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Lee J, Jang J, Cha SR, Lee SB, Hong SH, Bae HS, Lee YJ, Yang SR. Recombinant Human Bone Morphogenetic Protein-2 Priming of Mesenchymal Stem Cells Ameliorate Acute Lung Injury by Inducing Regulatory T Cells. Immune Netw 2023; 23:e48. [PMID: 38188599 PMCID: PMC10767548 DOI: 10.4110/in.2023.23.e48] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 12/11/2023] [Accepted: 12/11/2023] [Indexed: 01/09/2024] Open
Abstract
Mesenchymal stromal/stem cells (MSCs) possess immunoregulatory properties and their regulatory functions represent a potential therapy for acute lung injury (ALI). However, uncertainties remain with respect to defining MSCs-derived immunomodulatory pathways. Therefore, this study aimed to investigate the mechanism underlying the enhanced effect of human recombinant bone morphogenic protein-2 (rhBMP-2) primed ES-MSCs (MSCBMP2) in promoting Tregs in ALI mice. MSC were preconditioned with 100 ng/ml rhBMP-2 for 24 h, and then administrated to mice by intravenous injection after intratracheal injection of 1 mg/kg LPS. Treating MSCs with rhBMP-2 significantly increased cellular proliferation and migration, and cytokines array reveled that cytokines release by MSCBMP2 were associated with migration and growth. MSCBMP2 ameliorated LPS induced lung injury and reduced myeloperoxidase activity and permeability in mice exposed to LPS. Levels of inducible nitric oxide synthase were decreased while levels of total glutathione and superoxide dismutase activity were further increased via inhibition of phosphorylated STAT1 in ALI mice treated with MSCBMP2. MSCBMP2 treatment increased the protein level of IDO1, indicating an increase in Treg cells, and Foxp3+CD25+ Treg of CD4+ cells were further increased in ALI mice treated with MSCBMP2. In co-culture assays with MSCs and RAW264.7 cells, the protein level of IDO1 was further induced in MSCBMP2. Additionally, cytokine release of IL-10 was enhanced while both IL-6 and TNF-α were further inhibited. In conclusion, these findings suggest that MSCBMP2 has therapeutic potential to reduce massive inflammation of respiratory diseases by promoting Treg cells.
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Affiliation(s)
- Jooyeon Lee
- Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University, Chuncheon 24341, Korea
| | - Jimin Jang
- Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University, Chuncheon 24341, Korea
| | - Sang-Ryul Cha
- Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University, Chuncheon 24341, Korea
| | - Se Bi Lee
- Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University, Chuncheon 24341, Korea
| | - Seok-Ho Hong
- Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon 24341, Korea
| | - Han-Sol Bae
- Cellular Therapeutics Team, Daewoong Pharmaceutical, Yongin 17028, Korea
| | - Young Jin Lee
- Cellular Therapeutics Team, Daewoong Pharmaceutical, Yongin 17028, Korea
| | - Se-Ran Yang
- Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University, Chuncheon 24341, Korea
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Richter RF, Vater C, Korn M, Ahlfeld T, Rauner M, Pradel W, Stadlinger B, Gelinsky M, Lode A, Korn P. Treatment of critical bone defects using calcium phosphate cement and mesoporous bioactive glass providing spatiotemporal drug delivery. Bioact Mater 2023; 28:402-419. [PMID: 37361564 PMCID: PMC10285454 DOI: 10.1016/j.bioactmat.2023.06.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 05/22/2023] [Accepted: 06/01/2023] [Indexed: 06/28/2023] Open
Abstract
Calcium phosphate cements (CPC) are currently widely used bone replacement materials with excellent bioactivity, but have considerable disadvantages like slow degradation. For critical-sized defects, however, an improved degradation is essential to match the tissue regeneration, especially in younger patients who are still growing. We demonstrate that a combination of CPC with mesoporous bioactive glass (MBG) particles led to an enhanced degradation in vitro and in a critical alveolar cleft defect in rats. Additionally, to support new bone formation the MBG was functionalized with hypoxia conditioned medium (HCM) derived from rat bone marrow stromal cells. HCM-functionalized scaffolds showed an improved cell proliferation and the highest formation of new bone volume. This highly flexible material system together with the drug delivery capacity is adaptable to patient specific needs and has great potential for clinical translation.
