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Seth P, Friedrichs J, Limasale YDP, Fertala N, Freudenberg U, Zhang Y, Lampel A, Werner C. Interpenetrating Polymer Network Hydrogels with Tunable Viscoelasticity and Proteolytic Cleavability to Direct Stem Cells In Vitro. Adv Healthc Mater 2025; 14:e2402656. [PMID: 39506429 PMCID: PMC11973941 DOI: 10.1002/adhm.202402656] [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: 07/18/2024] [Revised: 10/18/2024] [Indexed: 11/08/2024]
Abstract
The dynamic nature of cellular microenvironments, regulated by the viscoelasticity and enzymatic cleavage of the extracellular matrix, remains challenging to emulate in engineered synthetic biomaterials. To address this, a novel platform of cell-instructive hydrogels is introduced, composed of two concurrently forming interpenetrating polymer networks (IPNs). These IPNs consist of the same basic building blocks - four-armed poly(ethylene glycol) and the sulfated glycosaminoglycan (sGAG) heparin - are cross-linked through either chemical or physical interactions, allowing for precise and selective tuning of the hydrogel's stiffness, viscoelasticity, and proteolytic cleavability. The studies of the individual and combined effects of these parameters on stem cell behavior revealed that human mesenchymal stem cells exhibited increased spreading and Yes-associated protein transcriptional activity in more viscoelastic and cleavable sGAG-IPN hydrogels. Furthermore, human induced pluripotent stem cell (iPSC) cysts displayed enhanced lumen formation, growth, and pluripotency maintenance when cultured in sGAG-IPN hydrogels with higher viscoelasticity. Inhibition studies emphasized the pivotal roles of actin dynamics and matrix metalloproteinase activity in iPSC cyst morphology, which varied with the viscoelastic properties of the hydrogels. Thus, the introduced sGAG-IPN hydrogel platform offers a powerful methodology for exogenous stem cell fate control.
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Affiliation(s)
- Prannoy Seth
- Leibniz Institute of Polymer Research DresdenMax Bergmann Center of Biomaterials Dresden01069DresdenGermany
| | - Jens Friedrichs
- Leibniz Institute of Polymer Research DresdenMax Bergmann Center of Biomaterials Dresden01069DresdenGermany
| | - Yanuar Dwi Putra Limasale
- Leibniz Institute of Polymer Research DresdenMax Bergmann Center of Biomaterials Dresden01069DresdenGermany
| | - Nicole Fertala
- Leibniz Institute of Polymer Research DresdenMax Bergmann Center of Biomaterials Dresden01069DresdenGermany
| | - Uwe Freudenberg
- Leibniz Institute of Polymer Research DresdenMax Bergmann Center of Biomaterials Dresden01069DresdenGermany
| | - Yixin Zhang
- Cluster of Excellence Physics of Lifeand B CUBE – Center for Molecular BioengineeringDresden University of Technology01307DresdenGermany
| | - Ayala Lampel
- Shmunis School of Biomedicine and Cancer ResearchGeorge S. Wise Faculty of Life SciencesCenter for Nanoscience and Nanotechnology Sagol Center for Regenerative Biotechnologyand Center for the Physics and Chemistry of Living Systems Tel Aviv UniversityTel Aviv69978Israel
| | - Carsten Werner
- Leibniz Institute of Polymer Research DresdenMax Bergmann Center of Biomaterials Dresden01069DresdenGermany
- Center for Regenerative Therapies Dresdenand Cluster of Excellence Physics of LifeDresden University of Technology01062DresdenGermany
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Gurel M, Zomer H, McFetridge C, Murfee WL, McFetridge PS. Physiologically-Modeled Dynamic Stimulation and Growth Factors Induce Differentiation of Mesenchymal Stem Cells to a Vascular Endothelial Cell Phenotype. Microcirculation 2025; 32:e70007. [PMID: 40120632 PMCID: PMC12012511 DOI: 10.1111/micc.70007] [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: 08/13/2024] [Revised: 03/04/2025] [Accepted: 03/14/2025] [Indexed: 03/25/2025]
Abstract
OBJECTIVE Mesenchymal stem cells (MSCs) represent an attractive option as an endothelial cell (EC) source for regenerative medicine therapies. However, the differentiation of MSCs toward an ECs phenotype can be regulated by a complex and dynamic microenvironment, including specific growth factors as well as local mechanical cues. The objective of this work was to evaluate whether Physiologically-modeled dynamic stimulation (PMDS) characterized by continuous variability in pulse frequencies mimicking the dynamic temporal range of cardiac function would enhance MSC differentiation toward ECs compared to a constant frequency stimulation. METHODS Mesenchymal stem cells were grown in a complex growth factor cocktail versus standard culture media to initiate the endothelial differentiation process, then subsequently exposed to PMDS that vary in duration and constant flow (CF) at a fixed 10 dynes/cm2 shear stress and 1.3 Hz frequency. RESULTS Both PMDS and media type strongly influence cell differentiation and function. Cells were shown to significantly upregulate eNOS activity and displayed lower TNF-a induced leukocyte adhesion compared to cells cultured under CF, consistent with a more quiescent ECs phenotype that regulates anti-inflammatory and anti-thrombotic states. CONCLUSION These findings suggest that the dynamic microenvironment created by perfusion, in contrast to constant frequency, combined with growth factors, enhances MSCs differentiation toward a vascular endothelial-like phenotype.
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Affiliation(s)
- Mediha Gurel
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
- Biotechnology Research and Application Center, Cukurova University, Adana, Turkey
- Electronic and Automation Department, Bitlis Eren University, Bitlis, Turkey
| | - Helena Zomer
- Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA
| | - Calum McFetridge
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
| | - Walter L Murfee
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
| | - Peter S McFetridge
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida, USA
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Ali A, Yun S. Multifaceted Role of Notch Signaling in Vascular Health and Diseases. Biomedicines 2025; 13:837. [PMID: 40299408 PMCID: PMC12024539 DOI: 10.3390/biomedicines13040837] [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: 02/19/2025] [Revised: 03/25/2025] [Accepted: 03/28/2025] [Indexed: 04/30/2025] Open
Abstract
Notch signaling is evolutionarily conserved from Drosophila to mammals and it functions as an essential modulator of vascular growth and development by directing endothelial cell specification, proliferation, migration, arteriovenous differentiation, inflammation, and apoptosis. The interplay between Notch and other signaling pathways plays a homeostatic role by modulating multiple vascular functions, including permeability regulation, angiogenesis, and vascular remodeling. This review explores current knowledge on Notch signaling in vascular development, homeostasis, and disease. It also discusses recent developments in understanding how endothelial Notch signaling affects vascular inflammation via cytokines or aberrant shear stress in endothelial cells while addressing the reciprocal relationship between Notch signaling and inflammation.
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Affiliation(s)
| | - Sanguk Yun
- Department of Biotechnology, Inje University, Gimhae 50834, Republic of Korea;
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Wang X, Cao X, Zhou B, Mei J, Li Y, Zhao X, Zhu W, Huang F, Sun L, Wang M. FGFR3 signaling is essential for gastric cancer cell triggering the transition of BM-MSCs into tumor-associated MSCs. Differentiation 2025; 143:100859. [PMID: 40106855 DOI: 10.1016/j.diff.2025.100859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 03/12/2025] [Accepted: 03/13/2025] [Indexed: 03/22/2025]
Abstract
Bone marrow-derived mesenchymal stem cells (BM-MSCs) tend to migrate towards tumor sites and interact with tumor cells, thus incorporating into tumor microenvironment by transition into various stromal cells, particularly tumor-associated MSCs. However, the mechanisms involved in this process is still not clarified. Herein, we focused on miR-99a-5p and confirmed its reduction in gastric cancer-associated MSCs (GC-MSCs) compared to BM-MSCs. Under-expression of miR-99a-5p stimulated BM-MSCs transition into GC-MSCs-like cells, while overexpression of this miRNA abrogated tumor-promoting roles of GC-MSCs. miR-99a-5p not only targeted modulation of fibroblast growth factor receptor (FGFR3) but also negatively affected its phosphorylated levels. Suppression of FGFR3 signaling by AZD4547 or siRNA against FGFR3 notably blocked the miR-99a-5p inhibitor-induced BM-MSCs transition and the oncogenic roles of GC-MSCs. However, miR-99a-5p overexpression did not diminish the ability of gastric cancer cells to educate BM-MSCs. The levels of phosphorylated FGFR3, but not total FGFR3, was increased in BM-MSCs educated by gastric cancer cells. AZD4547 significantly suppressed the education capacity of gastric cancer cells on BM-MSCs. Taken together, although manipulating miR-99a-5p to mimic its levels in GC-MSCs promotes the transition of BM-MSCs into GC-MSCs-like cells, FGFR3 signaling, rather than miR-99a-5p, is unexpectedly essential for the education of BM-MSCs by gastric cancer cells. This discovery provides a novel mechanism underlying the transition of BM-MSCs into tumor-associated MSCs and identifies potential therapeutic targets for gastric cancer.
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Affiliation(s)
- Xiang Wang
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China
| | - Xiaoli Cao
- Department of Laboratory Medicine, Affiliated Tumor Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Baocheng Zhou
- Department of Medical Laboratory, Lianyungang Maternal and Child Health Hospital, Lianyungang, Jiangsu Province, China
| | - Jingyu Mei
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China
| | - Yuanyuan Li
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China
| | - Xinlan Zhao
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China
| | - Wei Zhu
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China
| | - Feng Huang
- Department of Clinical Laboratory, Kunshan First People's Hospital, Affiliated to Jiangsu University, Kunshan, Jiangsu Province, China; Department of Clinical Laboratory, Maternal and Child Health Care Hospital of Kunshan, Suzhou, Jiangsu Province, China.
| | - Li Sun
- Department of Clinical Laboratory, Kunshan First People's Hospital, Affiliated to Jiangsu University, Kunshan, Jiangsu Province, China.
| | - Mei Wang
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China.
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Harper CV, Eccles L, Henstock J, Charnock JC. Trophoblast-derived factors drive human mesenchymal stem cell differentiation along an endothelial lineage: A model of early placental vasculogenesis. Reprod Biol 2025; 25:100994. [PMID: 39823693 DOI: 10.1016/j.repbio.2025.100994] [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: 10/08/2024] [Revised: 12/19/2024] [Accepted: 01/04/2025] [Indexed: 01/20/2025]
Abstract
Mechanisms controlling the process and patterning of blood vessel development in the placenta remain largely unknown. The close physical proximity of early blood vessels observed in the placenta and the cytotrophoblast, as well as the reported production of vasculogenic growth factors by the latter, suggests that signalling between these two niches may be important. Here, we have developed an in vitro model to address the hypothesis that the cytotrophoblast, by the secretion of soluble factors, drives differentiation of resident sub-trophoblastic mesenchymal stem cells (MSCs) along a vascular lineage, thereby establishing feto-placental circulation. BM-MSCs (a readily available model for placental stem cells) were treated with conditioned medium containing the secretome from human BeWo trophoblast cells, or endothelial growth medium (EGM2) supplemented with exogenous growth factors (VEGF, IGF1 and EGF) for 10-12 days. Trophoblast-conditioned media, found to contain detectable concentrations of cytokines including VEGF, uPAR, TIMP-1, TIMP-2, IL6 and placental growth factor, induced the expression of the endothelial genes CD31, von Willibrand factor (vWF), FLT-1, VEGFR2 and VE-Cadherin. Upregulation of vWF protein was also detected following growth in trophoblast-conditioned media, using immunocytochemistry. Wound healing (migration assay) and Matrigel-tube formation assays confirmed that the BM-MSCs cultured in trophoblast-conditioned media exhibited functional measures of endothelial cells in addition to expressing relevant markers. Identification of key trophoblast-secreted factors and their promotion of endothelial differentiation in BM-MSCs helps advance our theories regarding the close relationship of the mesenchymal stem cell-cytotrophoblast niche in coordinating the complex angiogenic events that occur in the placenta. The in vitro model presented here provides an accessible and reproducible tool for further investigations into placental development.
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Affiliation(s)
| | - Leah Eccles
- Department of Biology, Edge Hill University, L39 4QP, UK
| | - James Henstock
- Faculty of Health & Life Sciences, Northumbria University, Newcastle-upon-Tyne NE1 8SU, UK
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de Freitas ALP, Han SW, Martin PKM, Ferreira LM. Effect of adipose-derived mesenchymal stem cells on the viability of the transverse rectus abdominis myocutaneous flap in rats. Clinics (Sao Paulo) 2025; 80:100590. [PMID: 39908748 PMCID: PMC11847128 DOI: 10.1016/j.clinsp.2025.100590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 09/14/2024] [Accepted: 01/20/2025] [Indexed: 02/07/2025] Open
Abstract
INTRODUCTION The Transverse Rectus Abdominis Myocutaneous (TRAM) flap is used for breast reconstruction, but involves the risk of necrosis. Adipose tissue-derived mesenchymal Stem Cells (ADSCs) can be used to stimulate neovascularization and reduce the risk of TRAM flap necrosis. AIM Determine the effect of ADSCs on TRAM flap viability in rats. METHODS Twenty-four Wistar-EPM rats were distributed into three groups (n = 8). A right caudal pedicled TRAM flap was performed in all the animals and was the only procedure performed in Group TRAM. The additional procedures of intradermal injection of α-MEM culture medium and intradermal injection of α-MEM containing ADSCs labeled with a fluorescent marker were performed in Groups α-MEM and α-MEM-SC, respectively. The percentage of flap necrosis was determined, and the level of neovascularization and distribution of stem cells in the TRAM flap was assessed using immunohistochemical analysis and fluorescence microscopy, respectively. RESULTS The percentage of necrosis observed in Group α-MEM-SC was lower than that observed in Groups TRAM and α-MEM, namely 23.36 % vs. 50.42 % and 53.57 %, respectively (p < 0.05). In Zone IV of the flap, the number of vessels was greater in Group α-MEM-SC than in the other groups (p < 0.05). Multiple stem cells were observed in the four zones of the flap in Group α-MEM-SC. No stem cells were observed in Groups TRAM or α-MEM. CONCLUSION ADSCs increased TRAM flap viability and the number of vessels in Zone IV of the flap in rats.
