
METHODS: CXC chemokines such as CXCL5 and CXCL8 are induced in hMSCs during differentiation with osteogenic differentiation medium (OGM) and may be involved in angiogenic stimulation during bone repair. hMSCs were treated with conditioned medium (CM) from L-cells expressing non-canonical Wnt5a protein, or with control CM from wild type L-cells, or directly with sFRPs for up to 10 d in culture. mRNA expression levels of both CXCL5 and CXCL8 were quantitated by real-time reverse transcriptase-polymerase chain reaction and secreted protein levels of these proteins determined by ELISA. Dose- (0-500 ng/mL) and time-response curves were generated for treatment with sFRP1. Signal transduction pathways were explored by western blot analysis with pan- or phosphorylation-specific antibodies, through use of specific pathway inhibitors, and through use of siRNAs targeting specific frizzled receptors (Fzd)-2 and 5 or the receptor tyrosine kinase-like orphan receptor-2 (RoR2) prior to treatment with sFRPs.
RESULTS: CM from L-cells expressing Wnt5a, a non-canonical Wnt, stimulated an increase in CXCL5 mRNA expression and protein secretion in comparison to control L-cell CM. sFRP1, which should inhibit both canonical and non-canonical Wnt signaling, surprisingly enhanced the expression of CXCL5 at 7 and 10 d. Dickkopf1, an inhibitor of canonical Wnt signaling prevented the sFRP-stimulated induction of CXCL5 and actually inhibited basal levels of CXCL5 expression at 7 but not at 10 d post treatment. In addition, all four sFRPs isoforms induced CXCL8 expression in a dose- and time-dependent manner with maximum expression at 7 d with treatment at 150 ng/mL. The largest increases in CXCL5 expression were seen from stimulation with sFRP1 or sFRP2. Analysis of mitogen-activated protein kinase signaling pathways in the presence of OGM showed sFRP1-induced phosphorylation of extracellular signal-regulated kinase (ERK) (p44/42) maximally at 5 min after sFRP1 addition, earlier than that found in OGM alone. Addition of a phospholipase C (PLC) inhibitor also prevented sFRP-stimulated increases in CXCL8 mRNA. siRNA technology targeting the Fzd-2 and 5 and the non-canonical Fzd co-receptor RoR2 also significantly decreased sFRP1/2-stimulated CXCL8 mRNA levels.
CONCLUSION: CXC chemokine expression in hMSCs is controlled in part by sFRPs signaling through non-canonical Wnt involving Fzd2/5 and the ERK and PLC pathways.
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Ahmadzadeh A, Norozi F, Shahrabi S, Shahjahani M, Saki N. Wnt/β-catenin signaling in bone marrow niche. Cell Tissue Res 2015; 363:321-35. [PMID: 26475718 DOI: 10.1007/s00441-015-2300-y] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 09/20/2015] [Indexed: 12/14/2022]
Abstract
The bone marrow (BM) niche is a specific physiological environment for hematopoietic and non-hematopoietic stem cells (HSCs). Several signaling pathways (including Wnt/β-catenin) regulate various aspects of stem cell growth, function and death in the BM niche. In addition, the canonical Wnt pathway is crucial for directing self-renewal and differentiation as important mechanisms in many types of stem cells. We review the role of the Wnt/β-catenin pathway in the BM niche and its importance in stem cells. Relevant literature was identified by a PubMed search (1997-2014) of English-language literature by using the following keywords: BM niche, Wnt/β-catenin signaling, osteoblast, osteoclast and bone disease. The Wnt/β-catenin pathway regulates the stability of the β-catenin proto-oncogene. The stabilized β-catenin then translocates to the nucleus, forming a β-catenin-TCF/LEF complex regulating the transcription of specific target genes. Stem cells require β-catenin to mediate their response to Wnt signaling for maintenance and transition from the pluripotent state during embryogenesis. In adult stem cells, Wnt signaling functions at various hierarchical levels to contribute to the specification of the diverse tissues. Aberrant Wnt/β-catenin signaling and its downstream transcriptional regulators are observed in several malignant stem cells and human cancers. Because Wnt signaling can maintain stem cells and cancer cells, the ability to modulate the Wnt pathway either positively or negatively may be of therapeutic relevance. The controlled activation of Wnt signaling might allow us to enhance stem and progenitor cell activity when regeneration is needed.