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Affiliation(s)
- Richard Frank Richter
- Centre for Translational Bone, Joint and Soft Tissue Research, University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Corina Vater
- Centre for Translational Bone, Joint and Soft Tissue Research, University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Margarete Korn
- Department of Oral and Maxillofacial Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany
| | - Tilman Ahlfeld
- Centre for Translational Bone, Joint and Soft Tissue Research, University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Martina Rauner
- Department of Medicine III and Center for Healthy Aging, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany
| | - Winnie Pradel
- Department of Oral and Maxillofacial Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany
| | - Bernd Stadlinger
- Clinic of Cranio-Maxillofacial and Oral Surgery, Center of Dental Medicine, University of Zurich, Switzerland
| | - Michael Gelinsky
- Centre for Translational Bone, Joint and Soft Tissue Research, University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Anja Lode
- Centre for Translational Bone, Joint and Soft Tissue Research, University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Paula Korn
- Centre for Translational Bone, Joint and Soft Tissue Research, University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
- Department of Oral and Maxillofacial Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany
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Zeng M, Wang X, Chen T, Ruan G, Li J, Xue S, Zhao Y, Hu Z, Xie Y, Fan T, Chen S, Li Y, Wang Q, Zhang Y, Zhang R, Lin L, Ding C, Zhu Z. Comprehensive analysis on subchondral bone marrow lesions of human osteoarthritis by integrating bulk and single-cell transcriptomes. BMC Musculoskelet Disord 2023; 24:677. [PMID: 37626330 PMCID: PMC10463447 DOI: 10.1186/s12891-023-06676-4] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 06/29/2023] [Indexed: 08/27/2023] Open
Abstract
OBJECTIVE This study aims to demonstrate the cellular composition and underlying mechanisms in subchondral bone marrow lesions (BMLs) of knee osteoarthritis (OA). METHODS BMLs were assessed by MRI Osteoarthritis Knee Score (MOAKS)≥2. Bulk RNA-sequencing (bulk-seq) and BML-specific differentially expressed genes (DEGs) analysis were performed among subchondral bone samples (including OA-BML=3, paired OA-NBML=3; non-OA=3). The hub genes of BMLs were identified by verifying in independent datasets and multiple bioinformatic analyses. To further estimate cell-type composition of subchondral bone, we utilized two newly developed deconvolution algorithms (MuSiC, MCP-counter) in transcriptomic datasets, based on signatures from open-accessed single-cell RNA sequencing (scRNA-seq). Finally, competing endogenous RNA (ceRNA) and transcription factor (TF) networks were constructed through multiple predictive databases, and validated by public non-coding RNA profiles. RESULTS A total of 86 BML-specific DEGs (up 79, down 7) were identified. IL11 and VCAN were identified as core hub genes. The "has-miR-424-5p/lncRNA PVT1" was determined as crucial network, targeting IL11 and VCAN, respectively. More importantly, two deconvolution algorithms produced approximate estimations of cell-type composition, and the cluster of heterotopic-chondrocyte was discovered abundant in BMLs, and positively correlated with the expression of hub genes. CONCLUSION IL11 and VCAN were identified as the core hub genes of BMLs, and their molecular networks were determined as well. We profiled the characteristics of subchondral bone at single-cell level and determined that the heterotopic-chondrocyte was abundant in BMLs and was closely linked to IL11 and VCAN. Our study may provide new insights into the microenvironment and pathological molecular mechanism of BMLs, and could lead to novel therapeutic strategies.
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Affiliation(s)
- Muhui Zeng
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China
- Department of Orthopedics, General Hospital of Southern Theater Command of PLA, Guangzhou, Guangdong, China
| | - Xiaoshuai Wang
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China
- Department of Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Tianyu Chen
- Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Guangfeng Ruan
- Clinical Research Centre, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Jia Li
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China
- Department of Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Song Xue
- Department of Rheumatology and Immunology, Arthritis Research Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yang Zhao
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China
| | - Zhiyang Hu
- Sun Yat-sen University School of Medicine, Sun Yat-sen University, Shenzhen, China
| | - Ye Xie
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Tianxiang Fan
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China
| | - Shibo Chen
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China
| | - Yang Li
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China
| | - Qianyi Wang
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China
| | - Yue Zhang
- State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Rongkai Zhang
- Department of Orthopedics, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Lijun Lin
- Department of Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Changhai Ding
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China.