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Affiliation(s)
| | - Sang Won Han
- MSc Interdisciplinary Center for Gene Therapy (CINTERGEN), Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil
| | | | - Lydia Masako Ferreira
- Division of Plastic Surgery, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil
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Chen Y, Hong S, Wang Z, Hong X, Chen G, Huang Y, Lin Y, Xie X, Lin C, Lu W. Overexpression of HIF2α Enhances the Angiogenesis-Promoting Effect of hUC-MSC-Derived Extracellular Vesicles by Stimulating miR-146a. Protein Pept Lett 2025; 32:62-74. [PMID: 39592897 DOI: 10.2174/0109298665347753241028072130] [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: 07/30/2024] [Revised: 10/11/2024] [Accepted: 10/14/2024] [Indexed: 11/28/2024]
Abstract
OBJECTIVE This study aimed to explore whether excessive HIF2α can amplify the impact of human Umbilical Cord Mesenchymal Stem Cell-derived Extracellular Vesicles (hUC-MSC- EVs) on endothelial cells. METHODS In this study, we created HIF2α-overexpressing hUC-MSC-EVs and compared their pro-angiogenic effects with control EVs on Human Umbilical Vein Endothelial Cells (HUVECs). MTT assay and Edu staining were used to detect the viability and proliferation ability of HUVECs, and Transwell and Tube Formation Assays were used to detect cell migration and tube formation ability. qPCR assay was used to detect the expression of cellular angiogenic markers. Subsequently, miRNAs that might be regulated by HIF2α were predicted by bioinformatics analysis, and qPCR was used to detect the relative expression of miRNAs in HUVECs treated with hUC-MSC- EV, which over-expresses HIF2α. Subsequently, miR-146a inhibitors were used to investigate the role of miR-146a in mediating the pro-angiogenic effect of HIF2α on HUVECs by detecting cell viability, proliferation, migration, tube-forming ability, and expression of angiogenic markers. Finally, AKT/ERK phosphorylation and Spred1 expression were detected using Western blotting. RESULTS Our findings have indicated that overexpression of HIF2α significantly enhances the ability of hUC-MSC-EVs to stimulate proliferation, migration, and tube formation in HUVECs, as demonstrated by MTT/Edu staining, Transwell assay, and tube formation assay results, respectively. Mechanistically, excessive HIF2α has been found to induce the expression of miR-146a in HUVECs and the overexpression of a miR-146a inhibitor to negate the influence of excessive HIF2α on hUC-MSC-EV-induced activity in HUVECs. CONCLUSION The overexpression of HIF2α is an effective strategy for enhancing the pro-angiogenic function of hUC-MSC-EVs.
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Affiliation(s)
- Yihui Chen
- Department of Vascular Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
| | - Shichai Hong
- Department of Vascular Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
| | - Zhefeng Wang
- Biotherapy Center, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
| | - Xiang Hong
- Department of Vascular Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
| | - Gang Chen
- Department of Vascular Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
| | - Yulong Huang
- Department of Vascular Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
| | - Yue Lin
- Department of Vascular Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
| | - Xinsheng Xie
- Department of Vascular Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
| | - Chenwei Lin
- Department of Vascular Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
| | - Weifeng Lu
- Department of Vascular Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China
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Basmaeil Y, Subayyil AA, Kulayb HB, Kondkar AA, Alrodayyan M, Khatlani T. Partial Inhibition of Epithelial-to-Mesenchymal Transition (EMT) Phenotypes by Placenta-Derived DBMSCs in Human Breast Cancer Cell Lines, In Vitro. Cells 2024; 13:2131. [PMID: 39768220 PMCID: PMC11674051 DOI: 10.3390/cells13242131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 12/09/2024] [Accepted: 12/20/2024] [Indexed: 01/11/2025] Open
Abstract
Stem cell-based therapies hold significant potential for cancer treatment due to their unique properties, including migration toward tumor niche, secretion of bioactive molecules, and immunosuppression. Mesenchymal stem cells (MSCs) from adult tissues can inhibit tumor progression, angiogenesis, and apoptosis of cancer cells. We have previously reported the isolation and characterization of placenta-derived decidua basalis mesenchymal stem cells (DBMSCs), which demonstrated higher levels of pro-migratory and anti-apoptotic genes, indicating potential anti-cancer effects. In this study, we analyzed the anti-cancer effects of DBMSCs on human breast cancer cell lines MDA231 and MCF7, with MCF 10A used as control. We also investigated how these cancer cells lines affect the functional competence of DBMSCs. By co-culturing DBMSCs with cancer cells, we analyzed changes in functions of both cell types, as well as alterations in their genomic and proteomic profile. Our results showed that treatment with DBMSCs significantly reduced the functionality of MDA231 and MCF7 cells, while MCF 10A cells remained unaffected. DBMSC treatment decreased epithelial-to-mesenchymal transition (EMT)-related protein levels in MDA231 cells and modulated expression of other cancer-related genes in MDA231 and MCF7 cells. Although cancer cells reduced DBMSC proliferation, they increased their expression of anti-apoptotic genes. These findings suggest that DBMSCs can inhibit EMT-related proteins and reduce the invasive characteristics of MDA231 and MCF7 breast cancer cells, highlighting their potential as candidates for cell-based cancer therapies.
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Affiliation(s)
- Yasser Basmaeil
- Stem Cells and Regenerative Medicine Unit, Blood and Cancer Research (BCR) Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia; (Y.B.); (A.A.S.); (H.B.K.); (M.A.)
| | - Abdullah Al Subayyil
- Stem Cells and Regenerative Medicine Unit, Blood and Cancer Research (BCR) Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia; (Y.B.); (A.A.S.); (H.B.K.); (M.A.)
| | - Haya Bin Kulayb
- Stem Cells and Regenerative Medicine Unit, Blood and Cancer Research (BCR) Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia; (Y.B.); (A.A.S.); (H.B.K.); (M.A.)
| | - Altaf A. Kondkar
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia;
| | - Maha Alrodayyan
- Stem Cells and Regenerative Medicine Unit, Blood and Cancer Research (BCR) Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia; (Y.B.); (A.A.S.); (H.B.K.); (M.A.)
| | - Tanvir Khatlani
- Stem Cells and Regenerative Medicine Unit, Blood and Cancer Research (BCR) Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia; (Y.B.); (A.A.S.); (H.B.K.); (M.A.)
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Galhom RA, Ali SNS, El-Fark MMO, Ali MHM, Hussein HH. Assessment of therapeutic efficacy of adipose tissue-derived mesenchymal stem cells administration in hyperlipidemia-induced aortic atherosclerosis in adult male albino rats. Tissue Cell 2024; 90:102498. [PMID: 39079452 DOI: 10.1016/j.tice.2024.102498] [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: 06/20/2024] [Revised: 07/21/2024] [Accepted: 07/24/2024] [Indexed: 09/03/2024]
Abstract
Atherosclerosis (AS) is a common disease seriously detrimental to human health. AS is a chronic progressive disease related to inflammatory reactions. The present study aimed to characterize and evaluate the effects of adipose tissue stem cells (ADSCs) in high-fat diet-induced atherosclerosis in a rat model. The present study comprises thirty-six rats and they were divided into three groups: the control group, the high-fat diet (HFD) group; which received a high-fat diet, and the high-fat diet + stem cells (HFD+SC) group; which was fed with a high-fat diet along with the administration of intravenous ADSCs. Food was given to the animals for 20 weeks to establish dyslipidemia models. After 20 weeks, animals were sacrificed by cervical dislocation; blood was collected to measure total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL); aortae were collected to detect morphologic changes. Rats of the HFD group showed a significant increase in body weight (B.Wt), altered lipid profile increased expression of inducible nitric oxide synthase (iNOS), and decreased expression of endothelial nitric oxide synthase (eNOS). However, in HFD+SC there was a significant decrease in body weight gain and an improvement in lipid profile. Histopathological and ultrastructural variations observed in the aorta of the HFD group when treated with ADSCs showed preserved normal histological architecture and reduced atherosclerosis compared with the HFD group. This was evidenced by laboratory, histological, immunohistochemical, and morphometric studies. Thus, ADSCs reduced TC, TG, and LDL, reduced the expression of iNOS, and increased the expression of eNOS. The high-fat diet was likely to cause damage to the wall of blood vessels. Systemically transplanted ADSCs could home to the aorta, and further protect the aorta from HFD-induced damage.
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Affiliation(s)
- Rania A Galhom
- Department of Human Anatomy and Embryology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt; Department of Human Anatomy and Embryology, Faculty of Medicine, Badr University in Cairo (BUC), Egypt.
| | - Saleh Nasser Saleh Ali
- Department of Human Anatomy and Embryology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt; Department of Human Anatomy and Embryology, Faculty of Medicine and Health Sciences, Thamar University, Thamar, Yemen.
| | - Magdy Mohamed Omar El-Fark
- Department of Human Anatomy and Embryology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
| | - Mona Hassan Mohammed Ali
- Department of Human Anatomy and Embryology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
| | - Hoda Hassan Hussein
- Department of Human Anatomy and Embryology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
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Zacharovová K, Berková Z, Girman P, Saudek F. Adipose tissue-derived mesenchymal stem cells promote the vascularization of pancreatic islets transplanted into decellularized pancreatic skeletons. Transpl Immunol 2024; 86:102106. [PMID: 39128811 DOI: 10.1016/j.trim.2024.102106] [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: 12/20/2023] [Revised: 08/08/2024] [Accepted: 08/08/2024] [Indexed: 08/13/2024]
Abstract
We have recently developed a model of pancreatic islet transplantation into a decellularized pancreatic tail in rats. As the pancreatic skeletons completely lack endothelial cells, we investigated the effect of co-transplantation of mesenchymal stem cells and endothelial cells to promote revascularization. Decellularized matrix of the pancreatic tail was prepared by perfusion with Triton X-100, sodium dodecyl sulfate and DNase solution. Isolated pancreatic islets were infused into the skeletons via the splenic vein either alone, together with adipose tissue-derived mesenchymal stem cells (adMSCs), or with a combination of adMSCs and rat endothelial cells (rat ECs). Repopulated skeletons were transplanted into the subcutaneous tissue and explanted 9 days later for histological examination. Possible immunomodulatory effects of rat adMSCs on the survival of highly immunogenic green protein-expressing human ECs were also tested after their transplantation beneath the renal capsule. The immunomodulatory effects of adMSCs were also tested in vitro using the Invitrogen Click-iT EdU system. In the presence of adMSCs, the proliferation of splenocytes as a response to phytohaemagglutinin A was reduced by 47% (the stimulation index decreased from 1.7 to 0.9, P = 0.008) and the reaction to human ECs was reduced by 58% (the stimulation index decreased from 1.6 to 0.7, P = 0.03). Histological examination of the explanted skeletons seeded only with the islets showed their partial disintegration and only a rare presence of CD31-positive cells. However, skeletons seeded with a combination of islets and adMSCs showed preserved islet morphology and rich vascularity. In contrast, the addition of syngeneic rat ECs resulted in islet-cell necrosis with only few endothelial cells present. Live green fluorescence-positive endothelial cells transplanted either alone or with adMSCs were not detected beneath the renal capsule. Though the adMSCs significantly reduced in vitro proliferation stimulated by either phytohaemagglutinin A or by xenogeneic human ECs, in vivo co-transplanted adMSCs did not suppress the post-transplant immune response to xenogeneic ECs. Even in the syngeneic model, ECs co-transplantation did not lead to sufficient vascularization in the transplant area. In contrast, islet co-transplantation together with adMSCs successfully promoted the revascularization of extracellular matrix in the subcutaneous tissue.
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Affiliation(s)
- Klára Zacharovová
- Laboratory of Pancreatic Islets, Experimental Medicine Center, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague, Czech Republic.
| | - Zuzana Berková
- Laboratory of Pancreatic Islets, Experimental Medicine Center, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague, Czech Republic.
| | - Peter Girman
- Laboratory of Pancreatic Islets, Experimental Medicine Center, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague, Czech Republic; Diabetes Center, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague, Czech Republic.
| | - František Saudek
- Laboratory of Pancreatic Islets, Experimental Medicine Center, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague, Czech Republic; Diabetes Center, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague, Czech Republic.
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11
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Wu J, Feng Y, Wang Y, He X, Chen Z, Lan D, Wu X, Wen J, Tsung A, Wang X, Ma J, Wu Y. MG53 binding to CAV3 facilitates activation of eNOS/NO signaling pathway to enhance the therapeutic benefits of bone marrow-derived mesenchymal stem cells in diabetic wound healing. Int Immunopharmacol 2024; 136:112410. [PMID: 38843641 DOI: 10.1016/j.intimp.2024.112410] [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: 04/10/2024] [Revised: 05/24/2024] [Accepted: 06/02/2024] [Indexed: 06/17/2024]
Abstract
Impaired wound healing in diabetes results from a complex interplay of factors that disrupt epithelialization and wound closure. MG53, a tripartite motif (TRIM) family protein, plays a key role in repairing cell membrane damage and facilitating tissue regeneration. In this study, bone marrow-derived mesenchymal stem cells (BMSCs) were transduced with lentiviral vectors overexpressing MG53 to investigate their efficacy in diabetic wound healing. Using a db/db mouse wound model, we observed that BMSCs-MG53 significantly enhanced diabetic wound healing. This improvement was associated with marked increase in re-epithelialization and vascularization. BMSCs-MG53 promoted recruitment and survival of BMSCs, as evidenced by an increase in MG53/Ki67-positive BMSCs and their improved response to scratch wounding. The combination therapy also promoted angiogenesis in diabetic wound tissues by upregulating the expression of angiogenic growth factors. MG53 overexpression accelerated the differentiation of BMSCs into endothelial cells, manifested as the formation of mature vascular network structure and a remarkable increase in DiI-Ac-LDL uptake. Our mechanistic investigation revealed that MG53 binds to caveolin-3 (CAV3) and subsequently increases phosphorylation of eNOS, thereby activating eNOS/NO signaling. Notably, CAV3 knockdown reversed the promoting effects of MG53 on BMSCs endothelial differentiation. Overall, our findings support the notion that MG53 binds to CAV3, activates eNOS/NO signaling pathway, and accelerates the therapeutic effect of BMSCs in the context of diabetic wound healing. These insights hold promise for the development of innovative strategies for treating diabetic-related impairments in wound healing.
