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Karam M, Aqel S, Haider MZ, Fathima A, Charafedine A, Daher MA, Shaito A, El-Sabban M, Saliba J. Beyond the Injury: How Does Smoking Impair Stem Cell-Mediated Repair Mechanisms? A Dual Review of Smoking-Induced Stem Cell Damage and Stem Cell-Based Therapeutic Applications. Stem Cell Rev Rep 2025:10.1007/s12015-025-10886-9. [PMID: 40279029 DOI: 10.1007/s12015-025-10886-9] [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] [Accepted: 04/14/2025] [Indexed: 04/26/2025]
Abstract
While the literature on molecular and clinical effects of smoking on the lungs and other organs has been expansively reviewed, there is no comprehensive compilation of the effects of smoking on stem cell (SC) populations. Recent research has shown that tobacco exposure severely compromises the function of SC populations, particularly those involved in tissue regeneration: mesenchymal SCs (MSCs), neural progenitors, and hematopoietic SCs. SC-based therapies have emerged as a promising approach to counteract smoking-related damage. In particular, MSCs have been extensively studied for their immunomodulatory properties, demonstrating the ability to repair damaged tissues, reduce inflammation, and slow disease progression in conditions such as chronic obstructive pulmonary disease. Combination therapies, which integrate pharmaceuticals with SC treatments, have shown potential in enhancing regenerative outcomes. This review examines the impact of smoking on SC biology, describes the processes impairing SC-mediated repair mechanisms and highlights recent advancements in SC-based therapies in the treatment of smoking-induced diseases. This review has two prongs: (1) it attempts to explain potential smoking-related disease etiology, and (2) it addresses a gap in the literature on SC-mediated repair mechanisms in chronic smokers.
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Affiliation(s)
- Mario Karam
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Department of Translational Cancer Medicine, Faculty of Medicine, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, 00290, Helsinki, Helsinki, Finland
| | - Sarah Aqel
- Medical Research Center, Hamad Medical Corporation, Doha, Qatar
| | - Mohammad Z Haider
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar
| | - Aseela Fathima
- Biomedical Research Center and Department of Biomedical Sciences at College of Health Sciences, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar
| | - Adib Charafedine
- College Of Pharmacy, American University of Iraq-Baghdad, Baghdad, Iraq
| | - Mira Abou Daher
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Department of Public Health, Faculty of Health Sciences, University of Balamand, Sin El Fil, PO Box: 55251, Beirut, Lebanon
| | - Abdullah Shaito
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar
- Biomedical Research Center and Department of Biomedical Sciences at College of Health Sciences, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar
| | - Marwan El-Sabban
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Jessica Saliba
- Department of Public Health, Faculty of Health Sciences, University of Balamand, Sin El Fil, PO Box: 55251, Beirut, Lebanon.
- Department of Biology, Faculty of Science, Lebanese University, Beirut, Lebanon.
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Cong T, Morse KW, Sosa BR, Lane JM, Rodeo SA, Greenblatt MB. Skeletal Stem Cells: A Basis for Orthopaedic Pathology and Tissue Repair. J Bone Joint Surg Am 2025; 107:418-426. [PMID: 39693451 PMCID: PMC11839314 DOI: 10.2106/jbjs.24.00905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2024]
Abstract
➢ Skeletal stem cells (SSCs) continually replenish mature cell populations to support skeletal homeostasis.➢ SSCs repopulate by self-renewal, have multilineage potential, and are long-lived in vivo.➢ SSCs express specific combinations of cell surface markers that reflect their lineage identity.➢ SSCs adapt to their anatomic environment to support regional differences in skeletal behavior and pathology.