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Affiliation(s)
- Ahmad Ahmadzadeh
- Health Research Institute, Research Center of Thalassemia & Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Fatemeh Norozi
- Health Research Institute, Research Center of Thalassemia & Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Saeid Shahrabi
- Department of Biochemistry and Hematology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Mohammad Shahjahani
- Health Research Institute, Research Center of Thalassemia & Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Najmaldin Saki
- Health Research Institute, Research Center of Thalassemia & Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Secreted Frizzled Related Protein 3 in Chronic Heart Failure: Analysis from the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). PLoS One 2015; 10:e0133970. [PMID: 26288364 PMCID: PMC4545831 DOI: 10.1371/journal.pone.0133970] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 07/03/2015] [Indexed: 01/14/2023] Open
Abstract
Background We have previously demonstrated an association between increased sFRP3 expression and adverse outcome in a population of HF irrespective of cause and left ventricular ejection fraction. In this study we evaluated the prognostic value of sFRP3 in older patients with chronic systolic HF of ischemic origin. Methods We evaluated sFRP3, by tertiles, as a risk factor for the primary endpoint (cardiovascular [CV] mortality, nonfatal myocardial infarction, nonfatal stroke), all-cause mortality, CV mortality, death from worsening HF (WHF), any coronary event, including sudden death, as well as hospitalizations for CV causes and WHF in 1444 patients from the CORONA population, randomly assigned to 10 mg rosuvastatin or placebo. Results Kaplan-Meier curves for the primary endpoint, as well as all-cause- and CV mortality revealed a markedly better survival for patients with sFRP3 levels in the middle tertile of compared to the 1st and 3rd tertile. In multivariable Cox-regression, after full adjustment including high-sensitive CRP and NT-proBNP, a lower event rate for the primary end point, all cause and CV mortality was observed for patients with tertile 2 sFRP3 levels (HR 0.57 [0.44–0.74], 0.55 [0.44–0.74] and 0.52 [0.39–0.69]; p<0.001), as well as for the number of coronary events (HR 0.62 [0.47–0.82], p = 0.001) and sudden death (HR 0.55 [0.37–0.82], p = 0.002). Applying sFRP3 values to the fully adjusted regression model resulted in highly significant continuous net reclassification improvements for the primary endpoint, all cause and CV mortality, coronary events and sudden death (range 0.24–0.31; p≤0.002 for all). Conclusions Intermediate serum sFRP3 levels are associated with better survival and fewer CV events than low or high sFRP3 levels, independently of conventional risk factors, in older patients with chronic systolic HF of ischemic origin. Our study suggests that balanced Wnt activity might confer protective effects in a clinical HF setting. Trial Registration http://www.clinicaltrials.govNCT00206310
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Yoon N, Park MS, Peltier GC, Lee RH. Pre-activated human mesenchymal stromal cells in combination with doxorubicin synergistically enhance tumor-suppressive activity in mice. Cytotherapy 2015; 17:1332-41. [PMID: 26227206 DOI: 10.1016/j.jcyt.2015.06.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Revised: 05/11/2015] [Accepted: 06/18/2015] [Indexed: 12/17/2022]
Abstract