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
| | - Zhaohua Zhu
- Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China.
- Department of Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
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Combined application of BMP-2 and naturally occurring bioactive factor mixtures for the optimized therapy of segmental bone defects. Acta Biomater 2023; 157:162-174. [PMID: 36481501 DOI: 10.1016/j.actbio.2022.11.064] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 11/27/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022]
Abstract
Critical bone defects are the result of traumatic, infection- or tumor-induced segmental bone loss and represent a therapeutic problem that has not been solved by current reconstructive or regenerative strategies yet. Scaffolds functionalized with naturally occurring bioactive factor mixtures show a promising chemotactic and angiogenic potential in vitro and therefore might stimulate bone regeneration in vivo. To assess this prospect, the study targets at heparin-modified mineralized collagen scaffolds functionalized with naturally occurring bioactive factor mixtures and/or rhBMP-2. These scaffolds were implanted into a 2-mm segmental femoral defect in mice and analyzed in respect to newly formed bone volume (BV) and bone mineral density (BMD) by micro-computed tomography scans after an observation period of 6 weeks. To rate the degree of defect healing, the number of vessels, and the activity of osteoclasts and osteoblasts were analyzed histologically. The sole application of bioactive factor mixtures is inferior to the use of the recombinant growth factor rhBMP-2 regarding BV and degree of defect healing. A higher rhBMP-2 concentration or the combination with bioactive factor mixtures does not lead to a further enhancement in defect healing. Possibly, a synergistic effect can be achieved by further concentration or a prolonged release of bioactive factor mixtures. STATEMENT OF SIGNIFICANCE: The successful therapy of extended bone defects is still a major challenge in clinical routine. In this study we investigated the bone regenerative potential of naturally occuring bioactive factor mixtures derived from platelet concentrates, adipose tissue and cell secretomes as a cheap and promising alternative to recombinant growth factors in a murine segmental bone defect model. The mixtures alone were not able to induce complete bridging of the bone defect, but in combination with bone morphogenetic protein 2 bone healing seemed to be more physiological. The results show that naturally occuring bioactive factor mixtures are a promising add-on in a clinical setting.
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Hatori A, Fujii Y, Kawase-Koga Y, Ogasawara T, Chikira J, Minami S, Yamakawa D, Chikazu D. VCAM-1 and GFPT-2: Predictive markers of osteoblast differentiation in human dental pulp stem cells. Bone 2023; 166:116575. [PMID: 36195245 DOI: 10.1016/j.bone.2022.116575] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 09/24/2022] [Accepted: 09/27/2022] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Dental pulp stem cells (DPSCs) have high proliferative and multilineage differentiation potential in mesenchymal stem cells. However, several studies have indicated that there are individual differences in the potential for osteogenic differentiation of DPSCs, and the factors determining these differences are unknown. OBJECTIVE To identify the genes responsible for the individual differences in the osteogenic differentiation ability of DPSCs. METHODS We divided DPSCs into high and low osteogenic differentiation ability groups (HG or LG) with ALP and von Kossa stain, and compared the gene expression patterns using RNA-seq. In addition, genes that may affect osteogenic differentiation were knocked down using small interfering RNA (siRNA) and their effects were investigated. RESULTS The RNA-seq patterns revealed that VCAM1 and GFPT2 were significantly expressed at higher levels in the HG than in the LG. The results of siRNA analysis showed that VCAM1 and GFPT2 knockdown significantly reduced the expression of osteogenic markers. Furthermore, we analyzed the involvement of these two genes in cell signaling in DPSC differentiation. The results indicated that the VCAM1-mediated Ras-MEK-Erk and PI3K/Akt pathways are involved in the osteogenic differentiation of DPSCs, and that GFPT2-mediated HBP signaling influences the osteogenic differentiation of DPSCs. CONCLUSIONS These findings indicate that DPSCs that highly express VCAM1 and GFPT2 have a high capacity for osteogenic differentiation. Evaluation of VCAM1 and GFPT2 expression in undifferentiated DPSCs may predict the outcome of bone regenerative therapy using DPSCs. Moreover, the expression levels of VCAM1 and GFPT2 in DPSCs may be useful in setting criteria for selecting donors for allogeneic cell transplantation for bone regeneration.