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Affiliation(s)
- Ting Cong
- Department of Orthopaedic Surgery, UPMC Sports Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
- Department of Orthopedic Surgery, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania
| | - Kyle W Morse
- Hospital for Special Surgery, New York, NY
- Department of Orthopaedic Surgery, Weill Cornell Medicine, New York, NY
| | - Branden R Sosa
- Hospital for Special Surgery, New York, NY
- Department of Orthopaedic Surgery, Weill Cornell Medicine, New York, NY
| | - Joseph M Lane
- Hospital for Special Surgery, New York, NY
- Department of Orthopaedic Surgery, Weill Cornell Medicine, New York, NY
| | - Scott A Rodeo
- Hospital for Special Surgery, New York, NY
- Department of Orthopaedic Surgery, Weill Cornell Medicine, New York, NY
| | - Matthew B Greenblatt
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
- Research Division, Hospital for Special Surgery, New York, NY
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Zamudio-Cuevas Y, Fernández-Torres J, Aztatzi-Aguilar OG, Martínez-Cabello PR, López-Macay A, Ilizaliturri-Sánchez V, Vargas-Sandoval B, Sánchez-Sánchez R, Martínez-Flores K. Preliminary study on the potential damage of cigarette smoke extract in 3D human chondrocyte culture. In Vitro Cell Dev Biol Anim 2025; 61:214-227. [PMID: 39733182 DOI: 10.1007/s11626-024-00999-9] [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: 09/30/2024] [Accepted: 11/15/2024] [Indexed: 12/30/2024]
Abstract
Osteoarthritis (OA) is a chronic degenerative disease characterized by the progressive loss of articular cartilage. The role of cigarette smoke (CS) in OA is debated, with some studies suggesting a protective effect while others indicate it may pose a risk. Our preliminary findings suggest a link between smoking in young adults and severe knee OA, though the extent of this contribution is unclear. This study investigates the impact of cigarette smoke extract (CSE) on human chondrocytes. Human chondrocyte cultures were exposed to varying concentrations (0-10%) of CSE for 7 d. We evaluated cell viability, extracellular matrix (ECM) components, metalloproteinase expression and cytokines levels, and antioxidant enzymes (SOD1 and CAT) using calcein staining, immunohistochemistry and ELISA. Oxidative stress (OS) was assessed by measuring hydrogen peroxide (H2O2) and nitric oxide (NO) levels. Results were analyzed using ANOVA with Tukey post hoc tests, and Pearson correlation coefficients were calculated. Cell viability decreased at 10% CSE, and ECM components were diminished. MMP9 and MMP13 expression significantly increased at 5% and 10% CSE. H2O2 levels peaked at 1%, while IL-1β peaked at 2.5%. Antioxidant expression (SOD1 and CAT) decreased at higher concentrations, and heat shock protein 70 (HSP70) was notably expressed. MMPs expression was negatively correlated with both viability and ECM components. CSE induces cellular damage, alters ECM composition, and upregulates MMP expression via OS and IL-1β, while diminishing antioxidant defenses. These findings suggest that smoking may disrupt articular cartilage homeostasis, highlighting the need for further investigation into oxidative stress and inflammatory mediators.
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Affiliation(s)
- Yessica Zamudio-Cuevas
- Laboratorio de Líquido Sinovial, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra (INRLGII), Calzada México-Xochimilco No. 289, Col. Arenal de Guadalupe, 14389, Mexico City, Mexico
| | - Javier Fernández-Torres
- Laboratorio de Líquido Sinovial, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra (INRLGII), Calzada México-Xochimilco No. 289, Col. Arenal de Guadalupe, 14389, Mexico City, Mexico
- Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Circuito Exterior S/N, Coyoacán, Ciudad Universitaria, 04510, Mexico City, Mexico
| | - Octavio Gamaliel Aztatzi-Aguilar
- Laboratorio de Toxicología de Contaminantes Atmosféricos y Estrés Oxidativo, CINVESTAV, Av. Instituto Politécnico Nacional No. 2508, Col. San Pedro Zacatenco, 07360, Mexico City, Mexico
| | - Pedro Raymundo Martínez-Cabello
- Laboratorio de Líquido Sinovial, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra (INRLGII), Calzada México-Xochimilco No. 289, Col. Arenal de Guadalupe, 14389, Mexico City, Mexico
- División de CBS, Universidad Autónoma Metropolitana Unidad Iztapalapa (UAM-I), Av. San Rafael Atlixco No. 186, Col. Leyes de Reforma, 09340, Mexico City, Mexico
| | - Ambar López-Macay
- Laboratorio de Líquido Sinovial, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra (INRLGII), Calzada México-Xochimilco No. 289, Col. Arenal de Guadalupe, 14389, Mexico City, Mexico
| | - Victor Ilizaliturri-Sánchez
- División de Reconstrucción Articular Cadera y Rodilla-INRLGII, Calzada México-Xochimilco No. 289, Col. Arenal de Guadalupe, 14389, Mexico City, Mexico
| | - Bertha Vargas-Sandoval
- Laboratorio de Microscopía Electrónica-INRLGII, Calzada México-Xochimilco No. 289, Col. Arenal de Guadalupe, 14389, Mexico City, Mexico
| | - Roberto Sánchez-Sánchez
- Unidad de Ingeniería de Tejidos, Terapia Celular y Medicina Regenerativa. -INRLGII, Calzada México-Xochimilco No. 289, Col. Arenal de Guadalupe, 14389, Mexico City, Mexico
| | - Karina Martínez-Flores
- Laboratorio de Líquido Sinovial, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra (INRLGII), Calzada México-Xochimilco No. 289, Col. Arenal de Guadalupe, 14389, Mexico City, Mexico.