BACKGROUND AIMS Previously, we showed that human mesenchymal stromal cells (hMSCs) were activated to express tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) upon TNF-α stimulation, induced cell death in triple-negative breast cancer (TNBC) MDA-MB-231 cells (MDA), and RNA released from apoptotic MDA further increased TRAIL expression in hMSCs. This feed-forward stimulation increased apoptosis in MDA cells. Here, we tested whether TRAIL-expressing hMSCs, in combination with a sub-toxic-dose of a chemotherapy drug doxorubicin, would overcome TRAIL resistance and create synergistic effects on targeting metastatic TNBC. METHODS To optimize conditions for the combination treatment, we (i) selected an optimal condition to activate hMSCs for TRAIL expression, (ii) selected an optimal dose of doxorubicin treatment, (iii) examined underlying mechanisms in vitro and (iv) tested the efficacy of the optimized conditions in a xenograft mouse model of human breast cancer lung metastasis. RESULTS The results showed that DNA fragments from apoptotic MDA triggered hMSCs to increase further TRAIL expression in an absent in melanoma 2 (AIM2)-dependent manner, and thus higher TRAIL-expressing hMSCs stimulated with synthetic DNA, poly(deoxyadenylic-deoxythymidylic) acid [poly(dA:dT)], more effectively suppressed tumor progression in vivo. Furthermore, activated hMSCs increased apoptosis in MDA cells when combined with a sub-toxic dose of doxorubicin, which was mediated by up-regulating TRAIL and Fas-related pathways. When we combined the optimized conditions, pre-activated hMSCs with poly (dA:dT) synergistically reduced tumor burden even with minimal doxorubicin treatment in a xenograft mouse model of human breast cancer lung metastasis. CONCLUSIONS These results suggest that the treatment of hMSCs with a sub-toxic dose of doxorubicin can overcome TRAIL resistance and be a potential novel therapy for TNBC metastasis treatment.
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Affiliation(s)
- Nara Yoon
- Institute for Regenerative Medicine, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, USA
| | - Min Sung Park
- Institute for Regenerative Medicine, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, USA
| | - Grantham C Peltier
- Institute for Regenerative Medicine, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, USA
| | - Ryang Hwa Lee
- Institute for Regenerative Medicine, College of Medicine, Texas A&M University Health Science Center, Temple, Texas, USA.
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Hendijani F. Human mesenchymal stromal cell therapy for prevention and recovery of chemo/radiotherapy adverse reactions. Cytotherapy 2015; 17:509-25. [DOI: 10.1016/j.jcyt.2014.10.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 10/07/2014] [Accepted: 10/27/2014] [Indexed: 12/21/2022]
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Ashihara E, Takada T, Maekawa T. Targeting the canonical Wnt/β-catenin pathway in hematological malignancies. Cancer Sci 2015; 106:665-671. [PMID: 25788321 PMCID: PMC4471797 DOI: 10.1111/cas.12655] [Citation(s) in RCA: 93] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Revised: 02/26/2015] [Accepted: 03/04/2015] [Indexed: 12/14/2022] Open
Abstract
The canonical Wnt/β-catenin pathway plays an important role in different developmental processes through the regulation of stem cell functions. In the activation of the canonical Wnt/β-catenin pathway, β-catenin protein is imported into the nucleus and activates transcription of target genes including cyclin D1 and c-myc. Aberrant activation of the Wnt/β-catenin pathway contributes to carcinogenesis and malignant behaviors, and Wnt signaling is essential for the maintenance of cancer stem cells. The canonical Wnt/β-catenin pathway has been investigated extensively as a target in cancer treatment and several specific inhibitors of this signaling pathway have been identified through high-throughput screening. In this review, the significance of the canonical Wnt/β-catenin pathway in hematological carcinogenesis and screening methods for specific inhibitors are discussed.