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Affiliation(s)
- Junwei Wu
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yiyuan Feng
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yan Wang
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xiangfei He
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zheyu Chen
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Dongyang Lan
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xinchao Wu
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jianguo Wen
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Allan Tsung
- Division of Surgical Sciences, Department of Surgery, University of Virginia, VA, USA
| | - Xinxin Wang
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| | - Jianjie Ma
- Division of Surgical Sciences, Department of Surgery, University of Virginia, VA, USA.
| | - Yudong Wu
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
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12
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Eroz I, Kakkar PK, Lazar RA, El-Jawhari J. Mesenchymal Stem Cells in Myelodysplastic Syndromes and Leukaemia. Biomedicines 2024; 12:1677. [PMID: 39200142 PMCID: PMC11351218 DOI: 10.3390/biomedicines12081677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 07/17/2024] [Accepted: 07/24/2024] [Indexed: 09/01/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are one of the main residents in the bone marrow (BM) and have an essential role in the regulation of haematopoietic stem cell (HSC) differentiation and proliferation. Myelodysplastic syndromes (MDSs) are a group of myeloid disorders impacting haematopoietic stem and progenitor cells (HSCPs) that are characterised by BM failure, ineffective haematopoiesis, cytopenia, and a high risk of transformation through the expansion of MDS clones together with additional genetic defects. It has been indicated that MSCs play anti-tumorigenic roles such as in cell cycle arrest and pro-tumorigenic roles including the induction of metastasis in MDS and leukaemia. Growing evidence has shown that MSCs have impaired functions in MDS, such as decreased proliferation capacity, differentiation ability, haematopoiesis support, and immunomodulation function and increased inflammatory alterations within the BM through some intracellular pathways such as Notch and Wnt and extracellular modulators abnormally secreted by MSCs, including increased expression of inflammatory factors and decreased expression of haematopoietic factors, contributing to the development and progression of MDSs. Therefore, MSCs can be targeted for the treatment of MDSs and leukaemia. However, it remains unclear what drives MSCs to behave abnormally. In this review, dysregulations in MSCs and their contributions to myeloid haematological malignancies will be discussed.
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Affiliation(s)
- Ilayda Eroz
- Biosciences Department, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK (P.K.K.); (R.A.L.)
| | - Prabneet Kaur Kakkar
- Biosciences Department, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK (P.K.K.); (R.A.L.)
| | - Renal Antoinette Lazar
- Biosciences Department, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK (P.K.K.); (R.A.L.)
| | - Jehan El-Jawhari
- Biosciences Department, School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK (P.K.K.); (R.A.L.)
- Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
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13
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Dennison NR, Fusenig M, Grönnert L, Maitz MF, Ramirez Martinez MA, Wobus M, Freudenberg U, Bornhäuser M, Friedrichs J, Westenskow PD, Werner C. Precision Culture Scaling to Establish High-Throughput Vasculogenesis Models. Adv Healthc Mater 2024; 13:e2400388. [PMID: 38465502 DOI: 10.1002/adhm.202400388] [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: 02/21/2024] [Indexed: 03/12/2024]
Abstract
Hydrogel-based 3D cell cultures can recapitulate (patho)physiological phenomena ex vivo. However, due to their complex multifactorial regulation, adapting these tissue and disease models for high-throughput screening workflows remains challenging. In this study, a new precision culture scaling (PCS-X) methodology combines statistical techniques (design of experiment and multiple linear regression) with automated, parallelized experiments and analyses to customize hydrogel-based vasculogenesis cultures using human umbilical vein endothelial cells and retinal microvascular endothelial cells. Variations of cell density, growth factor supplementation, and media composition are systematically explored to induce vasculogenesis in endothelial mono- and cocultures with mesenchymal stromal cells or retinal microvascular pericytes in 384-well plate formats. The developed cultures are shown to respond to vasculogenesis inhibitors in a compound- and dose-dependent manner, demonstrating the scope and power of PCS-X in creating parallelized tissue and disease models for drug discovery and individualized therapies.
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Affiliation(s)
- Nicholas R Dennison
- Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials, 01069, Dresden, Germany
| | - Maximilian Fusenig
- Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials, 01069, Dresden, Germany
- Medical Clinic I, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307, Dresden, Germany
| | - Lisa Grönnert
- Ocular Technologies, Immunology, Infectious Diseases and Ophthalmology, Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, 4070, Switzerland
| | - Manfred F Maitz
- Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials, 01069, Dresden, Germany
| | | | - Manja Wobus
- Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials, 01069, Dresden, Germany
| | - Uwe Freudenberg
- Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials, 01069, Dresden, Germany
| | - Martin Bornhäuser
- Medical Clinic I, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307, Dresden, Germany
| | - Jens Friedrichs
- Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials, 01069, Dresden, Germany
| | - Peter D Westenskow
- Ocular Technologies, Immunology, Infectious Diseases and Ophthalmology, Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, 4070, Switzerland
| | - Carsten Werner
- Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials, 01069, Dresden, Germany
- Medical Clinic I, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307, Dresden, Germany
- Center for Regenerative Therapies Dresden and Cluster of Excellence Physics of Life, Technische Universität Dresden, 01307, Dresden, Germany
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14
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Hung HS, Shen CC, Wu JT, Yueh CY, Yang MY, Yang YC, Cheng WY. Assessment of the Biocompatibility Ability and Differentiation Capacity of Mesenchymal Stem Cells on Biopolymer/Gold Nanocomposites. Int J Mol Sci 2024; 25:7241. [PMID: 39000351 PMCID: PMC11242884 DOI: 10.3390/ijms25137241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 06/14/2024] [Accepted: 06/27/2024] [Indexed: 07/16/2024] Open
Abstract
This study assessed the biocompatibility of two types of nanogold composites: fibronectin-gold (FN-Au) and collagen-gold (Col-Au). It consisted of three main parts: surface characterization, in vitro biocompatibility assessments, and animal models. To determine the structural and functional differences between the materials used in this study, atomic force microscopy, Fourier-transform infrared spectroscopy, and ultraviolet-visible spectrophotometry were used to investigate their surface topography and functional groups. The F-actin staining, proliferation, migration, reactive oxygen species generation, platelet activation, and monocyte activation of mesenchymal stem cells (MSCs) cultured on the FN-Au and Col-Au nanocomposites were investigated to determine their biological and cellular behaviors. Additionally, animal biocompatibility experiments measured capsule formation and collagen deposition in female Sprague-Dawley rats. The results showed that MSCs responded better on the FN-Au and Col-AU nanocomposites than on the control (tissue culture polystyrene) or pure substances, attributed to their incorporation of an optimal Au concentration (12.2 ppm), which induced significant surface morphological changes, nano topography cues, and better biocompatibility. Moreover, neuronal, endothelial, bone, and adipose tissues demonstrated better differentiation ability on the FN-Au and Col-Au nanocomposites. Nanocomposites have a crucial role in tissue engineering and even vascular grafts. Finally, MSCs were demonstrated to effectively enhance the stability of the endothelial structure, indicating that they can be applied as promising alternatives to clinics in the future.
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Affiliation(s)
- Huey-Shan Hung
- Graduate Institute of Biomedical Science, China Medical University, Taichung 404328, Taiwan (J.-T.W.)
- Translational Medicine Research, China Medical University Hospital, Taichung 404327, Taiwan
| | - Chiung-Chyi Shen
- Department of Minimally Invasive Skull Base Neurosurgery, Neurological Institute, Taichung Veterans General Hospital, Taichung 407204, Taiwan; (C.-C.S.); (Y.-C.Y.)
| | - Jyun-Ting Wu
- Graduate Institute of Biomedical Science, China Medical University, Taichung 404328, Taiwan (J.-T.W.)
| | - Chun-Yu Yueh
- School of Medicine, China Medical University, Taichung 404333, Taiwan
| | - Meng-Yin Yang
- Department of Minimally Invasive Skull Base Neurosurgery, Neurological Institute, Taichung Veterans General Hospital, Taichung 407204, Taiwan; (C.-C.S.); (Y.-C.Y.)
| | - Yi-Chin Yang
- Department of Minimally Invasive Skull Base Neurosurgery, Neurological Institute, Taichung Veterans General Hospital, Taichung 407204, Taiwan; (C.-C.S.); (Y.-C.Y.)
| | - Wen-Yu Cheng
- Department of Minimally Invasive Skull Base Neurosurgery, Neurological Institute, Taichung Veterans General Hospital, Taichung 407204, Taiwan; (C.-C.S.); (Y.-C.Y.)
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402202, Taiwan
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung 402202, Taiwan
- Taiwan Department of Physical Therapy, Hung Kuang University, Taichung 433304, Taiwan
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15
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Rofaani E, Mardani MW, Yutiana PN, Amanda O, Darmawan N. Differentiation of mesenchymal stem cells into vascular endothelial cells in 3D culture: a mini review. Mol Biol Rep 2024; 51:781. [PMID: 38913199 DOI: 10.1007/s11033-024-09743-8] [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: 01/22/2024] [Accepted: 06/20/2024] [Indexed: 06/25/2024]
Abstract
Mesenchymal Stem Cells, mesodermal origin and multipotent stem cells, have ability to differentiate into vascular endothelial cells. The cells are squamous in morphology, inlining, and protecting blood vessel tissue, as well as maintaining homeostatic conditions. ECs are essential in vascularization and blood vessels formation. The differentiation process, generally carried out in 2D culture systems, were relied on growth factors induction. Therefore, an artificial extracellular matrix with relevant mechanical properties is essential to build 3D culture models. Various 3D fabrication techniques, such as hydrogel-based and fibrous scaffolds, scaffold-free, and co-culture to endothelial cells were reviewed and summarized to gain insights. The obtained MSCs-derived ECs are shown by the expression of endothelial gene markers and tubule-like structure. In order to mimicking relevant vascular tissue, 3D-bioprinting facilitates to form more complex microstructures. In addition, a microfluidic chip with adequate flow rate allows medium perfusion, providing mechanical cues like shear stress to the artificial vascular vessels.
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Affiliation(s)
- E Rofaani
- Group Research of Theranostics, Research Center for Vaccine and Drug, Research Organization of Health, National Research and Innovation Agency, LAPTIAB Building No 611 PUSPIPTEK or KST BJ Habibie, Tangerang Selatan, Banten, 15315, Indonesia.
| | - M W Mardani
- Department of Biology, Faculty of Mathematics and Natural Sciences, Sebelas Maret University, Ir. Sutami Street No. 36A, Jebres District, Surakarta, Central Java, 57126, Indonesia
| | - P N Yutiana
- Department of Biology, Faculty of Mathematics and Natural Sciences, Sebelas Maret University, Ir. Sutami Street No. 36A, Jebres District, Surakarta, Central Java, 57126, Indonesia
| | - O Amanda
- Department of Technique of Biomedis, Faculty of Technique of Industry, Institut Teknologi Sumatera, Jalan Terusan Ryacudu, Way Huwi, Jati Agung, Lampung Selatan, Lampung, 35365, Indonesia
| | - N Darmawan
- Laboratory of Inorganic Chemistry, Department of Chemistry, Faculty of Mathematics and Natural Sciences, IPB University, Kampus IPB Dramaga, Bogor, West Java, 16880, Indonesia
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16
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Ramirez-Velandia F, Mensah E, Salih M, Wadhwa A, Young M, Muram S, Taussky P, Ogilvy CS. Endothelial Progenitor Cells: A Review of Molecular Mechanisms in the Pathogenesis and Endovascular Treatment of Intracranial Aneurysms. Neuromolecular Med 2024; 26:25. [PMID: 38886284 DOI: 10.1007/s12017-024-08791-4] [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: 02/19/2024] [Accepted: 05/09/2024] [Indexed: 06/20/2024]
Abstract
This comprehensive review explores the multifaceted role of endothelial progenitor cells (EPCs) in vascular diseases, focusing on their involvement in the pathogenesis and their contributions to enhancing the efficacy of endovascular treatments for intracranial aneurysms (IAs). Initially discovered as CD34+ bone marrow-derived cells implicated in angiogenesis, EPCs have been linked to vascular repair, vasculogenesis, and angiogenic microenvironments. The origin and differentiation of EPCs have been subject to debate, challenging the conventional notion of bone marrow origin. Quantification methods, including CD34+ , CD133+ , and various assays, reveal the influence of factors, like age, gender, and comorbidities on EPC levels. Cellular mechanisms highlight the interplay between bone marrow and angiogenic microenvironments, involving growth factors, matrix metalloproteinases, and signaling pathways, such as phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK). In the context of the pathogenesis of IAs, EPCs play a role in maintaining vascular integrity by replacing injured and dysfunctional endothelial cells. Recent research has also suggested the therapeutic potential of EPCs after coil embolization and flow diversion, and this has led the development of device surface modifications aimed to enhance endothelialization. The comprehensive insights underscore the importance of further research on EPCs as both therapeutic targets and biomarkers in IAs.
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Affiliation(s)
- Felipe Ramirez-Velandia
- Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
| | - Emmanuel Mensah
- Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
| | - Mira Salih
- Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
| | - Aryan Wadhwa
- Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Boston, MA, 02215, USA
| | - Michael Young
- Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
| | - Sandeep Muram
- Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
| | - Philipp Taussky
- Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Boston, MA, 02215, USA
- Harvard Medical School, Boston, MA, USA
| | - Christopher S Ogilvy
- Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Boston, MA, 02215, USA.
- Harvard Medical School, Boston, MA, USA.
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17
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Goto T, Nakamura Y, Ito Y, Miyagawa S. Regenerative medicine in cardiovascular disease. Regen Ther 2024; 26:859-866. [PMID: 39430582 PMCID: PMC11490749 DOI: 10.1016/j.reth.2024.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 09/04/2024] [Accepted: 09/11/2024] [Indexed: 10/22/2024] Open
Abstract
Owing to the rapid increase in the number of people with severe heart failure, regenerative medicine is anticipated to play a role in overcoming the limitations inherent in existing surgical interventions. There are essentially two types of cardiac regenerative therapies for a failing heart. Cellular regenerative therapies using various stem cells improve the functional recovery of the heart mainly by cytokine paracrine effects. The implantation of induced pluripotent stem cell-derived cardiomyocytes can contribute not only to the inhibition of adverse heart remodeling by paracrine effects but also to the supply of newly born functional myocytes with the recipient myocardium as "mechanically working cells." Cell transplantation, including autologous myoblast transplantation, reduces heart failure exacerbations and benefits patients without the need for other treatment options. Although cellular therapy is currently the mainstream approach, it requires an in-house cell-processing center with an aseptic environment. In addition, these stem cells are usually introduced via several invasive delivery methods, including intracoronary administration, and cellular sheet implantation. Simplifying the culture methods for these cells is a crucial problem that needs to be resolved. Drug-induced regenerative therapy is another option that enhances self-endogenous regenerative systems in the human body and does not require invasive methods or cell cultures. Therefore, drug-induced regenerative therapies may overcome the disadvantages of these cellular therapies. The purpose of this report is to summarize cell transplantation therapy in the cardiovascular system and regenerative therapy for heart failure using an autologous endogenous regenerative system.