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Affiliation(s)
- Ayano Hatori
- Department of Oral and Maxillofacial Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
| | - Yasuyuki Fujii
- Department of Oral and Maxillofacial Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.
| | - Yoko Kawase-Koga
- Department of Oral and Maxillofacial Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan; Department of Oral and Maxillofacial Surgery, School of Medicine, Tokyo Women's Medical University, 8-1 Kawadachou, Shinjuku-ku, Tokyo 160-0023, Japan
| | - Toru Ogasawara
- Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Jin Chikira
- Department of Oral and Maxillofacial Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
| | - Sakura Minami
- Department of Oral and Maxillofacial Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
| | - Daiki Yamakawa
- Department of Oral and Maxillofacial Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
| | - Daichi Chikazu
- Department of Oral and Maxillofacial Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
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Krüger T, Wehner R, Herbig M, Kräter M, Kramer M, Middeke JM, Stölzel F, List C, Egger-Heidrich K, Teipel R, Oelschlägel U, Wermke M, Jambor H, Wobus M, Schetelig J, Jöhrens K, Tonn T, Subburayalu J, Schmitz M, Bornhauser M, von Bonin M. Perturbations of mesenchymal stromal cells after allogeneic hematopoietic cell transplantation predispose for bone marrow graft-versus-host-disease. Front Immunol 2022; 13:1005554. [PMID: 36311725 PMCID: PMC9599394 DOI: 10.3389/fimmu.2022.1005554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 09/27/2022] [Indexed: 12/04/2022] Open
Abstract
Functional impairment of the bone marrow (BM) niche has been suggested as a major reason for prolonged cytopenia and secondary graft failure after allogeneic hematopoietic cell transplantation (alloHCT). Because mesenchymal stromal cells (MSCs) serve as multipotent progenitors for several niche components in the BM, they might play a key role in this process. We used collagenase digested trephine biopsies to directly quantify MSCs in 73 patients before (n = 18) and/or after alloHCT (n = 65). For the first time, we demonstrate that acute graft-versus-host disease (aGvHD, n = 39) is associated with a significant decrease in MSC numbers. MSC reduction can be observed even before the clinical onset of aGvHD (n = 10). Assessing MSCs instantly after biopsy collection revealed phenotypic and functional differences depending on the occurrence of aGvHD. These differences vanished during ex vivo expansion. The MSC endotypes observed revealed an enhanced population of donor-derived classical dendritic cells type 1 and alloreactive T cells as the causing agent for compartmental inflammation and MSC damage before clinical onset of aGvHD was ascertained. In conclusion, MSCs endotypes may constitute a predisposing conductor of alloreactivity after alloHCT preceding the clinical diagnosis of aGvHD.
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Affiliation(s)
- Thomas Krüger
- Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
- *Correspondence: Thomas Krüger,
| | - Rebekka Wehner
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT), Dresden, Germany
| | - Maik Herbig
- Max Planck Institute for Science of Light and Max-Planck-Zentrum für Physik und Medizin, Erlangen, Germany
- Biotechnology Center, Center for Molecular and Cellular Bioengineering Technical University (TU) Dresden Tatzberg, Dresden, Germany
- Center for Regenerative Therapies (CRTD), Dresden, Germany
| | - Martin Kräter
- Max Planck Institute for Science of Light and Max-Planck-Zentrum für Physik und Medizin, Erlangen, Germany
- Biotechnology Center, Center for Molecular and Cellular Bioengineering Technical University (TU) Dresden Tatzberg, Dresden, Germany
| | - Michael Kramer
- Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Jan Moritz Middeke
- Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Friedrich Stölzel
- Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Catrin List
- Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
| | | | - Raphael Teipel
- Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Uta Oelschlägel
- Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Martin Wermke
- Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
- University Cancer Centrum (UCC), Early Clinical Trial Unit (ECTU), University Hospital Carl Gustav Carus, Dresden, Germany
| | - Helena Jambor
- Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Manja Wobus
- Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Johannes Schetelig
- Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Korinna Jöhrens