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Affiliation(s)
- Eishi Ashihara
- Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Tetsuya Takada
- Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Taira Maekawa
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan
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Inhibition of Wnt/β-catenin signal is alleviated reactive gliosis in rats with hydrocephalus. Childs Nerv Syst 2015; 31:227-34. [PMID: 25564198 DOI: 10.1007/s00381-014-2613-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Accepted: 12/22/2014] [Indexed: 10/24/2022]
Abstract
BACKGROUND Reactive gliosis has been implicated in the pathogenesis of communicating hydrocephalus. Because the activation of Wnt/β-catenin signaling pathway is considered as a significant factor to contribute to brain development, neurodegenerative process, and reactive gliosis, we target this pathway for intervention by using sFRP-l and investigated the expression of β-catenin, cyclin D-1, and glial fibrillary acidic protein (GFAP) in the brain of experimental hydrocephalic rats in terms of protein and gene expression. METHODS Therefore, 30 adult SD rats were randomly divided into the normal group (n = 5), the sham operation group (n = 5), the hydrocephalus group (n = 10), and the sFRP-l group (n = 10). Hydrocephalic rat models were induced by intraventricular injections of 3% kaolin while sFRP-l group was treated by sFRP-l with kaolin injections. The ventricular dilatation was examinated by MRI at 2-week post-operation. After that, β-catenin, cyclin D-1, and GFAP were qualified by Western blot and immunohistochemistry. RESULTS According to the result, the expression of β-catenin and cyclin D-1 increased (P < 0. 05) in the brain tissue of the hydrocephalus group compared with that of the sham group, while GFAP expression in the hydrocephalus group is more obvious (P < 0. 05). In the sFRP-l group, the expression of β-catenin and cyclin D-1 and GFAP expression is lower (P < 0. 05) compared with those of the hydrocephalus group. We demonstrated that the Wnt/β-catenin pathway is activated in the experimental hydrocephalic rat brain. sFRP-l inhibited the expression of β-catenin and cyclin D-1 and alleviated reactive gliosis in the hydrocephalic rat brain tissue, while the development of hydrocephalus was delayed. CONCLUSION These results suggest that regulating Wnt/β-catenin signaling pathway may provide new therapeutic methods for hydrocephalic patients.
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Huang L, Ma W, Ma Y, Feng D, Chen H, Cai B. Exosomes in mesenchymal stem cells, a new therapeutic strategy for cardiovascular diseases? Int J Biol Sci 2015; 11:238-45. [PMID: 25632267 PMCID: PMC4308409 DOI: 10.7150/ijbs.10725] [Citation(s) in RCA: 111] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2014] [Accepted: 12/09/2014] [Indexed: 12/20/2022] Open
Abstract
Cardiovascular diseases (CVDs) are still a major cause of people deaths worldwide, and mesenchymal stem cells (MSCs) transplantation holds great promise due to its capacity to differentiate into cardiovascular cells and secrete protective cytokines, which presents an important mechanism of MSCs therapy for CVDs. Although the capability of MSCs to differentiate into cardiomyocytes (CMCs), endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) has been well recognized in massive previous experiments both in vitro and in vivo, low survival rate of transplanted MSCs in recipient hearts suggests that therapeutic effects of MSCs transplantation might be also correlated with other underlying mechanisms. Notably, recent studies uncovered that MSCs were able to secret cholesterol-rich, phospholipid exosomes which were enriched with microRNAs (miRNAs). The released exosomes from MSCs acted on hearts and vessels, and then exerted anti-apoptosis, cardiac regeneration, anti-cardiac remodeling, anti-inflammatory effects, neovascularization and anti-vascular remodeling, which are considered as novel molecular mechanisms of therapeutic potential of MSCs transplantation. Here we summarized recent advances about the role of exosomes in MSCs therapy for CVDs, and discussed exosomes as a novel approach in the treatment of CVDs in the future.