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Affiliation(s)
- Takasumi Goto
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
- Department of Cardiovascular Surgery, Toyonaka Municipal Hospital, Osaka, Japan
| | - Yuki Nakamura
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yoshito Ito
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Shigeru Miyagawa
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
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18
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Higashihara M, Enomoto H, Sumi T, Moriyama T, Zaima N. Similar Distribution between EPA-containing Phosphatidylcholine and Mesenchymal Stem Marker Positive Cells in the Aortic Wall of Abdominal Aortic Aneurysm Model Rat Fed a Low-EPA Content Diet. J Oleo Sci 2024; 73:895-903. [PMID: 38797690 DOI: 10.5650/jos.ess23269] [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] [Indexed: 05/29/2024] Open
Abstract
Abdominal aortic aneurysm (AAA) is a vascular disease characterized by progressive dilation of the abdominal aorta. Previous studies have suggested that dietary components are closely associated with AAA. Among those dietary components, eicosapentaenoic acid (EPA) is considered to have suppressive effects on AAA. In the AAA wall of AAA model animals bred under EPA-rich condition, the distribution of EPA-containing phosphatidylcholine (EPA-PC) has been reported to be similar to that of the markers of mesenchymal stem cells (MSCs) and M2 macrophages. These data suggest that the suppressive effects of EPA on AAA are related to preferential distribution of specific cells in the aortic wall. However, the distribution of EPA-PC in the AAA wall of AAA model animals fed a diet containing small amounts of EPA, which has not been reported to inhibit AAA, has not yet been explored. In the present study, we visualized the distribution of EPA-PCs in the AAA wall of AAA model animals fed a diet containing small amounts of EPA (1.5% EPA in the fatty acid composition) to elucidate the vasoprotective effects of EPA. Positive areas for markers of MSCs were significantly higher in the region where EPA-PC was abundant compared to the regions where EPA-PC was weakly detected, but not for markers of M2 macrophages, matrix metalloproteinase (MMP)-2, and MMP-9. The distribution of MSC markers was similar to that of EPA-PC but not that of M2 macrophages and MMPs. These data suggest preferential incorporation of EPA into MSCs under the conditions used in this study. The incorporation of EPA into certain cells may differ according to dietary conditions, which affect the development of AAA.
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Affiliation(s)
- Mayo Higashihara
- Department of Applied Biological Chemistry, Graduate School of Agriculture, Kindai University
| | - Hirofumi Enomoto
- Department of Biosciences, Faculty of Science and Engineering, Teikyo University
- Division of Integrated Science and Engineering, Graduate School of Science and Engineering, Teikyo University
- Advanced Instrumental Analysis Center, Teikyo University
| | - Tomoko Sumi
- Department of Applied Biological Chemistry, Graduate School of Agriculture, Kindai University
| | - Tatsuya Moriyama
- Department of Applied Biological Chemistry, Graduate School of Agriculture, Kindai University
- Agricultural Technology and Innovation Research Institute, Kindai University
| | - Nobuhiro Zaima
- Department of Applied Biological Chemistry, Graduate School of Agriculture, Kindai University
- Agricultural Technology and Innovation Research Institute, Kindai University
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19
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(Ogi) Suzuki K, Okamoto T, Tamai K, Tabata Y, Hatano E. Enhancement of tracheal cartilage regeneration by local controlled release of stromal cell-derived factor 1α with gelatin hydrogels and systemic administration of high-mobility group box 1 peptide. Regen Ther 2024; 26:415-424. [PMID: 39070123 PMCID: PMC11282968 DOI: 10.1016/j.reth.2024.06.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 06/19/2024] [Accepted: 06/27/2024] [Indexed: 07/30/2024] Open
Abstract
Introduction This present study evaluated the effect of combination therapy with stromal cell-derived factor 1α (SDF-1α) and high-mobility group box 1 (HMGB1) peptide on the regeneration of tracheal injury in a rat model. Methods To improve this effect, SDF-1α was incorporated into a gelatin hydrogel, which was then applied to the damaged tracheal cartilage of rats for local release. Furthermore, HMGB1 peptide was repeatedly administered intravenously. Regeneration of damaged tracheal cartilage was evaluated in terms of cell recruitment. Results Mesenchymal stem cells (MSC) with C-X-C motif chemokine receptor 4 (CXCR4) were mobilized more into the injured area, and consequently the fastest tracheal cartilage regeneration was observed in the combination therapy group eight weeks after injury. Conclusions The present study demonstrated that combination therapy with gelatin hydrogel incorporating SDF-1α and HMGB1 peptide injected intravenously can enhance the recruitment of CXCR4-positive MSC, promoting the regeneration of damaged tracheal cartilage.
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Affiliation(s)
- Kumiko (Ogi) Suzuki
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
- Department of Biomaterials, Field of Tissue Engineering, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Tatsuya Okamoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Katsuto Tamai
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Japan
| | - Yasuhiko Tabata
- Department of Biomaterials, Field of Tissue Engineering, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Etsuro Hatano
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
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20
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Ding H, Hou X, Gao Z, Guo Y, Liao B, Wan J. Challenges and Strategies for Endothelializing Decellularized Small-Diameter Tissue-Engineered Vessel Grafts. Adv Healthc Mater 2024; 13:e2304432. [PMID: 38462702 DOI: 10.1002/adhm.202304432] [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: 12/13/2023] [Revised: 02/26/2024] [Indexed: 03/12/2024]
Abstract
Vascular diseases are the leading cause of ischemic necrosis in tissues and organs, necessitating using vascular grafts to restore blood supply. Currently, small vessels for coronary artery bypass grafts are unavailable in clinical settings. Decellularized small-diameter tissue-engineered vessel grafts (SD-TEVGs) hold significant potential. However, they face challenges, as simple implantation of decellularized SD-TEVGs in animals leads to thrombosis and calcification due to incomplete endothelialization. Consequently, research and development focus has shifted toward enhancing the endothelialization process of decellularized SD-TEVGs. This paper reviews preclinical studies involving decellularized SD-TEVGs, highlighting different strategies and their advantages and disadvantages for achieving rapid endothelialization of these vascular grafts. Methods are analyzed to improve the process while addressing potential shortcomings. This paper aims to contribute to the future commercial viability of decellularized SD-TEVGs.
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Affiliation(s)
- Heng Ding
- Department of Cardiovascular Surgery, The Affiliated Hospital, Southwest Medical University, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Key Laboratory of cardiovascular remodeling and dysfunction, Luzhou, Sichuan, 646000, China
- Nanjing Medical University, Nanjing, 211166, P. R. China
| | - Xiaojie Hou
- Department of Cardiovascular Surgery and Cardiovascular Surgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Zhen Gao
- Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100069, China
| | - Yingqiang Guo
- Department of Cardiovascular Surgery and Cardiovascular Surgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Bin Liao
- Department of Cardiovascular Surgery, The Affiliated Hospital, Southwest Medical University, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Key Laboratory of cardiovascular remodeling and dysfunction, Luzhou, Sichuan, 646000, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Juyi Wan
- Department of Cardiovascular Surgery, The Affiliated Hospital, Southwest Medical University, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Key Laboratory of cardiovascular remodeling and dysfunction, Luzhou, Sichuan, 646000, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China
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21
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Ou S, Kim TY, Jung E, Shin SY. p38 mitogen-activated protein kinase contributes to TNFα-induced endothelial tube formation of bone-marrow-derived mesenchymal stem cells by activating the JAK/STAT/TIE2 signaling axis. BMB Rep 2024; 57:238-243. [PMID: 37915133 PMCID: PMC11139678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 09/04/2023] [Accepted: 10/28/2023] [Indexed: 11/03/2023] Open
Abstract
Bone marrow-derived mesenchymal stem cells (BM-MSCs) can differentiate into endothelial cells in an inflammatory microenvironment. However, the regulatory mechanisms underlying this process are not entirely understood. Here, we found that TIE2 in BM-MSCs was upregulated at the transcriptional level after stimulation with tumor necrosis factor-alpha (TNFα), a major pro-inflammatory cytokine. Additionally, the STAT-binding sequence within the proximal region of TIE2 was necessary for TNFα-induced TIE2 promoter activation. TIE2 and STAT3 knockdown reduced TNFα-induced endothelial tube formation in BMMSCs. Among the major TNFα-activated MAP kinases (ERK1/2, JNK1/2, and p38 MAPK) in BM-MSCs, only inhibition of the p38 kinase abrogated TNFα-induced TIE2 upregulation by inhibiting the JAK-STAT signaling pathway. These findings suggest that p38 MAP contributes to the endothelial differentiation of BM-MSCs by activating the JAK-STAT-TIE2 signaling axis in the inflammatory microenvironment. [BMB Reports 2024; 57(5): 238-243].
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Affiliation(s)
- Sukjin Ou
- Department of Biological Sciences, Sanghuh College of Lifesciences, Konkuk University, Seoul 05029, Korea
| | - Tae Yoon Kim
- Department of Biological Sciences, Sanghuh College of Lifesciences, Konkuk University, Seoul 05029, Korea
| | - Euitaek Jung
- Department of Biological Sciences, Sanghuh College of Lifesciences, Konkuk University, Seoul 05029, Korea
| | - Soon Young Shin
- Department of Biological Sciences, Sanghuh College of Lifesciences, Konkuk University, Seoul 05029, Korea
- Cancer and Metabolism Institute, Konkuk University, Seoul 05029, Korea
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22
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Ichise T, Ichise H, Shimizu Y. Development of a Mouse Experimental System for the In Vivo Characterization of Bioengineered Adipose-Derived Stromal Cells. Cells 2024; 13:582. [PMID: 38607021 PMCID: PMC11011746 DOI: 10.3390/cells13070582] [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: 02/29/2024] [Revised: 03/23/2024] [Accepted: 03/26/2024] [Indexed: 04/13/2024] Open
Abstract
Human adipose-derived stromal cells (ADSCs) are an important resource for cell-based therapies. However, the dynamics of ADSCs after transplantation and their mechanisms of action in recipients remain unclear. Herein, we generated genetically engineered mouse ADSCs to clarify their biodistribution and post-transplantation status and to analyze their role in recipient mesenchymal tissue modeling. Immortalized ADSCs (iADSCs) retained ADSC characteristics such as stromal marker gene expression and differentiation potential. iADSCs expressing a fluorescent reporter gene were seeded into biocompatible nonwoven fabric sheets and transplanted into the dorsal subcutaneous region of neonatal mice. Transplanted donor ADSCs were distributed as CD90-positive stromal cells on the sheets and survived 1 month after transplantation. Although accumulation of T lymphocytes or macrophages inside the sheet was not observed with or without donor cells, earlier migration and accumulation of recipient blood vascular endothelial cells (ECs) inside the sheet was observed in the presence of donor cells. Thus, our mouse model can help in studying the interplay between donor ADSCs and recipient cells over a 1-month period. This system may be of value for assessing and screening bioengineered ADSCs in vivo for optimal cell-based therapies.
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Affiliation(s)
- Taeko Ichise
- Department of Plastic and Reconstructive Surgery, University of the Ryukyus Hospital, 207 Uehara, Nishihara 903-0215, Japan; (T.I.); (Y.S.)
| | - Hirotake Ichise
- Institute for Animal Research, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara 903-0215, Japan
| | - Yusuke Shimizu
- Department of Plastic and Reconstructive Surgery, University of the Ryukyus Hospital, 207 Uehara, Nishihara 903-0215, Japan; (T.I.); (Y.S.)
- Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara 903-0215, Japan
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23
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Ghoneim MA, Gabr MM, El-Halawani SM, Refaie AF. Current status of stem cell therapy for type 1 diabetes: a critique and a prospective consideration. Stem Cell Res Ther 2024; 15:23. [PMID: 38281991 PMCID: PMC10823744 DOI: 10.1186/s13287-024-03636-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 01/10/2024] [Indexed: 01/30/2024] Open
Abstract
Over the past decade, there had been progress in the development of cell therapy for insulin-dependent diabetes. Nevertheless, important hurdles that need to be overcome still remain. Protocols for the differentiation of pluripotent stem cells into pancreatic progenitors or fully differentiated β-cells have been developed. The resulting insulin-producing cells can control chemically induced diabetes in rodents and were the subject of several clinical trials. However, these cells are immunogenic and possibly teratogenic for their transplantation, and an immunoisolation device and/or immunosuppression is needed. A growing number of studies have utilized genetic manipulations to produce immune evasive cells. Evidence must be provided that in addition to the expected benefit, gene manipulations should not lead to any unforeseen complications. Mesenchymal stem/stromal cells (MSCs) can provide a viable alternative. MSCs are widely available from many tissues. They can form insulin-producing cells by directed differentiation. Experimentally, evidence has shown that the transplantation of allogenic insulin-producing cells derived from MSCs is associated with a muted allogeneic response that does not interfere with their functionality. This can be explained by the immunomodulatory functions of the MSC subpopulation that did not differentiate into insulin-producing cells. Recently, exosomes derived from naive MSCs have been used in the experimental domain to treat diabetes in rodents with varying degrees of success. Several mechanisms for their beneficial functions were proposed including a reduction in insulin resistance, the promotion of autophagy, and an increase in the T regulatory population. However, euglycemia was not achieved in any of these experiments. We suggest that exosomes derived from β-cells or insulin-producing cells (educated) can provide a better therapeutic effect than those derived from undifferentiated cells.