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Salah B, Shahin D, Sarhan M, Al-Karmi J, Al-Kurdi B, Al-Atoom R, Ismail MA, Hammad N, Jafar H, Awidi A, Ababneh NA. Effect of cigarette smoke on the proliferation, viability, gene expression, and cellular functions of adipose-derived mesenchymal stem cells from smoking and non-smoking donors. Biol Open 2024; 13:bio061665. [PMID: 39625294 PMCID: PMC11646114 DOI: 10.1242/bio.061665] [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: 08/04/2024] [Accepted: 10/11/2024] [Indexed: 12/16/2024] Open
Abstract
Cigarette smoking negatively impacts mesenchymal stem cell functionality, including proliferation, viability, and differentiation potential. Adipose-derived mesenchymal stem cells (ADMSCs) are increasingly used for therapeutic purposes, but the specific effects of smoking in vivo on these cells are poorly understood. This study investigates the effects of cigarette smoke on the proliferation, viability, gene expression, and cellular functions of ADMSCs from smoking and non-smoking donors. In this study, ADMSCs were isolated from healthy smokers and non-smokers, and cell proliferation was assessed using the MTT assay, viability with apoptosis assays, mitochondrial membrane potential (MMP), and gene expression related to oxidative stress and cellular functions. Cell cycle analysis was also conducted. Our findings reveal a significant decrease in the proliferation of ADMSCs from smokers. Apoptosis assays showed reduced viable cells in smokers without a significant change in MMP, suggesting alternative pathways contributing to decreased viability. Gene expression analysis indicated the upregulation of genes associated with oxidative stress response and cellular defense mechanisms and the downregulation of genes related to inflammatory signaling, detoxification, and cellular metabolism. Cell cycle analysis indicates cycle arrest or delay in smokers, possibly due to stress and potential DNA damage. Smoking negatively affects ADMSCs' proliferation, viability, and function through oxidative stress and gene expression alterations. These findings highlight the importance of considering smoking status in ADMSC therapies and the need for further research to mitigate the effect of smoking on stem cells.
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Affiliation(s)
- Bareqa Salah
- General Surgery Department/Plastic & Reconstructive, Jordan University Hospital, the University of Jordan, 11942
| | - Diana Shahin
- Cell Therapy Center, the University of Jordan, Amman, Jordan, 11942
| | - Momen Sarhan
- Cell Therapy Center, the University of Jordan, Amman, Jordan, 11942
- School of Medicine, the University of Jordan, Amman, Jordan, 11942
| | - Joud Al-Karmi
- School of Medicine, the University of Jordan, Amman, Jordan, 11942
| | - Ban Al-Kurdi
- Cell Therapy Center, the University of Jordan, Amman, Jordan, 11942
| | - Renata Al-Atoom
- Cell Therapy Center, the University of Jordan, Amman, Jordan, 11942
| | | | - Nouran Hammad
- School of Medicine, Jordan University of Science and Technology, Al-Ramtha, Jordan, 22110
| | - Hanan Jafar
- Cell Therapy Center, the University of Jordan, Amman, Jordan, 11942
| | - Abdalla Awidi
- Cell Therapy Center, the University of Jordan, Amman, Jordan, 11942
- Hemostasis and Thrombosis Laboratory, School of Medicine, the University of Jordan, Amman, Jordan, 11942
- Department of Hematology and Oncology, Jordan University Hospital, Amman, Jordan, 11492
| | - Nidaa A. Ababneh
- Cell Therapy Center, the University of Jordan, Amman, Jordan, 11942
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Iwamae M, Tamai K, Nishino K, Orita K, Kobayashi Y, Terai H, Nakamura H. Does cessation of combustible cigarette and heated tobacco product smoking immediately following a fracture benefit fracture healing? In vivo and in vitro validation. Biochem Biophys Res Commun 2024; 736:150512. [PMID: 39142235 DOI: 10.1016/j.bbrc.2024.150512] [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: 07/20/2024] [Revised: 07/24/2024] [Accepted: 08/05/2024] [Indexed: 08/16/2024]
Abstract
Combustible cigarette and heated tobacco products (HTPs), the two most frequently used tobacco products, negatively affect bone healing. However, whether smoking cessation following fracture benefits bone healing is unclear. Therefore, this study investigated the effect of smoking cessation immediately after surgery on reduced fracture healing induced by smoking. Smoking combustible cigarettes and heated tobacco products generates cigarette smoking extracts (CSE) (extracts from combustible cigarettes [cCSE] and from HTPs [hCSE], respectively). In vivo, CSEs were injected intraperitoneally into rat models for 3 weeks before femoral midshaft osteotomy and fixation. The rats were then divided into CSE continuation and cessation groups postoperatively. Micro-computed tomography (μCT) and biomechanical analyses were performed 6 weeks postoperatively to assess bone union at the fracture site. In vivo study showed μCT assessment also revealed significantly higher cortical bone mineral density (p = 0.013) and content (p = 0.013), and a higher bone union score (p = 0.046) at the fracture site in the cCSE cessation group than in the cCSE continuation group. Biomechanical assessment revealed that elasticity at the fracture site was significantly higher in the cCSE cessation group than in the cCSE continuation group (p = 0.041). These findings provide that smoking cessation, particularly of combustible cigarette, immediately after a fracture accelerates bone fracture healing and increases mechanical strength at the fracture site.