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Affiliation(s)
- Lina Huang
- Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin 150081, China
| | - Wenya Ma
- Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin 150081, China
| | - Yidi Ma
- Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin 150081, China
| | - Dan Feng
- Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin 150081, China
| | - Hongyang Chen
- Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin 150081, China
| | - Benzhi Cai
- Department of Pharmacology, Harbin Medical University (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin 150081, China
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Chen D, Shen H, He Y, Chen Y, Wang Q, Lu J, Jiang Y. Synergetic effects of hBMSCs and hPCs in osteogenic differentiation and their capacity in the repair of critical-sized femoral condyle defects. Mol Med Rep 2014; 11:1111-9. [PMID: 25373389 DOI: 10.3892/mmr.2014.2883] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2013] [Accepted: 04/28/2014] [Indexed: 02/01/2023] Open
Abstract
Tissue-engineered bone grafts require an osteoblastic cellular source to be utilized in bone transplantation therapy. Human bone marrow stem cells (hBMSCs) and periosteal-derived stem cells (hPCs) are the commonly used cellular sources for bone tissue engineering and are essential in fracture healing. In the present study, hBMSCs and hPCs were co-cultured from the same donors, as the cellular source. In monolayer cultivation, co-culturing hBMSCs and hPCs demonstrated more robust mineralized nodule formation and stronger alkaline phosphatase (ALP) positive staining than hBMSCs or hPCs. Three-dimensional (3-D) culturing on porous β-tricalcium phosphate (TCP) scaffolds and co-culturing of hBMSCs and hPCs significantly promoted the osteogenic specific mRNA expression of COL1α1, BMP-2, osteopontin (OPN) and osteocalcin (OC). For in vivo bone formation and neovascularization assessment, the cellular-β-TCP scaffolds were transplanted into critical-sized femoral condyle defects in rabbits. The results confirmed that co-culturing hBMSCs and hPCs accelerated bone regeneration and enhanced mature bone formation, but also facilitated central vascularization in scaffold pores. Based on these data, we recommend co-culturing hBMSCs and hPCs as a promising cellular source for bone tissue engineering applications.
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Affiliation(s)
- Daoyun Chen
- Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200233, P.R. China
| | - Hao Shen
- Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200233, P.R. China
| | - Yaohua He
- Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200233, P.R. China
| | - Yunsu Chen
- Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200233, P.R. China
| | - Qi Wang
- Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200233, P.R. China
| | - Jianxi Lu
- Department of Orthopedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University, Shanghai 200011, P.R. China
| | - Yao Jiang
- Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200233, P.R. China
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Deng K, Lin DL, Hanzlicek B, Balog B, Penn MS, Kiedrowski MJ, Hu Z, Ye Z, Zhu H, Damaser MS. Mesenchymal stem cells and their secretome partially restore nerve and urethral function in a dual muscle and nerve injury stress urinary incontinence model. Am J Physiol Renal Physiol 2014; 308:F92-F100. [PMID: 25377914 DOI: 10.1152/ajprenal.00510.2014] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Childbirth injures muscles and nerves responsible for urinary continence. Mesenchymal stem cells (MSCs) or their secretome given systemically could provide therapeutic benefit for this complex multisite injury. We investigated whether MSCs or their secretome, as collected from cell culture, facilitate recovery from simulated childbirth injury. Age-matched female Sprague-Dawley rats received pudendal nerve crush and vaginal distension (PNC+VD) and a single intravenous (iv) injection of 2 million MSCs or saline. Controls received sham injury and iv saline. Additional rats received PNC+VD and a single intraperitoneal (ip) injection of concentrated media conditioned by MSCs (CCM) or concentrated control media (CM). Controls received a sham injury and ip CM. Urethral and nerve function were assessed with leak point pressure (LPP) and pudendal nerve sensory branch potential (PNSBP) recordings 3 wk after injury. Urethral and pudendal nerve anatomy were assessed qualitatively by blinded investigators. Quantitative data were analyzed using one-way ANOVA and Holm-Sidak post hoc tests with P < 0.05 indicating significant differences. Both LPP and PNSBP were significantly decreased 3 wk after PNC+VD with saline or CM compared with sham-injured rats, but not with MSC or CCM. Elastic fiber density in the urethra increased and changed in orientation after PNC+VD, with a greater increase in elastic fibers with MSC or CCM. Pudendal nerve fascicles were less dense and irregularly shaped after PNC+VD and had reduced pathology with MSC or CCM. MSC and CCM provide similar protective effects after PNC+VD, suggesting that MSCs act via their secretions in this dual muscle and nerve injury.