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24
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Yang GD, Ma DS, Ma CY, Bai Y. Research Progress on Cardiac Tissue Construction of Mesenchymal Stem Cells for Myocardial Infarction. Curr Stem Cell Res Ther 2024; 19:942-958. [PMID: 37612870 DOI: 10.2174/1574888x18666230823091017] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 07/13/2023] [Accepted: 07/26/2023] [Indexed: 08/25/2023]
Abstract
Heart failure is still the main complication affecting the prognosis of acute myocardial infarction (AMI), and mesenchymal stem cells (MSCs) are an effective treatment to replace necrotic myocardium and improve cardiac functioning. However, the transplant survival rate of MSCs still presents challenges. In this review, the biological characteristics of MSCs, the progress of mechanism research in the treatment of myocardial infarction, and the advances in improving the transplant survival rate of MSCs in the replacement of necrotic myocardial infarction are systematically described. From a basic to advanced clinical research, MSC transplants have evolved from a pure injection, an exosome injection, the genetic modification of MSCs prior to injection to the cardiac tissue engineering of MSC patch grafting. This study shows that MSCs have wide clinical applications in the treatment of AMI, suggesting improved myocardial tissue creation. A broader clinical application prospect will be explored and developed to improve the survival rate of MSC transplants and myocardial vascularization.
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Affiliation(s)
- Guo-Dong Yang
- Department of Cardiac Surgery, The First Hospital of Jilin University, Changchun, 130021, China
| | - Da-Shi Ma
- Department of Cardiac Surgery, The First Hospital of Jilin University, Changchun, 130021, China
| | - Chun-Ye Ma
- Department of Cardiac Surgery, The First Hospital of Jilin University, Changchun, 130021, China
| | - Yang Bai
- Department of Cardiac Surgery, The First Hospital of Jilin University, Changchun, 130021, China
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25
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Tantuway V, Jeyaraman M, Nallakumarasamy A, Prikh MB, Sharma AK, Sharma R. Functional Outcome Analysis of Autologous Stromal Vascular Fraction (SVF) (Sahaj Therapy ®) Using Direct Sonication in Osteonecrosis of the Femoral Head (ONFH): A 6-Year Follow-Up Study. Indian J Orthop 2024; 58:68-78. [PMID: 38161400 PMCID: PMC10754810 DOI: 10.1007/s43465-023-01041-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 10/28/2023] [Indexed: 01/03/2024]
Abstract
Introduction We investigated the safety, efficacy, functional, and clinical outcomes of intra-osseous implantation of mechanically isolated, autologous stromal vascular fraction (SVF), an Australian patented direct ultrasonication technology (Sahaj Therapy®) in osteonecrosis of the femoral head (ONFH). Materials and Methods A total of 32 cases of ONFH were enrolled in the study after confirming with an MRI of the affected hip. All cases were treated with an intra-osseous autologous SVF implantation [4-5 cc with the cellular dosage of 8.0 × 107 cells with a viability of > 85% SVF cells] on the same surgical sitting. All the cases were followed up clinically, functionally, and radiologically at regular intervals. A comparison of mean HOOS scores at different follow-ups was done using Paired 't'-test. A P value of < 0.05 was considered significant. Results In our study, male preponderance was seen (53.1%). According to the modified Ficat and Arlet classification, the most common grade of ONFH was grade 2 [right: 25 hips and left: 25 hips]. There was a statistically significant improvement in the mean HOOS score of the right hip (n = 10) and left hip (n = 9) from preoperative time till 72 months (P < 0.05). The follow-up MRI of the affected hips shows improved osteogenesis without any further worsening of the contour of the femoral head. No adverse effects were seen in any of the study participants. Conclusion For individuals with ONFH, treated with intra-osseous autologous SVF implantation in the same surgical procedure is an innovative and promising treatment modality. Even after 6 years of follow-up, the study participants with ONFH have shown good clinical and functional outcomes with autologous SVF.
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Affiliation(s)
- Vinay Tantuway
- Department of Orthopaedics and Traumatology, Index Medical College Hospital and Research Centre, Indore, Madhya Pradesh India
- Sahaj Regenerative Cell Therapeutics, Indore, Madhya Pradesh India
| | - Madhan Jeyaraman
- Sahaj Regenerative Cell Therapeutics, Indore, Madhya Pradesh India
- Department of Orthopaedics, ACS Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai, Tamil Nadu India
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh India
- South Texas Orthopaedic Research Institute (STORI Inc.), Laredo, TX USA
| | - Arulkumar Nallakumarasamy
- Department of Orthopaedics, ACS Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai, Tamil Nadu India
| | - Mittal B. Prikh
- Department of Orthopaedics, Navjivan Hospital, Ahmedabad, Gujarat India
| | - Aashish K. Sharma
- Department of Orthopaedics and Joint Replacement, CK Birla Hospitals, Jaipur, Rajasthan India
| | - Raj Sharma
- Sahaj Regenerative Cell Therapeutics, Indore, Madhya Pradesh India
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26
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Castaño IM, Raftery RM, Chen G, Cavanagh B, Quinn B, Duffy GP, Curtin CM, O'Brien FJ. Dual scaffold delivery of miR-210 mimic and miR-16 inhibitor enhances angiogenesis and osteogenesis to accelerate bone healing. Acta Biomater 2023; 172:480-493. [PMID: 37797708 DOI: 10.1016/j.actbio.2023.09.049] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 08/30/2023] [Accepted: 09/28/2023] [Indexed: 10/07/2023]
Abstract
Angiogenesis is critical for successful bone repair, and interestingly, miR-210 and miR-16 possess counter-active targets involved in both angiogenesis and osteogenesis: miR-210 acts as an activator by silencing EFNA3 & AcvR1b, while miR-16 inhibits both pathways by silencing VEGF & Smad5. It was thus hypothesized that dual delivery of both a miR-210 mimic and a miR-16 inhibitor from a collagen-nanohydroxyapatite scaffold system may hold significant potential for bone repair. Therefore, this systems potential to rapidly accelerate bone repair by directing enhanced angiogenic-osteogenic coupling in host cells in a rat calvarial defect model at a very early 4 week timepoint was assessed. In vitro, the treatment significantly enhanced angiogenic-osteogenic coupling of human mesenchymal stem cells, with enhanced calcium deposition after just 10 days in 2D and 14 days on scaffolds. In vivo, these dual-miRNA loaded scaffolds showed more than double bone volume and vessel recruitment increased 2.3 fold over the miRNA-free scaffolds. Overall, this study demonstrates the successful development of a dual-miRNA mimic/inhibitor scaffold for enhanced in vivo bone repair for the first time, and the possibility of extending this 'off-the-shelf' platform system to applications beyond bone offers immense potential to impact a myriad of other tissue engineering areas. STATEMENT OF SIGNIFICANCE: miRNAs have potential as a new class of bone healing therapeutics as they can enhance the regenerative capacity of bone-forming cells. However, angiogenic-osteogenic coupling is critical for successful bone repair. Therefore, this study harnesses the delivery of miR-210, known to be an activator of both angiogenesis and osteogenesis, and miR-16 inhibitor, as miR-16 is known to inhibit both pathways, from a collagen-nanohydroxyapatite scaffold system to rapidly enhance osteogenesis in vitro and bone repair in vivo in a rat calvarial defect model. Overall, it describes the successful development of the first dual-miRNA mimic/inhibitor scaffold for enhanced in vivo bone repair. This 'off-the-shelf' platform system offers immense potential to extend beyond bone applications and impact a myriad of other tissue engineering areas.
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Affiliation(s)
- Irene Mencía Castaño
- Tissue Engineering Research Group, Department of Anatomy, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, Dublin 2, Ireland
| | - Rosanne M Raftery
- Tissue Engineering Research Group, Department of Anatomy, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, Dublin 2, Ireland; School of Pharmacy, RCSI, Dublin, Ireland
| | - Gang Chen
- Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Microsurgical Research and Training Facility, RCSI, Dublin 2, Ireland
| | | | - Brian Quinn
- Tissue Engineering Research Group, Department of Anatomy, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, Dublin 2, Ireland
| | - Garry P Duffy
- Tissue Engineering Research Group, Department of Anatomy, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, Dublin 2, Ireland; Trinity Centre for Biomedical Engineering, Trinity College Dublin (TCD), College Green, Dublin 2, Ireland; Advanced Materials and Bioengineering Research Centre (AMBER), RCSI and TCD, Dublin 2, Ireland; Anatomy, School of Medicine, College of Medicine Nursing and Health Sciences, University of Galway, University Road, Galway, Ireland
| | - Caroline M Curtin
- Tissue Engineering Research Group, Department of Anatomy, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, Dublin 2, Ireland; Trinity Centre for Biomedical Engineering, Trinity College Dublin (TCD), College Green, Dublin 2, Ireland; Advanced Materials and Bioengineering Research Centre (AMBER), RCSI and TCD, Dublin 2, Ireland.
| | - Fergal J O'Brien
- Tissue Engineering Research Group, Department of Anatomy, Royal College of Surgeons in Ireland (RCSI), 123 St. Stephens Green, Dublin 2, Ireland; Trinity Centre for Biomedical Engineering, Trinity College Dublin (TCD), College Green, Dublin 2, Ireland; Advanced Materials and Bioengineering Research Centre (AMBER), RCSI and TCD, Dublin 2, Ireland.
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27
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Fila M, Pawlowska E, Szczepanska J, Blasiak J. Different Aspects of Aging in Migraine. Aging Dis 2023; 14:2028-2050. [PMID: 37199585 PMCID: PMC10676778 DOI: 10.14336/ad.2023.0313] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 03/13/2023] [Indexed: 05/19/2023] Open
Abstract
Migraine is a common neurological disease displaying an unusual dependence on age. For most patients, the peak intensity of migraine headaches occurs in 20s and lasts until 40s, but then headache attacks become less intense, occur less frequently and the disease is more responsive to therapy. This relationship is valid in both females and males, although the prevalence of migraine in the former is 2-4 times greater than the latter. Recent concepts present migraine not only as a pathological event, but rather as a part of evolutionary adaptive response to protect organism against consequences of stress-induced brain energy deficit. However, these concepts do not fully explain that unusual dependence of migraine prevalence on age. Many aspects of aging, both molecular/cellular and social/cognitive, are interwound in migraine pathogenesis, but they neither explain why only some persons are affected by migraine, nor suggest any causal relationship. In this narrative/hypothesis review we present information on associations of migraine with chronological aging, brain aging, cellular senescence, stem cell exhaustion as well as social, cognitive, epigenetic, and metabolic aging. We also underline the role of oxidative stress in these associations. We hypothesize that migraine affects only individuals who have inborn, genetic/epigenetic, or acquired (traumas, shocks or complexes) migraine predispositions. These predispositions weakly depend on age and affected individuals are more prone to migraine triggers than others. Although the triggers can be related to many aspects of aging, social aging may play a particularly important role as the prevalence of its associated stress has a similar age-dependence as the prevalence of migraine. Moreover, social aging was shown to be associated with oxidative stress, important in many aspects of aging. In perspective, molecular mechanisms underlying social aging should be further explored and related to migraine with a closer association with migraine predisposition and difference in prevalence by sex.
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Affiliation(s)
- Michal Fila
- Department of Developmental Neurology and Epileptology, Polish Mother’s Memorial Hospital Research Institute, 93-338 Lodz, Poland.
| | - Elzbieta Pawlowska
- Department of Pediatric Dentistry, Medical University of Lodz, 92-216 Lodz, Poland.
| | - Joanna Szczepanska
- Department of Pediatric Dentistry, Medical University of Lodz, 92-216 Lodz, Poland.
| | - Janusz Blasiak
- Department of Molecular Genetics, University of Lodz, Pomorska 141/143, 90-236, Lodz, Poland.
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28
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Rehman A, Nigam A, Laino L, Russo D, Todisco C, Esposito G, Svolacchia F, Giuzio F, Desiderio V, Ferraro G. Mesenchymal Stem Cells in Soft Tissue Regenerative Medicine: A Comprehensive Review. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1449. [PMID: 37629738 PMCID: PMC10456353 DOI: 10.3390/medicina59081449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/01/2023] [Accepted: 08/03/2023] [Indexed: 08/27/2023]
Abstract
Soft tissue regeneration holds significant promise for addressing various clinical challenges, ranging from craniofacial and oral tissue defects to blood vessels, muscle, and fibrous tissue regeneration. Mesenchymal stem cells (MSCs) have emerged as a promising tool in regenerative medicine due to their unique characteristics and potential to differentiate into multiple cell lineages. This comprehensive review explores the role of MSCs in different aspects of soft tissue regeneration, including their application in craniofacial and oral soft tissue regeneration, nerve regeneration, blood vessel regeneration, muscle regeneration, and fibrous tissue regeneration. By examining the latest research findings and clinical advancements, this article aims to provide insights into the current state of MSC-based therapies in soft tissue regenerative medicine.
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Affiliation(s)
- Ayesha Rehman
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Via L. Armanni 5, 80138 Naples, Italy; (A.R.); (A.N.)
| | - Aditya Nigam
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Via L. Armanni 5, 80138 Naples, Italy; (A.R.); (A.N.)
| | - Luigi Laino
- Multidisciplinary Department of Medicine for Surgery and Orthodontics, University of Campania “Luigi Vanvitelli”, Via L. Armanni 5, 80138 Naples, Italy; (L.L.); (D.R.); (G.F.)
| | - Diana Russo
- Multidisciplinary Department of Medicine for Surgery and Orthodontics, University of Campania “Luigi Vanvitelli”, Via L. Armanni 5, 80138 Naples, Italy; (L.L.); (D.R.); (G.F.)
| | | | | | - Fabiano Svolacchia
- Departments of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 00118 Rome, Italy;
| | - Federica Giuzio
- Department of Sciences, University of Basilicata, Via Nazario Sauro 85, 85100 Potenza, Italy;
- U.O.S.D. of Plastic Surgery A.O.R “San Carlo”, 85100 Potenza, Italy
| | - Vincenzo Desiderio
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Via L. Armanni 5, 80138 Naples, Italy; (A.R.); (A.N.)
| | - Giuseppe Ferraro
- Multidisciplinary Department of Medicine for Surgery and Orthodontics, University of Campania “Luigi Vanvitelli”, Via L. Armanni 5, 80138 Naples, Italy; (L.L.); (D.R.); (G.F.)