- Institute of Pathology, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Torsten Tonn
- Institute of Transfusion Medicine, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- German Red Cross Blood Donation Service North-East, Dresden, Germany
| | - Julien Subburayalu
- Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Center for Regenerative Therapies (CRTD), Dresden, Germany
- Mildred Scheel Early Career Center, Medical Faculty, Technische Universität Dresden, Dresden, Germany
| | - Marc Schmitz
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT), Dresden, Germany
- Center for Regenerative Therapies (CRTD), Dresden, Germany
| | - Martin Bornhauser
- Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Dresden, Germany
- Center for Regenerative Therapies (CRTD), Dresden, Germany
| | - Malte von Bonin
- Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
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Shi MY, Liu L, Yang FY. Strategies to improve the effect of mesenchymal stem cell therapy on inflammatory bowel disease. World J Stem Cells 2022; 14:684-699. [PMID: 36188115 PMCID: PMC9516464 DOI: 10.4252/wjsc.v14.i9.684] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/07/2022] [Accepted: 09/07/2022] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) includes Crohn’s disease and ulcerative colitis and is an idiopathic, chronic inflammatory disease of the colonic mucosa. The occurrence of IBD, causes irreversible damage to the colon and increases the risk of carcinoma. The routine clinical treatment of IBD includes drug treatment, endoscopic treatment and surgery. The vast majority of patients are treated with drugs and biological agents, but the complete cure of IBD is difficult. Mesenchymal stem cells (MSCs) have become a new type of cell therapy for the treatment of IBD due to their immunomodulatory and nutritional functions, which have been confirmed in many clinical trials. This review discusses some potential mechanisms of MSCs in the treatment of IBD, summarizes the experimental results, and provides new insights to enhance the therapeutic effects of MSCs in future applications.
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Affiliation(s)
- Meng-Yue Shi
- School of Medicine, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Lian Liu
- Department of Pharmacology, Medical School of Yangtze University, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Fu-Yuan Yang
- Health Science Center, Yangtze University, Jingzhou 434020, Hubei Province, China
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8
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Li T, Zhou L, Fan M, Chen Z, Yan L, Lu H, Jia M, Wu H, Shan L. Human Umbilical Cord-Derived Mesenchymal Stem Cells Ameliorate Skin Aging of Nude Mice Through Autophagy-Mediated Anti-Senescent Mechanism. Stem Cell Rev Rep 2022; 18:2088-2103. [PMID: 35864432 DOI: 10.1007/s12015-022-10418-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/22/2022] [Indexed: 10/17/2022]
Abstract
Skin aging is a currently irreversible process, affected by increased oxidative stress, activated cellular senescence, and lacked regeneration of the dermal layer. Mesenchymal stem cells (MSCs), such as human umbilical cord-derived MSCs (hucMSCs), have pro-regeneration and anti-aging potencies. To explore whether hucMSCs can be used to treat skin aging, this study employed skin-aging model of nude mice to conduct in vivo assays, including biochemical analysis of superoxide dismutase (SOD) and malondialdehyde (MDA), gross observation, histopathological observation, and immunohistochemical analysis. To clarify how hucMSCs work on skin aging, this study employed skin-aging model of human dermal fibroblasts (HDFs) to conduct in vitro assays by applying conditional medium of hucMSCs (CMM), including wound healing assay, senescence staining, flow cytometric oxidative detection, real time PCR, and western blot analysis. The in vivo data demonstrated that hucMSCs dose-dependently removed wrinkles, smoothed skin texture, and increased dermal thickness and collagen production of aged skin by reversing SOD and MDA levels and up-regulating Col-1 and VEGF expressions, indicating anti-oxidative and pro-regenerative effects against skin aging. The in vitro data revealed that hucMSCs significantly reversed the senescence of HDFs by promoting cell migration, inhibiting ROS production, and restoring the overexpressions of oxidative and senescent markers through paracrine mode of action, and the paracrine mechanism was mediated by the inhibition of autophagy. This study provided novel knowledge regarding the anti-aging efficacy and paracrine mechanism of hucMSCs on skin, making hucMSCs-based therapy a promising regime for skin aging treatment.