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Affiliation(s)
- Kangli Deng
- Advanced Platform Technology Center, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio; Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio
| | - Dan Li Lin
- Advanced Platform Technology Center, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio; Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio
| | - Brett Hanzlicek
- Advanced Platform Technology Center, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio; Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio
| | - Brian Balog
- Advanced Platform Technology Center, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio; Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio
| | - Marc S Penn
- Department of Integrative Medical Sciences, Northeast Ohio University College of Medicine, Rootstown, Ohio; Summa Cardiovascular Institute, Summa Health System, Akron, Ohio; and
| | - Matthew J Kiedrowski
- Department of Integrative Medical Sciences, Northeast Ohio University College of Medicine, Rootstown, Ohio
| | - Zhiquan Hu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhangqun Ye
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hui Zhu
- Advanced Platform Technology Center, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio; Glickman Urologic and Kidney Institute, Cleveland Clinic, Cleveland, Ohio
| | - Margot S Damaser
- Advanced Platform Technology Center, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio; Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio; Glickman Urologic and Kidney Institute, Cleveland Clinic, Cleveland, Ohio
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Huang CC, Liao ZX, Chen DY, Hsiao CW, Chang Y, Sung HW. Injectable cell constructs fabricated via culture on a thermoresponsive methylcellulose hydrogel system for the treatment of ischemic diseases. Adv Healthc Mater 2014; 3:1133-48. [PMID: 24470263 DOI: 10.1002/adhm.201300605] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Revised: 12/06/2013] [Indexed: 01/06/2023]
Abstract
Cell transplantation via direct intramuscular injection is a promising therapy for patients with ischemic diseases. However, following injections, retention of transplanted cells in engrafted areas remains problematic, and can be deleterious to cell-transplantation therapy. In this Progress Report, a thermoresponsive hydrogel system composed of aqueous methylcellulose (MC) blended with phosphate-buffered saline is constructed to grow cell sheet fragments and cell bodies for the treatment of ischemic diseases. The as-prepared MC hydrogel system undergoes a sol-gel reversible transition upon heating or cooling at ≈32 °C. Via this unique property, the grown cell sheet fragments (cell bodies) can be harvested without using proteolytic enzymes; consequently, their inherent extracellular matrices (ECMs) and integrative adhesive agents remain well preserved. In animal studies using rats and pigs with experimentally created myocardial infarction, the injected cell sheet fragments (cell bodies) become entrapped in the interstices of muscular tissues and adhere to engraftment sites, while a minimal number of cells exist in the group receiving dissociated cells. Moreover, transplantation of cell sheet fragments (cell bodies) significantly increases vascular density, thereby improving the function of an infarcted heart. These experimental results demonstrate that cell sheet fragments (cell bodies) function as a cell-delivery construct by providing a favorable ECM environment to retain transplanted cells locally and consequently, improving the efficacy of therapeutic cell transplantation.
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Affiliation(s)
- Chieh-Cheng Huang
- Department of Chemical Engineering and Institute of Biomedical Engineering; National Tsing Hua University; Hsinchu 30013 Taiwan (ROC)
| | - Zi-Xian Liao
- Department of Chemical Engineering and Institute of Biomedical Engineering; National Tsing Hua University; Hsinchu 30013 Taiwan (ROC)
| | - Ding-Yuan Chen
- Department of Chemical Engineering and Institute of Biomedical Engineering; National Tsing Hua University; Hsinchu 30013 Taiwan (ROC)
| | - Chun-Wen Hsiao
- Department of Chemical Engineering and Institute of Biomedical Engineering; National Tsing Hua University; Hsinchu 30013 Taiwan (ROC)
| | - Yen Chang
- Division of Cardiovascular Surgery; Veterans General Hospital at Taichung; Taichung 40705 Taiwan (ROC)
- College of Medicine, National Yang-Ming University; Taipei 11221 Taiwan (ROC)
| | - Hsing-Wen Sung
- Department of Chemical Engineering and Institute of Biomedical Engineering; National Tsing Hua University; Hsinchu 30013 Taiwan (ROC)