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29
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Zhao S, Zhang Q, Liu M, Du J, Wang T, Li Y, Zeng W. Application of stem cells in engineered vascular graft and vascularized organs. Semin Cell Dev Biol 2023; 144:31-40. [PMID: 36411157 DOI: 10.1016/j.semcdb.2022.10.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 10/16/2022] [Accepted: 10/17/2022] [Indexed: 11/19/2022]
Abstract
Recent studies report that stem cell therapies have been applied successfully to patients, This has increased anticipations that this regeneration strategy could be a potential method to treat a wide range of intractable diseases some day. Stem cells offer new prospects for the treatment of incurable diseases and for tissue regeneration and repairation because of their unique biological properties. Angiogenesis a key process in tissue regeneration and repairation. Vascularization of organs is one of the main challenges hindering the clinical application of engineered tissues. Efficient production of engineered vascular grafts and vascularized organs is of critical importance for regenerative medicine. In this review, we focus on the types of stem cells that are widely used in tissue engineering and regeneration, as well as their application of these stem cells in the construction of tissue-engineered vascular grafts and vascularization of tissue-engineered organs.
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Affiliation(s)
- Shanlan Zhao
- Department of Cell Biology, Third Military Medical University, Chongqing, China
| | - Qiao Zhang
- Department of Cell Biology, Third Military Medical University, Chongqing, China; Department of Pain and Rehabilitation, Xinqiao Hospital, Third Military Medical University, Chongqing 400038, China
| | - Min Liu
- Department of Cell Biology, Third Military Medical University, Chongqing, China
| | - Jiahui Du
- Department of Cell Biology, Third Military Medical University, Chongqing, China
| | - Tingting Wang
- Department of Cell Biology, Third Military Medical University, Chongqing, China
| | - Yanzhao Li
- Department of Anatomy, Third Military Medical University, Chongqing, China.
| | - Wen Zeng
- Department of Cell Biology, Third Military Medical University, Chongqing, China; Jinfeng Laboratory, Chongqing 401329, People's Republic China; State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing, China.
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30
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Yang X, Wang Y, Rovella V, Candi E, Jia W, Bernassola F, Bove P, Piacentini M, Scimeca M, Sica G, Tisone G, Mauriello A, Wei L, Melino G, Shi Y. Aged mesenchymal stem cells and inflammation: from pathology to potential therapeutic strategies. Biol Direct 2023; 18:40. [PMID: 37464416 PMCID: PMC10353240 DOI: 10.1186/s13062-023-00394-6] [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: 06/17/2023] [Accepted: 06/27/2023] [Indexed: 07/20/2023] Open
Abstract
Natural ageing of organisms and corresponding age-related diseases result mainly from stem cell ageing and "inflammaging". Mesenchymal stem cells (MSCs) exhibit very high immune-regulating capacity and are promising candidates for immune-related disease treatment. However, the effect of MSC application is not satisfactory for some patients, especially in elderly individuals. With ageing, MSCs undergo many changes, including altered cell population reduction and differentiation ability, reduced migratory and homing capacity and, most important, defective immunosuppression. It is necessary to explore the relationship between the "inflammaging" and aged MSCs to prevent age-related diseases and increase the therapeutic effects of MSCs. In this review, we discuss changes in naturally ageing MSCs mainly from an inflammation perspective and propose some ideas for rejuvenating aged MSCs in future treatments.
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Affiliation(s)
- Xue Yang
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, Jiangsu China
| | - Ying Wang
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, Jiangsu China
| | - Valentina Rovella
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
| | - Eleonora Candi
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
| | - Wei Jia
- Center for Translational Medicine, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200233 China
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong China
| | - Francesca Bernassola
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
| | - Pierluigi Bove
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
| | - Mauro Piacentini
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
| | - Manuel Scimeca
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
| | - Giuseppe Sica
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
| | - Giuseppe Tisone
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
| | - Alessandro Mauriello
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
| | - Lixin Wei
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438 China
| | - Gerry Melino
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, Rome, 00133 Italy
| | - Yufang Shi
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, Jiangsu China
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Razi S, Haghparast A, Chodari Khameneh S, Ebrahimi Sadrabadi A, Aziziyan F, Bakhtiyari M, Nabi-Afjadi M, Tarhriz V, Jalili A, Zalpoor H. The role of tumor microenvironment on cancer stem cell fate in solid tumors. Cell Commun Signal 2023; 21:143. [PMID: 37328876 PMCID: PMC10273768 DOI: 10.1186/s12964-023-01129-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 04/15/2023] [Indexed: 06/18/2023] Open
Abstract
In the last few decades, the role of cancer stem cells in initiating tumors, metastasis, invasion, and resistance to therapies has been recognized as a potential target for tumor therapy. Understanding the mechanisms by which CSCs contribute to cancer progression can help to provide novel therapeutic approaches against solid tumors. In this line, the effects of mechanical forces on CSCs such as epithelial-mesenchymal transition, cellular plasticity, etc., the metabolism pathways of CSCs, players of the tumor microenvironment, and their influence on the regulating of CSCs can lead to cancer progression. This review focused on some of these mechanisms of CSCs, paving the way for a better understanding of their regulatory mechanisms and developing platforms for targeted therapies. While progress has been made in research, more studies will be required in the future to explore more aspects of how CSCs contribute to cancer progression. Video Abstract.
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Affiliation(s)
- Sara Razi
- Vira Pioneers of Modern Science (VIPOMS), Tehran, Iran
| | | | | | - Amin Ebrahimi Sadrabadi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACER, Tehran, Iran
- Cytotech and Bioinformatics Research Group, Tehran, Iran
| | - Fatemeh Aziziyan
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Maryam Bakhtiyari
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Mohsen Nabi-Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Vahideh Tarhriz
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, P.O. Box 5163639888, Tabriz, Iran.
| | - Arsalan Jalili
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACER, Tehran, Iran.
- Parvaz Research Ideas Supporter Institute, Tehran, Iran.
| | - Hamidreza Zalpoor
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran.
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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32
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Kahrizi MS, Mousavi E, Khosravi A, Rahnama S, Salehi A, Nasrabadi N, Ebrahimzadeh F, Jamali S. Recent advances in pre-conditioned mesenchymal stem/stromal cell (MSCs) therapy in organ failure; a comprehensive review of preclinical studies. Stem Cell Res Ther 2023; 14:155. [PMID: 37287066 DOI: 10.1186/s13287-023-03374-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 05/10/2023] [Indexed: 06/09/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs)-based therapy brings the reassuring capability to regenerative medicine through their self-renewal and multilineage potency. Also, they secret a diversity of mediators, which are complicated in moderation of deregulated immune responses, and yielding angiogenesis in vivo. Nonetheless, MSCs may lose biological performance after procurement and prolonged expansion in vitro. Also, following transplantation and migration to target tissue, they encounter a harsh milieu accompanied by death signals because of the lack of proper tensegrity structure between the cells and matrix. Accordingly, pre-conditioning of MSCs is strongly suggested to upgrade their performances in vivo, leading to more favored transplantation efficacy in regenerative medicine. Indeed, MSCs ex vivo pre-conditioning by hypoxia, inflammatory stimulus, or other factors/conditions may stimulate their survival, proliferation, migration, exosome secretion, and pro-angiogenic and anti-inflammatory characteristics in vivo. In this review, we deliver an overview of the pre-conditioning methods that are considered a strategy for improving the therapeutic efficacy of MSCs in organ failures, in particular, renal, heart, lung, and liver.
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Affiliation(s)
| | - Elnaz Mousavi
- Department of Endodontics, School of Dentistry, Guilan University of Medical Sciences, Rasht, Iran
| | - Armin Khosravi
- Department of Periodontics, Dental School, Islamic Azad University, Isfahan (Khorasgan) Branch, Isfahan, Iran
| | - Sara Rahnama
- Department of Pediatric Dentistry, School of Dentistry, Semnan University of Medical Sciences, Semnan, Iran
| | - Ali Salehi
- Department of Oral and Maxillofacial Radiology, School of Dentistry, Islamic Azad University, Isfahan (Khorasgan) Branch, Isfahan, Iran
| | - Navid Nasrabadi
- Department of Endodontics, School of Dentistry, Birjand University of Medical Sciences, Birjand, Iran
| | - Farnoosh Ebrahimzadeh
- Department of Internal Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Samira Jamali
- Department of Endodontics, Stomatological Hospital, College of Stomatology, Xi'an Jiaotong University, Shaanxi, People's Republic of China.
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Zimmermann R, Nitschke M, Magno V, Freudenberg U, Sockel K, Stölzel F, Wobus M, Platzbecker U, Werner C. Discriminant Principal Component Analysis of ToF-SIMS Spectra for Deciphering Compositional Differences of MSC-Secreted Extracellular Matrices. SMALL METHODS 2023; 7:e2201157. [PMID: 36978251 DOI: 10.1002/smtd.202201157] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 01/19/2023] [Indexed: 06/09/2023]
Abstract
Identifying characteristic extracellular matrix (ECM) variants is a key challenge in mechanistic biology, bioengineering, and medical diagnostics. The reported study demonstrates the potential of time-of-flight secondary ion mass spectrometry (ToF-SIMS) to detect subtle differences between human mesenchymal stromal cell (MSC)-secreted ECM types as induced by exogenous stimulation or emerging pathology. ToF-SIMS spectra of decellularized ECM samples are evaluated by discriminant principal component analysis (DPCA), an advanced multivariate analysis technique, to decipher characteristic compositional features. To establish the approach, signatures of major ECM proteins are determined from samples of pre-defined mixtures. Based on that, sets of ECM variants produced by MSCs in vitro are analyzed. Differences in the content of collagen, fibronectin, and laminin in the ECM resulting from the combined supplementation of MSC cultures with polymers that induce macromolecular crowding and with ascorbic acid are detected from the DPCA of ToF-SIMS spectra. The results are verified by immunostaining. Finally, the comparative ToF-SIMS analysis of ECM produced by MSCs of healthy donors and patients suffering from myelodysplastic syndrome display the potential of the novel methodology to reveal disease-associated alterations of the ECM composition.
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Affiliation(s)
- Ralf Zimmermann
- Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials, 01069, Dresden, Germany
| | - Mirko Nitschke
- Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials, 01069, Dresden, Germany
| | - Valentina Magno
- Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials, 01069, Dresden, Germany
| | - Uwe Freudenberg
- Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials, 01069, Dresden, Germany
| | - Katja Sockel
- Medical Clinic and Policlinic I, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307, Dresden, Germany
| | - Friedrich Stölzel
- Medical Clinic and Policlinic I, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307, Dresden, Germany
- Division of Stem Cell Transplantation and Cellular Immunotherapies, Department of Internal Medicine II, University Hospital Schleswig-Holstein, Arnold-Heller-Straße 3, 24105, Kiel, Germany
| | - Manja Wobus
- Medical Clinic and Policlinic I, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307, Dresden, Germany
| | - Uwe Platzbecker
- Hematology and Cellular Therapy, University Hospital Leipzig, 04103, Leipzig, Germany
| | - Carsten Werner
- Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials, 01069, Dresden, Germany
- Center for Regenerative Therapies Dresden and Cluster of Excellence Physics of Life, Technische Universität Dresden, 01307, Dresden, Germany
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34
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Subayyil AA, Basmaeil YS, Kulayb HB, Alrodayyan M, Alhaber LAA, Almanaa TN, Khatlani T. Preconditioned Chorionic Villus Mesenchymal Stem/Stromal Cells (CVMSCs) Minimize the Invasive Phenotypes of Breast Cancer Cell Line MDA231 In Vitro. Int J Mol Sci 2023; 24:ijms24119569. [PMID: 37298519 DOI: 10.3390/ijms24119569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 03/30/2023] [Accepted: 04/03/2023] [Indexed: 06/12/2023] Open
Abstract
Among the newer choices of targeted therapies against cancer, stem cell therapy is gaining importance because of their antitumor properties. Stem cells suppress growth, metastasis, and angiogenesis, and induce apoptosis in cancer cells. In this study, we have examined the impact of the cellular component and the secretome of preconditioned and naïve placenta-derived Chorionic Villus Mesenchymal Stem Cells (CVMSCs) on the functional characteristics of the Human Breast Cancer cell line MDA231. MDA231 cells were treated with preconditioned CVMSCs and their conditioned media (CM), followed by an evaluation of their functional activities and modulation in gene and protein expression. Human Mammary Epithelial Cells (HMECs) were used as a control. CM obtained from the preconditioned CVMSCs significantly altered the proliferation of MDA231 cells, yet no change in other phenotypes, such as adhesion, migration, and invasion, were observed at various concentrations and time points tested. However, the cellular component of preconditioned CVMSCs significantly inhibited several phenotypes of MDA231 cells, including proliferation, migration, and invasion. CVMSCs-treated MDA231 cells exhibited modulation in the expression of various genes involved in apoptosis, oncogenesis, and Epithelial to Mesenchymal Transition (EMT), explaining the changes in the invasive behavior of MDA231 cells. These studies reveal that preconditioned CVMSCs may make useful candidate in a stem cell-based therapy against cancer.
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Affiliation(s)
- Abdullah Al Subayyil
- Blood and Cancer Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia
| | - Yasser S Basmaeil
- Blood and Cancer Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia
| | - Hayaa Bin Kulayb
- Blood and Cancer Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia
| | - Maha Alrodayyan
- Blood and Cancer Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia
| | - Lama Abdulaziz A Alhaber
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Taghreed N Almanaa
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Tanvir Khatlani
- Blood and Cancer Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU), Ministry of National Guard Health Affairs (MNGHA), Riyadh 11426, Saudi Arabia
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35
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Moradi-Gharibvand N, Hashemibeni B. The Effect of Stem Cells and Vascular Endothelial Growth Factor on Cancer Angiogenesis. Adv Biomed Res 2023; 12:124. [PMID: 37434939 PMCID: PMC10331557 DOI: 10.4103/abr.abr_378_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 04/17/2022] [Accepted: 04/24/2022] [Indexed: 07/13/2023] Open
Abstract
The formation of new vessels from pre-existing vessels is known as angiogenesis. The process is controlled by stimuli and inhibitors. Angiogenesis starts as a result of the unbalance of these factors, where balance has a tendency toward the stimulus. One of the most important factors promoting angiogenesis is the vascular endothelial growth factor (VEGF). In addition to being involved in vascular regeneration in normal tissues, VEGF also takes part in tumor tissue angiogenesis. These factors affect endothelial cells (ECs) directly as well as differentiate tumor cells from endothelial cells and play an active role in tumor tissue angiogenesis. Angiogenesis partakes in the growth and proliferation of tumor tissue. Because anti-angiogenic treatment is favorable in existing cancer therapies, the potential benefits should be considered. One of these new therapies is cell therapy using mesenchymal stem cells (MSCs). Research on MSCs remains controversial because much of the earlier research on MSCs has shown their effectiveness, but more recent research has identified harmful effects of these cells. This article reviews the role of stem cells and their secretions in the angiogenesis of tumor tissues.