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Affiliation(s)
- Ting Li
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Department of Plastic and Aesthetic Center, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Li Zhou
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, China
| | - Mengqiang Fan
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zuxiang Chen
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, China
| | - Li Yan
- Cell Resource Bank and Integrated Cell Preparation Center of Xiaoshan District, Hangzhou Regional Cell Preparation Center (Shangyu Biotechnology Co., Ltd), Hangzhou, China
| | - Haishan Lu
- Department of Dermatology, PLA 903 Hospital, Hangzhou, China
| | - Ming Jia
- Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Huiling Wu
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. .,Department of Plastic and Aesthetic Center, The First Affiliated Hospital of Zhejiang University, Hangzhou, China.
| | - Letian Shan
- The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, China. .,Cell Resource Bank and Integrated Cell Preparation Center of Xiaoshan District, Hangzhou Regional Cell Preparation Center (Shangyu Biotechnology Co., Ltd), Hangzhou, China.
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Teufelsbauer M, Lang C, Plangger A, Rath B, Moser D, Staud C, Radtke C, Neumayer C, Hamilton G. Effects of metformin on human bone-derived mesenchymal stromal cell-breast cancer cell line interactions. Med Oncol 2022; 39:54. [PMID: 35150338 PMCID: PMC8840908 DOI: 10.1007/s12032-022-01655-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 01/10/2022] [Indexed: 11/29/2022]
Abstract
Metformin is used to treat patients with type 2 diabetes mellitus and was found to lower the incidence of cancer. Bone metastasis is a common impairment associated with advanced breast cancer. The present study investigated the effects of metformin on human bone-derived mesenchymal stromal cells (BM-MSC)—breast cancer cell line interactions. BM-MSCs grown from box chisels were tested for growth-stimulating and migration-controlling activity on four breast cancer cell lines either untreated or after pretreatment with metformin. Growth stimulation was tested in MTT tests and migration in scratch assays. Furthermore, the expression of adipokines of BM-MSCs in response to metformin was assessed using Western blot arrays. Compared to breast cancer cell lines (3.6 ± 1.4% reduction of proliferation), 500 µM metformin significantly inhibited the proliferation of BM-MSC lines (mean 12.3 ± 2.2 reduction). Pretreatment of BM-MSCs with metformin showed variable effects of the resulting conditioned media (CM) on breast cancer cell lines depending on the specific BM-MSC—cancer line combination. Metformin significantly reduced the migration of breast cancer cell lines MDA-MB-231 and MDA-MB-436 in response to CM of drug-pretreated BM-MSCs. Assessment of metformin-induced alterations in the expression of adipokines by BM-MSC CM indicated increased osteogenic signaling and possibly impairment of metastasis. In conclusion, the anticancer activities of metformin are the result of a range of direct and indirect mechanisms that lower tumor proliferation and progression. A lower metformin-induced protumor activity of BM-MSCs in the bone microenvironment seem to contribute to the positive effects of the drug in selected breast cancer patients.
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Affiliation(s)
- Maryana Teufelsbauer
- Department of Plastic and Reconstructive Surgery, Medical University of Vienna, Vienna, Austria
| | - Clemens Lang
- Department of Trauma Surgery, Sozialmedizinisches Zentrum Ost, Donauspital, Vienna, Austria
| | - Adelina Plangger
- Institute of Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Barbara Rath
- Institute of Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Doris Moser
- Department of Cranio, Maxillofacial and Oral Surgery, Medical University of Vienna, Vienna, Austria
| | - Clement Staud
- Department of Plastic and Reconstructive Surgery, Medical University of Vienna, Vienna, Austria
| | - Christine Radtke
- Department of Plastic and Reconstructive Surgery, Medical University of Vienna, Vienna, Austria
| | - Christoph Neumayer
- Department of Vascular Surgery, Medical University of Vienna, Vienna, Austria
| | - Gerhard Hamilton
- Institute of Pharmacology, Medical University of Vienna, Vienna, Austria.