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Hsu SH, Ho TT, Huang NC, Yao CL, Peng LH, Dai NT. Substrate-dependent modulation of 3D spheroid morphology self-assembled in mesenchymal stem cell-endothelial progenitor cell coculture. Biomaterials 2014; 35:7295-307. [DOI: 10.1016/j.biomaterials.2014.05.033] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 05/14/2014] [Indexed: 11/26/2022]
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Hart ML, Neumayer KMH, Vaegler M, Daum L, Amend B, Sievert KD, Di Giovanni S, Kraushaar U, Guenther E, Stenzl A, Aicher WK. Cell-based therapy for the deficient urinary sphincter. Curr Urol Rep 2014; 14:476-87. [PMID: 23824516 DOI: 10.1007/s11934-013-0352-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
When sterile culture techniques of mammalian cells first became state of the art, there was tremendous anticipation that such cells could be eventually applied for therapeutic purposes. The discovery of adult human stem or progenitor cells further motivated scientists to pursue research in cell-based therapies. Although evidence from animal studies suggests that application of cells yields measurable benefits, in urology and many other disciplines, progenitor-cell-based therapies are not yet routinely clinically available. Stress urinary incontinence (SUI) is a condition affecting a large number of patients. The etiology of SUI includes, but is not limited to, degeneration of the urinary sphincter muscle tissue and loss of innervation, as well as anatomical and biomechanical causes. Therefore, different regimens were developed to treat SUI. However, at present, a curative functional treatment is not at hand. A progenitor-cell-based therapy that can tackle the etiology of incontinence, rather than the consequences, is a promising strategy. Therefore, several research teams have intensified their efforts to develop such a therapy for incontinence. Here, we introduce candidate stem and progenitor cells suitable for SUI treatment, show how the functional homogeneity and state of maturity of differentiated cells crucial for proper tissue integration can be assessed electrophysiologically prior to their clinical application, and discuss the trophic potential of adult mesenchymal stromal (or stem) cells in regeneration of neuronal function.
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Affiliation(s)
- Melanie L Hart
- KFO273, Department of Urology, UKT, University of Tuebingen, Paul-Ehrlich-Str. 15, 72076, Tuebingen, Germany
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Askevold ET, Aukrust P, Nymo SH, Lunde IG, Kaasbøll OJ, Aakhus S, Florholmen G, Ohm IK, Strand ME, Attramadal H, Fiane A, Dahl CP, Finsen AV, Vinge LE, Christensen G, Yndestad A, Gullestad L, Latini R, Masson S, Tavazzi L, Ueland T. The cardiokine secreted Frizzled-related protein 3, a modulator of Wnt signalling, in clinical and experimental heart failure. J Intern Med 2014; 275:621-30. [PMID: 24330105 DOI: 10.1111/joim.12175] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
OBJECTIVES Experimental studies have shown involvement of Wnt signalling in heart failure (HF). We hypothesized that secreted frizzled-related protein 3 (sFRP3), a modulator of Wnt signalling, is related to the progression of HF. DESIGN Circulating sFRP3 was measured in 153 HF patients and compared with 25 healthy controls. The association of sFRP3 with mortality was evaluated in 1202 patients (GISSI-HF trial). sFRP3 mRNA expression was assessed in failing human and murine left ventricles (LV), and cellular localization was determined after fractioning of myocardial tissue. In vitro studies were carried out in cardiac fibroblasts subjected to cyclic mechanical stretch. RESULTS (i) Heart failure patients had significantly raised serum sFRP3 levels compared with controls, (ii) during a median follow-up of 47 months, 315 patients died in the GISSI-HF substudy. In univariable Cox regression, tertiles of baseline sFRP3 concentration were significantly associated with all-cause and cardiovascular mortality. After adjustment for demographic and clinical variables, but not for CRP and NT-proBNP, the associations with mortality remained significant for the third tertile (all-cause, HR 1.45, P = 0.011; cardiovascular, HR 1.66, P = 0.003), (iii) sFRP3 mRNA expression was increased in failing human LV, with a decline following LV assist device therapy. LV from post-MI mice showed an increased sFRP3 mRNA level, particularly in cardiac fibroblasts, and (iv) mechanical stretch enhanced sFRP3 expression and release in myocardial fibroblasts. CONCLUSION There is an association between increased sFRP3 expression and adverse outcome in HF, suggesting that the failing myocardium itself contributes to an increase in circulating sFRP3.
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Affiliation(s)
- E T Askevold
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; Center for Heart Failure Research, University of Oslo, Oslo, Norway
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