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Affiliation(s)
- Nahid Moradi-Gharibvand
- Abadan University of Medical Sciences, Abadan, Iran
- Department of Anatomical Sciences and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Batool Hashemibeni
- Department of Anatomical Sciences and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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36
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Anderson JR, Morin EE, Brayer KJ, Salbato S, Gonzalez Bosc LV, Kanagy NL, Naik JS. Single-cell transcriptomic heterogeneity between conduit and resistance mesenteric arteries in rats. Physiol Genomics 2023; 55:179-193. [PMID: 36912534 PMCID: PMC10085562 DOI: 10.1152/physiolgenomics.00126.2022] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 02/03/2023] [Accepted: 03/08/2023] [Indexed: 03/14/2023] Open
Abstract
The endothelium contains morphologically similar cells throughout the vasculature, but individual cells along the length of a single vascular tree or in different regional circulations function dissimilarly. When observations made in large arteries are extrapolated to explain the function of endothelial cells (ECs) in the resistance vasculature, only a fraction of these observations are consistent between artery sizes. To what extent endothelial (EC) and vascular smooth muscle cells (VSMCs) from different arteriolar segments of the same tissue differ phenotypically at the single-cell level remains unknown. Therefore, single-cell RNA-seq (10x Genomics) was performed using a 10X Genomics Chromium system. Cells were enzymatically digested from large (>300 µm) and small (<150 µm) mesenteric arteries from nine adult male Sprague-Dawley rats, pooled to create six samples (3 rats/sample, 3 samples/group). After normalized integration, the dataset was scaled before unsupervised cell clustering and cluster visualization using UMAP plots. Differential gene expression analysis allowed us to infer the biological identity of different clusters. Our analysis revealed 630 and 641 differentially expressed genes (DEGs) between conduit and resistance arteries for ECs and VSMCs, respectively. Gene ontology analysis (GO-Biological Processes, GOBP) of scRNA-seq data discovered 562 and 270 pathways for ECs and VSMCs, respectively, that differed between large and small arteries. We identified eight and seven unique ECs and VSMCs subpopulations, respectively, with DEGs and pathways identified for each cluster. These results and this dataset allow the discovery and support of novel hypotheses needed to identify mechanisms that determine the phenotypic heterogeneity between conduit and resistance arteries.
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Affiliation(s)
- Jacob R Anderson
- Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
| | - Emily E Morin
- Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
| | - Kathryn J Brayer
- Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
| | - Sophia Salbato
- Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
| | - Laura V Gonzalez Bosc
- Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
| | - Nancy L Kanagy
- Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
| | - Jay S Naik
- Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States
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37
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Administration of stem cells against cardiovascular diseases with a focus on molecular mechanisms: Current knowledge and prospects. Tissue Cell 2023; 81:102030. [PMID: 36709696 DOI: 10.1016/j.tice.2023.102030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 01/15/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023]
Abstract
Cardiovascular diseases (CVDs) are a serious global concern for public and human health. Despite the emergence of significant therapeutic advances, it is still the leading cause of death and disability worldwide. As a result, extensive efforts are underway to develop practical therapeutic approaches. Stem cell-based therapies could be considered a promising strategy for the treatment of CVDs. The efficacy of stem cell-based therapeutic approaches is demonstrated through recent laboratory and clinical studies due to their inherent regenerative properties, proliferative nature, and their capacity to differentiate into different cells such as cardiomyocytes. These properties could improve cardiovascular functioning leading to heart regeneration. The two most common types of stem cells with the potential to cure heart diseases are induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs). Several studies have demonstrated the use, efficacy, and safety of MSC and iPSCs-based therapies for the treatment of CVDs. In this study, we explain the application of stem cells, especially iPSCs and MSCs, in the treatment of CVDs with a focus on cellular and molecular mechanisms and then discuss the advantages, disadvantages, and perspectives of using this technology in the treatment of these diseases.
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38
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In Search of the Holy Grail: Stem Cell Therapy as a Novel Treatment of Heart Failure with Preserved Ejection Fraction. Int J Mol Sci 2023; 24:ijms24054903. [PMID: 36902332 PMCID: PMC10003723 DOI: 10.3390/ijms24054903] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/20/2023] [Accepted: 02/25/2023] [Indexed: 03/06/2023] Open
Abstract
Heart failure, a leading cause of hospitalizations and deaths, is a major clinical problem. In recent years, the increasing incidence of heart failure with preserved ejection fraction (HFpEF) has been observed. Despite extensive research, there is no efficient treatment for HFpEF available. However, a growing body of evidence suggests stem cell transplantation, due to its immunomodulatory effect, may decrease fibrosis and improve microcirculation and therefore, could be the first etiology-based therapy of the disease. In this review, we explain the complex pathogenesis of HFpEF, delineate the beneficial effects of stem cells in cardiovascular therapy, and summarize the current knowledge concerning cell therapy in diastolic dysfunction. Furthermore, we identify outstanding knowledge gaps that may indicate directions for future clinical studies.
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Preliminary In Vitro Assessment of Decellularized Porcine Descending Aorta for Clinical Purposes. J Funct Biomater 2023; 14:jfb14030141. [PMID: 36976065 PMCID: PMC10058365 DOI: 10.3390/jfb14030141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
Conduit substitutes are increasingly in demand for cardiovascular and urological applications. In cases of bladder cancer, radical cystectomy is the preferred technique: after removing the bladder, a urinary diversion has to be created using autologous bowel, but several complications are associated with intestinal resection. Thus, alternative urinary substitutes are required to avoid autologous intestinal use, preventing complications and facilitating surgical procedures. In the present paper, we are proposing the exploitation of the decellularized porcine descending aorta as a novel and original conduit substitute. After being decellularized with the use of two alternative detergents (Tergitol and Ecosurf) and sterilized, the porcine descending aorta has been investigated to assess its permeability to detergents through methylene blue dye penetration analysis and to study its composition and structure by means of histomorphometric analyses, including DNA quantification, histology, two-photon microscopy, and hydroxyproline quantification. Biomechanical tests and cytocompatibility assays with human mesenchymal stem cells have been also performed. The results obtained demonstrated that the decellularized porcine descending aorta preserves its major features to be further evaluated as a candidate material for urological applications, even though further studies have to be carried out to demonstrate its suitability for the specific application, by performing in vivo tests in the animal model.
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40
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Sun P, Wu H, Bai X, Zhang L, Zhang C, Wang X, Lou C, Li B, Li Z, Bai H. Decellularized fish swim bladder patch loaded with mesenchymal stem cells inhibits neointimal hyperplasia. J Biomed Mater Res B Appl Biomater 2023; 111:551-559. [PMID: 36200602 DOI: 10.1002/jbm.b.35172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 07/07/2022] [Accepted: 09/03/2022] [Indexed: 01/21/2023]
Abstract
We previously showed decellularized fish swim bladder can be used as vascular patch and tube graft in rats, mesenchymal stem cells (MSCs) have showed the capability to inhibit neointimal hyperplasia in different animal models. We hypothesized that decellularized fish swim bladder patch loaded with MSCs (bioinspired patch) can inhibit neointimal hyperplasia in a rat aortic patch angioplasty model. Rat MSCs were grown in vitro and flow cytometry was used to confirm their quality. 3.6 × 105 MSCs were mixed into 100 μl of sodium alginate (SA)/hyaluronic acid (HA) hydrogel, two layers of fish swim bladders (5 mm × 5 mm) were sutured together, bioinspired patch was created by injection of hydrogel with MSCs into the space between two layers of fish swim bladder patches. Decellularized rat thoracic aorta patch was used as control. Patches were harvested at days 1 and 14 after implantation. Samples were examined by histology, immunohistochemistry, and immunofluorescence. The decellularized rat thoracic aorta patch and the fish swim bladder patch had a similar healing process after implantation. The bioinspired patch had a similar structure like native aorta. Bioinspired patch showed a decreased neointimal thickness (p = .0053), fewer macrophages infiltration (p = .0090), and lower proliferation rate (p = .0291) compared to the double layers fish swim bladder patch group. Decellularized fish swim bladder patch loaded with MSCs can inhibit neointimal hyperplasia effectively. Although this is a preliminary animal study, it may have a potential application in large animals or clinical research.
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Affiliation(s)
- Peng Sun
- Department of Vascular and Endovascular Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Haoliang Wu
- Department of Vascular and Endovascular Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiche Bai
- Key Vascular Physiology and Applied Research Laboratory of Zhengzhou City, Zhengzhou, China.,The First Zhongyuan Middle School, Zhengzhou, China
| | - Liwei Zhang
- Department of Vascular and Endovascular Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Cong Zhang
- Department of Vascular and Endovascular Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xueyun Wang
- Department of Physiology, Medical School of Zhengzhou University, Zhengzhou, China
| | - Chunyang Lou
- Department of Vascular and Endovascular Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Bo Li
- Department of Physiology, Medical School of Zhengzhou University, Zhengzhou, China
| | - Zhuo Li
- Key Vascular Physiology and Applied Research Laboratory of Zhengzhou City, Zhengzhou, China.,Department of Neurology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hualong Bai
- Department of Vascular and Endovascular Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Key Vascular Physiology and Applied Research Laboratory of Zhengzhou City, Zhengzhou, China
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41
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Szydlak R. Mesenchymal stem cells in ischemic tissue regeneration. World J Stem Cells 2023; 15:16-30. [PMID: 36909782 PMCID: PMC9993139 DOI: 10.4252/wjsc.v15.i2.16] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/10/2022] [Accepted: 01/19/2023] [Indexed: 02/21/2023] Open
Abstract
Diseases caused by ischemia are one of the leading causes of death in the world. Current therapies for treating acute myocardial infarction, ischemic stroke, and critical limb ischemia do not complete recovery. Regenerative therapies opens new therapeutic strategy in the treatment of ischemic disorders. Mesenchymal stem cells (MSCs) are the most promising option in the field of cell-based therapies, due to their secretory and immunomodulatory abilities, that contribute to ease inflammation and promote the regeneration of damaged tissues. This review presents the current knowledge of the mechanisms of action of MSCs and their therapeutic effects in the treatment of ischemic diseases, described on the basis of data from in vitro experiments and preclinical animal studies, and also summarize the effects of using these cells in clinical trial settings. Since the obtained therapeutic benefits are not always satisfactory, approaches aimed at enhancing the effect of MSCs in regenerative therapies are presented at the end.
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Affiliation(s)
- Renata Szydlak
- Chair of Medical Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, Kraków 31-034, Poland
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42
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Velasco MG, Satué K, Chicharro D, Martins E, Torres-Torrillas M, Peláez P, Miguel-Pastor L, Del Romero A, Damiá E, Cuervo B, Carrillo JM, Cugat R, Sopena JJ, Rubio M. Multilineage-Differentiating Stress-Enduring Cells (Muse Cells): The Future of Human and Veterinary Regenerative Medicine. Biomedicines 2023; 11:biomedicines11020636. [PMID: 36831171 PMCID: PMC9953712 DOI: 10.3390/biomedicines11020636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/13/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
In recent years, several studies have been conducted on Muse cells mainly due to their pluripotency, high tolerance to stress, self-renewal capacity, ability to repair DNA damage and not being tumoral. Additionally, since these stem cells can be isolated from different tissues in the adult organism, obtaining them is not considered an ethical problem, providing an advantage over embryonic stem cells. Regarding their therapeutic potential, few studies have reported clinical applications in the treatment of different diseases, such as aortic aneurysm and chondral injuries in the mouse or acute myocardial infarction in the swine, rabbit, sheep and in humans. This review aims to describe the characterization of Muse cells, show their biological characteristics, explain the differences between Muse cells and mesenchymal stem cells, and present their contribution to the treatment of some diseases.
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Affiliation(s)
- María Gemma Velasco
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Katy Satué
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Deborah Chicharro
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Emma Martins
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Marta Torres-Torrillas
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Pau Peláez
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Laura Miguel-Pastor
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Ayla Del Romero
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Elena Damiá
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - Belén Cuervo
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
| | - José María Carrillo
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Ramón Cugat
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
| | - Joaquín Jesús Sopena
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
- Correspondence:
| | - Mónica Rubio
- Bioregenerative Medicine and Applied Surgery Research Group, Department of Animal Medicine and Surgery, CEU Cardenal Herrera University, CEU Universities, C/Tirant lo Blanc, 7, Alfara del Patriarca, 46115 Valencia, Spain
- Garcia Cugat Foundation CEU-UCH Chair of Medicine and Regenerative Surgery, 08006 Barcelona, Spain
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Mazzotti MC, Teti G, Giorgetti A, Carano F, Pelletti G, Pascali JP, Falconi M, Pelotti S, Fais P. Insights in opiates toxicity: impairment of human vascular mesenchymal stromal cells. Int J Legal Med 2023:10.1007/s00414-023-02961-y. [PMID: 36786894 PMCID: PMC10247844 DOI: 10.1007/s00414-023-02961-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 01/31/2023] [Indexed: 02/15/2023]
Abstract
The most common pulmonary findings in opiate-related fatalities are congestion and oedema, as well as acute and/or chronic alveolar haemorrhage, the cause of which is thought to be a damage to the capillary endothelium related to ischemia. Human vascular mesenchymal stromal cells (vMSCs) play a fundamental role in tissue regeneration and repair after endothelial cell injury, and they express opioid receptors. The aim of this study was to assess the effect of in vitro morphine exposure on the physiological activity and maintenance of human vMSCs. vMSCs were obtained from abdominal aorta fragments collected during surgery repair and were exposed to incremental doses (0.1 mM, 0.4 mM, 0.8 mM and 1 mM) of morphine sulphate for 7 days. The effect was investigated through cell viability assessment, proliferation assay, reactive oxygen species (ROS) detection assay, senescence-associated β-galactosidase assay, senescent-related markers (p21WAF1/CIP1 and p16INK4) and the apoptosis-related marker caspase 3. Moreover, an ultrastructural analysis by transmission electron microscopy and in vitro vascular differentiation were evaluated. Results showed a decrease of the cellular metabolic activity, a pro-oxidant and pro-senescence effect, an increase in intracellular ROS and the activation of the apoptosis signalling, as well as ultrastructural modifications and impairment of vascular differentiation after morphine treatment of vMSC. Although confirmation studies are required on real fatal opiate intoxications, the approach based on morphological and immunofluorescence methodologies may have a high potential also as a useful tool or as a complementary method in forensic pathology. The application of these techniques in the future may lead to the identification of new markers and morphological parameters useful as complementary investigations for drug-related deaths.