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Affiliation(s)
- Masayoshi Iwamae
- Department of Orthopaedics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Koji Tamai
- Department of Orthopaedics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan.
| | - Kazuya Nishino
- Department of Orthopaedics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Kumi Orita
- Department of Orthopaedics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Yuto Kobayashi
- Department of Orthopaedics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Hidetomi Terai
- Department of Orthopaedics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Hiroaki Nakamura
- Department of Orthopaedics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
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Kawamoto R, Kikuchi A, Ninomiya D, Abe M, Kumagi T. Smoking Status and Premature Death Among Japanese Rural Community-Dwelling Persons. Tob Use Insights 2024; 17:1179173X241275881. [PMID: 39363976 PMCID: PMC11447718 DOI: 10.1177/1179173x241275881] [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: 06/03/2024] [Revised: 07/27/2024] [Accepted: 08/01/2024] [Indexed: 10/05/2024] Open
Abstract
Background: Smoking status is known to be an independent and significant predictor of health outcomes related to aging and plays a crucial role in overall mortality rates. This cohort study investigated the relationship between smoking status and survival outcomes over follow-up periods of 9 and 21 years. Methods: The sample consisted of 3526 participants with a mean age of 64 ± 12 years, 44.1% of whom were male. The median follow-up duration was 6315 days, with an interquartile range of 3441 to 7727 days. Smoking status [i.e., Brinkmann index (BI)] was calculated by multiplying the number of years smoked by the number of cigarettes smoked daily. Based on this, participants were categorized into non-smokers, former smokers, and current smokers. The data were analyzed using Cox regression, employing age as the time variable and accounting for various risk factors. Results: A total of 1111 participants (49.2%) were confirmed to have died. Among these, 564 were male (36.2% of all male participants), and 547 were female (27.8% of all female participants). The multivariate-adjusted odds ratio (95% confidence interval) for all-cause mortality compared with never-smokers was 1.51 (1.17-1.96) for former smokers with BI > 800, 1.61 (1.20-2.17) for current smokers with BI of 400-799 and 1.62 (95% CI, 1.24-2.10) with BI of ≥800 (P for trend <0.001). Participants who died within three years of follow-up were excluded to avoid the possibility of reverse causation, but the results were essentially unchanged. Conclusion: We found that the BI is a valid predictor of future mortality risk and that BI 800 for former smokers and BI 400 for current smokers were useful cutoff values. Efforts to control smoking should focus not only on current smokers but also on former smokers to reduce the risk of premature death associated with smoking.