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Kelishadi MR, Naeini AA, Khorvash F, Askari G, Heidari Z. The beneficial effect of Alpha-lipoic acid supplementation as a potential adjunct treatment in episodic migraines. Sci Rep 2022; 12:271. [PMID: 34997178 PMCID: PMC8742085 DOI: 10.1038/s41598-021-04397-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 12/20/2021] [Indexed: 01/10/2023] Open
Abstract
The current study was performed to evaluate the effects of alpha-lipoic acid (ALA) supplementation on lactate, nitric oxide (NO), vascular cell adhesion molecule-1 (VCAM-1) levels, and clinical symptoms in women with episodic migraines. Considering the inclusion and exclusion criteria, ninety-two women with episodic migraines participated in this randomized, double-blind, placebo-controlled, parallel-design trial. The participants were randomly assigned to receive either 300 mg/day ALA or placebo, twice per day for 12 weeks. The primary outcomes included headache severity, headache frequency per month, and duration of attacks and the secondary outcomes included lactate (a marker of mitochondrial function), NO, and VCAM-1 serum levels were measured at baseline and the end of the intervention. At the end of the study, there was a significant decrease in lactate serum levels (- 6.45 ± 0.82 mg/dl vs - 2.27 ± 1.17 mg/dl; P = 0.039) and VCAM-1 (- 2.02 ± 0.30 ng/ml vs - 1.21 ± 0.36 ng/ml; P = 0.025) in the ALA as compared to the placebo group. In addition, the severity (P < 0.001), frequency (P = 0.001), headache impact test (HIT-6) (P < 0.001), headache dairy results (HDR) (P = 0.003), and migraine headache index score (MHIS) (P < 0.001) had significantly decreased in the intervention as compared to the control group. No significant changes were observed for NO levels and duration of migraine pains. ALA supplementation can be considered a potential adjunct treatment in patients with migraine due to its improving mitochondrial and endothelial functions and clinical symptoms.
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Affiliation(s)
- Mahnaz Rezaei Kelishadi
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Amirmansour Alavi Naeini
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Fariborz Khorvash
- Department of Neurology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Gholamreza Askari
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Zahra Heidari
- Department of Biostatistics and Epidemiology, School of Health, Isfahan University of Medical Sciences, Isfahan, Iran
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11
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Shin S, Lee J, Kwon Y, Park KS, Jeong JH, Choi SJ, Bang SI, Chang JW, Lee C. Comparative Proteomic Analysis of the Mesenchymal Stem Cells Secretome from Adipose, Bone Marrow, Placenta and Wharton's Jelly. Int J Mol Sci 2021; 22:ijms22020845. [PMID: 33467726 PMCID: PMC7829982 DOI: 10.3390/ijms22020845] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/12/2021] [Accepted: 01/13/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have the potential to be a viable therapy against various diseases due to their paracrine effects, such as secretion of immunomodulatory, trophic and protective factors. These cells are known to be distributed within various organs and tissues. Although they possess the same characteristics, MSCs from different sources are believed to have different secretion potentials and patterns, which may influence their therapeutic effects in disease environments. We characterized the protein secretome of adipose (AD), bone marrow (BM), placenta (PL), and Wharton’s jelly (WJ)-derived human MSCs by using conditioned media and analyzing the secretome by mass spectrometry and follow-up bioinformatics. Each MSC secretome profile had distinct characteristics depending on the source. However, the functional analyses of the secretome from different sources showed that they share similar characteristics, such as cell migration and negative regulation of programmed cell death, even though differences in the composition of the secretome exist. This study shows that the secretome of fetal-derived MSCs, such as PL and WJ, had a more diverse composition than that of AD and BM-derived MSCs, and it was assumed that their therapeutic potential was greater because of these properties.
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Affiliation(s)
- Sungho Shin
- Center for Theragnosis, Korea Institute of Science and Technology, Seoul 02792, Korea; (S.S.); (Y.K.)
- KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Korea;
| | - Jeongmin Lee
- Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Seoul 06351, Korea;
- R&D Center, ENCell Co., Ltd., Seoul 06351, Korea
| | - Yumi Kwon
- Center for Theragnosis, Korea Institute of Science and Technology, Seoul 02792, Korea; (S.S.); (Y.K.)
| | - Kang-Sik Park
- KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Korea;
- Department of Physiology, School of Medicine, Kyung Hee University, Seoul 02447, Korea
| | - Jae-Hoon Jeong
- Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Korea;
| | - Suk-Joo Choi
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea;
| | - Sa Ik Bang
- Department of Plastic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea;
| | - Jong Wook Chang
- Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Seoul 06351, Korea;
- R&D Center, ENCell Co., Ltd., Seoul 06351, Korea
- Correspondence: (J.W.C.); (C.L.)
| | - Cheolju Lee
- Center for Theragnosis, Korea Institute of Science and Technology, Seoul 02792, Korea; (S.S.); (Y.K.)
- KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Korea;
- Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Korea
- Correspondence: (J.W.C.); (C.L.)
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