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Affiliation(s)
- Maria Carla Mazzotti
- Department of Medical and Surgical Sciences, Unit of Legal Medicine, University of Bologna, Via Irnerio 49, 40126, Bologna, Italy
| | - Gabriella Teti
- Department of Biomedical and Neuromotor Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy
| | - Arianna Giorgetti
- Department of Medical and Surgical Sciences, Unit of Legal Medicine, University of Bologna, Via Irnerio 49, 40126, Bologna, Italy.
| | - Francesco Carano
- Department of Biomedical and Neuromotor Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy
| | - Guido Pelletti
- Department of Medical and Surgical Sciences, Unit of Legal Medicine, University of Bologna, Via Irnerio 49, 40126, Bologna, Italy
| | - Jennifer Paola Pascali
- Department of Cardiologic, Thoracic and Vascular Sciences, University of Padova, Via Giustiniani, 2, 35127, Padua, Italy
| | - Mirella Falconi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy
| | - Susi Pelotti
- Department of Medical and Surgical Sciences, Unit of Legal Medicine, University of Bologna, Via Irnerio 49, 40126, Bologna, Italy
| | - Paolo Fais
- Department of Medical and Surgical Sciences, Unit of Legal Medicine, University of Bologna, Via Irnerio 49, 40126, Bologna, Italy
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44
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Borges MF, Maurmann N, Pranke P. Easy-to-Assembly System for Decellularization and Recellularization of Liver Grafts in a Bioreactor. MICROMACHINES 2023; 14:449. [PMID: 36838149 PMCID: PMC9962055 DOI: 10.3390/mi14020449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 01/31/2023] [Accepted: 02/10/2023] [Indexed: 06/18/2023]
Abstract
Decellularization of organs creates an acellular scaffold, ideal for being repopulated by cells. In this work, a low-cost perfusion system was created to be used in the process of liver decellularization and as a bioreactor after recellularization. It consists of a glass chamber to house the organ coupled to a peristaltic pump to promote liquid flow through the organ vascular tree. The rats' liver decellularization was made with a solution of sodium dodecyl sulfate. The recellularization was made with 108 mesenchymal stromal/stem cells and cultivated for seven days. The decellularized matrices showed an absence of DNA while preserving the collagen and glycosaminoglycans quantities, confirming the efficiency of the process. The functional analyses showed a rise in lactate dehydrogenase levels occurring in the first days of the cultivation, suggesting that there is cell death in this period, which stabilized on the seventh day. Histological analysis showed conservation of the collagen web and some groups of cells next to the vessels. It was possible to establish a system for decellularization and a bioreactor to use for the recellularization method. It is easy to assemble, can be ready to use in little time and be easily sterilized.
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Affiliation(s)
- Maurício Felisberto Borges
- Hematology and Stem Cell Laboratory, Faculty of Pharmacy, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90610-000, Brazil
| | - Natasha Maurmann
- Postgraduate Program in Physiology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90050-170, Brazil
| | - Patricia Pranke
- Hematology and Stem Cell Laboratory, Faculty of Pharmacy, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre 90610-000, Brazil
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45
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Molecular Mechanisms Responsible for Mesenchymal Stem Cell-Based Modulation of Obstructive Sleep Apnea. Int J Mol Sci 2023; 24:ijms24043708. [PMID: 36835120 PMCID: PMC9958695 DOI: 10.3390/ijms24043708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 01/20/2023] [Accepted: 01/26/2023] [Indexed: 02/16/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are adult stem cells that reside in almost all postnatal tissues where, due to the potent regenerative, pro-angiogenic and immunomodulatory properties, regulate tissue homeostasis. Obstructive sleep apnea (OSA) induces oxidative stress, inflammation and ischemia which recruit MSCs from their niches in inflamed and injured tissues. Through the activity of MSC-sourced anti-inflammatory and pro-angiogenic factors, MSCs reduce hypoxia, suppress inflammation, prevent fibrosis and enhance regeneration of damaged cells in OSA-injured tissues. The results obtained in large number of animal studies demonstrated therapeutic efficacy of MSCs in the attenuation of OSA-induced tissue injury and inflammation. Herewith, in this review article, we emphasized molecular mechanisms which are involved in MSC-based neo-vascularization and immunoregulation and we summarized current knowledge about MSC-dependent modulation of OSA-related pathologies.
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46
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Jung E, Ou S, Ahn SS, Yeo H, Lee YH, Shin SY. The JNK-EGR1 signaling axis promotes TNF-α-induced endothelial differentiation of human mesenchymal stem cells via VEGFR2 expression. Cell Death Differ 2023; 30:356-368. [PMID: 36371601 PMCID: PMC9950069 DOI: 10.1038/s41418-022-01088-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 10/24/2022] [Accepted: 11/04/2022] [Indexed: 11/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) can differentiate into endothelial cells; however, the mechanisms underlying this process in the tumor microenvironment (TME) remain elusive. This study shows that tumor necrosis factor alpha (TNF-α), a key cytokine present in the TME, promotes the endothelial differentiation of MSCs by inducing vascular endothelial growth factor receptor 2 (VEGFR2) gene expression. EGR1 is a member of the zinc-finger transcription factor family induced by TNF-α. Our findings indicate that EGR1 directly binds to the VEGFR2 promoter and transactivates VEGFR2 expression. We also demonstrate that EGR1 forms a complex with c-JUN activated by c-JUN N-terminal kinase (JNK) to promote VEGFR2 transcription and endothelial differentiation in MSCs in response to TNF-α stimulation. The shRNA-mediated silencing of EGR1 or c-JUN abrogates TNF-α-induced VEGFR2 transcription and the endothelial differentiation of MSCs. To further evaluated the role of EGR1 in the endothelial differentiation of BM-MSCs, we used a syngenic tumor implantation model. 4T1 mouse mammary tumor cells were injected subcutaneously into BALB/c mice with primary mBM-MSCs isolated from wild-type (Egr1+/+) or Egr1-null (Egr1-/-) mice. CD31-positive cells were predominantly observed at the border of the tumor in the 4T1 plus wild-type MSC group, while staining less in the 4T1 alone or 4T1 plus Egr1-null MSC group. Collectively, these findings demonstrate that the JNK-EGR1 signaling axis plays a crucial role in the TNF-α-induced endothelial differentiation of MSCs in the TME, which could be a potential therapeutic target for solid tumors vasculatures.
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Affiliation(s)
- Euitaek Jung
- Department of Biological Sciences, Sanghuh College of Lifescience, Konkuk University, Seoul, 05029, Republic of Korea
| | - Sukjin Ou
- Department of Biological Sciences, Sanghuh College of Lifescience, Konkuk University, Seoul, 05029, Republic of Korea
| | - Sung Shin Ahn
- Department of Biological Sciences, Sanghuh College of Lifescience, Konkuk University, Seoul, 05029, Republic of Korea
| | - Hyunjin Yeo
- Department of Biological Sciences, Sanghuh College of Lifescience, Konkuk University, Seoul, 05029, Republic of Korea
| | - Young Han Lee
- Department of Biological Sciences, Sanghuh College of Lifescience, Konkuk University, Seoul, 05029, Republic of Korea
| | - Soon Young Shin
- Department of Biological Sciences, Sanghuh College of Lifescience, Konkuk University, Seoul, 05029, Republic of Korea.
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47
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Yao T, Chen H, Wang R, Rivero R, Wang F, Kessels L, Agten SM, Hackeng TM, Wolfs TG, Fan D, Baker MB, Moroni L. Thiol-ene conjugation of a VEGF peptide to electrospun scaffolds for potential applications in angiogenesis. Bioact Mater 2023; 20:306-317. [PMID: 35755423 PMCID: PMC9192696 DOI: 10.1016/j.bioactmat.2022.05.029] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 05/07/2022] [Accepted: 05/23/2022] [Indexed: 01/17/2023] Open
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Watson E, Mikos AG. Advances in In Vitro and In Vivo Bioreactor-Based Bone Generation for Craniofacial Tissue Engineering. BME FRONTIERS 2023; 4:0004. [PMID: 37849672 PMCID: PMC10521661 DOI: 10.34133/bmef.0004] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 11/17/2022] [Indexed: 10/19/2023] Open
Abstract
Craniofacial reconstruction requires robust bone of specified geometry for the repair to be both functional and aesthetic. While native bone from elsewhere in the body can be harvested, shaped, and implanted within a defect, using either an in vitro or in vivo bioreactors eliminates donor site morbidity while increasing the customizability of the generated tissue. In vitro bioreactors utilize cells harvested from the patient, a scaffold, and a device to increase mass transfer of nutrients, oxygen, and waste, allowing for generation of larger viable tissues. In vivo bioreactors utilize the patient's own body as a source of cells and of nutrient transfer and involve the implantation of a scaffold with or without growth factors adjacent to vasculature, followed by the eventual transfer of vascularized, mineralized tissue to the defect site. Several different models of in vitro bioreactors exist, and several different implantation sites have been successfully utilized for in vivo tissue generation and defect repair in humans. In this review, we discuss the specifics of each bioreactor strategy, as well as the advantages and disadvantages of each and the future directions for the engineering of bony tissues for craniofacial defect repair.
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Affiliation(s)
- Emma Watson
- Department of Bioengineering, Rice University, Houston, TX 77030, USA
| | - Antonios G. Mikos
- Department of Bioengineering, Rice University, Houston, TX 77030, USA
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Wen J, Zhao Z, Fang F, Xiao J, Wang L, Cheng J, Wu J, Miao Y. Prussian Blue Nanoparticle-Entrapped GelMA Gels Laden with Mesenchymal Stem Cells as Prospective Biomaterials for Pelvic Floor Tissue Repair. Int J Mol Sci 2023; 24:ijms24032704. [PMID: 36769027 PMCID: PMC9916949 DOI: 10.3390/ijms24032704] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/13/2023] [Accepted: 01/26/2023] [Indexed: 02/04/2023] Open
Abstract
Pelvic organ prolapse (POP) seriously affects elderly patients' quality of life, and new repair materials are urgently needed. To solve this problem, we synthesized methacrylated gelatin (GelMA) hydrogels and incorporated photothermally active Prussian blue nanoparticles (PBNPs) to synthesize PBNP@GelMA. Then, MSCs were encapsulated in the PBNP@GelMA and exposed to a 1.0 W/cm2 of 808 nm laser for 10 min to perform heat shock pretreatment for the implantation of mesenchymal stem cells (MSCs). Next, we tested the repair efficacy of scaffold-cell complexes both in vitro and in vivo. Our results reveal that the heat shock treatment induced by PBNP@GelMA improved the viability of MSCs, and the underlying mechanism may be related to HSP70. Furthermore, 2 weeks after implantation in the SD rat model, the collagen content increased in the MSC implantation group and PBNP@GelMA implantation group. However, the muscle regeneration at the implanting position was mostly enhanced after the implantation of the heat-shock-pretreated MSCs, which illustrates that heat shock treatment can further promote the MSC-mediated muscle regeneration. Therefore, manipulating the cell environment and providing proper heat stimulus by using PBNP@GelMA with NIR is a novel strategy to enhance the regenerative potential of MSCs and to promote pelvic tissue repair.
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Affiliation(s)
- Jirui Wen
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu 610041, China
- Deep Underground Space Medical Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhiwei Zhao
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Fei Fang
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Jingyue Xiao
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Ling Wang
- Deep Underground Space Medical Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Juan Cheng
- Deep Underground Space Medical Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jiang Wu
- Deep Underground Space Medical Center, West China Hospital, Sichuan University, Chengdu 610041, China
- Correspondence: (J.W.); (Y.M.)
| | - Yali Miao
- Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu 610041, China
- Correspondence: (J.W.); (Y.M.)
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50
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Jang HH, Son Y, Park G, Park KS. Bone Marrow-Derived Vasculogenic Mesenchymal Stem Cells Enhance In Vitro Angiogenic Sprouting of Human Umbilical Vein Endothelial Cells. Int J Mol Sci 2022; 24:ijms24010413. [PMID: 36613857 PMCID: PMC9820660 DOI: 10.3390/ijms24010413] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 12/16/2022] [Accepted: 12/21/2022] [Indexed: 12/28/2022] Open
Abstract
Vasculogenic properties of bone marrow-derived mesenchymal stem cells (MSCs) have been reported, but it is still unclear whether the vasculogenic properties are restricted to some populations of MSCs or whether the entire population of MSCs has these properties. We cultured two different populations of MSCs in different culture media and their vasculogenic properties were evaluated using In vitro spheroid sprouting assay. Neither population of MSCs expressed markers of endothelial progenitor cells (EPCs), but they were different in the profiling of angiogenic factor expression as well as vasculogenic properties. One population of MSCs expressed basic fibroblast growth factor (bFGF) and another expressed hepatocyte growth factor (HGF). MSCs expressing HGF exhibited In vitro angiogenic sprouting capacity in response to bFGF derived from other MSCs as well as to their autocrine HGF. The vasculogenic mesenchymal stem cells (vMSCs) derived from the bone marrow also enhanced In vitro angiogenic sprouting capacity of human umbilical vein endothelial cells (HUVECs) in an HGF-dependent manner. These results suggest that MSCs exhibit different vasculogenic properties, and vMSCs that are different from EPCs may contribute to neovascularization and could be a promising cellular therapy for cardiovascular diseases.
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Affiliation(s)
- Hyun Hee Jang
- Graduate School of Biotechnology, Kyung Hee University, Yongin 17104, Republic of Korea
| | - Youngsook Son
- Graduate School of Biotechnology, Kyung Hee University, Yongin 17104, Republic of Korea
| | - Gabee Park
- Graduate School of Biotechnology, Kyung Hee University, Yongin 17104, Republic of Korea
| | - Ki-Sook Park
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
- East-West Medical Research Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Correspondence: ; Tel.: +82-2-958-9368
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