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Affiliation(s)
- Ryuichi Kawamoto
- Department of Community Medicine, Ehime University Graduate School of Medicine, Toon, Japan
- Department of Internal Medicine, Seiyo Municipal Nomura Hospital, Seiyo, Japan
| | - Asuka Kikuchi
- Department of Community Medicine, Ehime University Graduate School of Medicine, Toon, Japan
- Department of Internal Medicine, Seiyo Municipal Nomura Hospital, Seiyo, Japan
| | - Daisuke Ninomiya
- Department of Community Medicine, Ehime University Graduate School of Medicine, Toon, Japan
- Department of Internal Medicine, Seiyo Municipal Nomura Hospital, Seiyo, Japan
| | - Masanori Abe
- Department of Community Medicine, Ehime University Graduate School of Medicine, Toon, Japan
| | - Teru Kumagi
- Department of Community Medicine, Ehime University Graduate School of Medicine, Toon, Japan
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Xie G, Huang C, Jiang S, Li H, Gao Y, Zhang T, Zhang Q, Pavel V, Rahmati M, Li Y. Smoking and osteoimmunology: Understanding the interplay between bone metabolism and immune homeostasis. J Orthop Translat 2024; 46:33-45. [PMID: 38765605 PMCID: PMC11101877 DOI: 10.1016/j.jot.2024.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 03/07/2024] [Accepted: 04/10/2024] [Indexed: 05/22/2024] Open
Abstract
Smoking continues to pose a global threat to morbidity and mortality in populations. The detrimental impact of smoking on health and disease includes bone destruction and immune disruption in various diseases. Osteoimmunology, which explores the communication between bone metabolism and immune homeostasis, aims to reveal the interaction between the osteoimmune systems in disease development. Smoking impairs the differentiation of mesenchymal stem cells and osteoblasts in bone formation while promoting osteoclast differentiation in bone resorption. Furthermore, smoking stimulates the Th17 response to increase inflammatory and osteoclastogenic cytokines that promote the receptor activator of NF-κB ligand (RANKL) signaling in osteoclasts, thus exacerbating bone destruction in periodontitis and rheumatoid arthritis. The pro-inflammatory role of smoking is also evident in delayed bone fracture healing and osteoarthritis development. The osteoimmunological therapies are promising in treating periodontitis and rheumatoid arthritis, but further research is still required to block the smoking-induced aggravation in these diseases. Translational potential This review summarizes the adverse effect of smoking on mesenchymal stem cells, osteoblasts, and osteoclasts and elucidates the smoking-induced exacerbation of periodontitis, rheumatoid arthritis, bone fracture healing, and osteoarthritis from an osteoimmune perspective. We also propose the therapeutic potential of osteoimmunological therapies for bone destruction aggravated by smoking.
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Affiliation(s)
- Guangyang Xie
- Deparment of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
- Xiangya School of Medicine, Central South University, Changsha 410083, Hunan, China
| | - Cheng Huang
- Department of Orthopeadics, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Shide Jiang
- The Central Hospital of Yongzhou, Yongzhou, 425000, China
| | - Hengzhen Li
- Deparment of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Yihan Gao
- Deparment of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
- Xiangya School of Medicine, Central South University, Changsha 410083, Hunan, China
| | - Tingwei Zhang
- Department of Orthopaedics, Wendeng Zhenggu Hospital of Shandong Province, Weihai, 264400, China
| | - Qidong Zhang
- Department of Orthopeadics, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Volotovski Pavel
- Republican Scientific and Practical Center of Traumatology and Orthopedics, Minsk 220024, Belarus
| | - Masoud Rahmati
- Department of Physical Education and Sport Sciences, Faculty of Literature and Human Sciences, Lorestan University, Khoramabad, Iran
- Department of Physical Education and Sport Sciences, Faculty of Literature and Humanities, Vali-E-Asr University of Rafsanjan, Rafsanjan, Iran
| | - Yusheng Li
- Deparment of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
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Gheisari M, Nosrati S, Zare S, Dara M, Zolghadri S, Razeghian-Jahromi I. The impact of high nicotine concentrations on the viability and cardiac differentiation of mesenchymal stromal cells: a barrier to regenerative therapy for smokers. Front Cell Dev Biol 2024; 12:1323691. [PMID: 38638529 PMCID: PMC11024539 DOI: 10.3389/fcell.2024.1323691] [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: 10/18/2023] [Accepted: 03/20/2024] [Indexed: 04/20/2024] Open
Abstract
Background: Current treatment methods are not successful in restoring the lost cardiomyocytes after injury. Stem cell-based strategies have attracted much attention in this regard. Smoking, as a strong cardiovascular risk factor, not only affects the cardiac cells adversely but also deteriorates the function of stem cells. Since mesenchymal stem cells (MSCs) are one of the popular candidates in cardiovascular disease (CVD) clinical trials, we investigated the impact of nicotine on the regenerative properties (viability and cardiac differentiation) of these cells. Methods: MSCs were isolated from rat bone marrow and characterized based on morphology, differentiation capability, and the expression of specific mesenchymal markers. The MTT assay was used to assess the viability of MSCs after being exposed to different concentrations of nicotine. Based on MTT findings and according to the concentration of nicotine in smokers' blood, the growth curve and population doubling time were investigated for eight consecutive days. Cells were treated with 5-azacytidine (an inducer of cardiac differentiation), and then the expressions of cardiac-specific markers were calculated by qPCR. Results: MSCs were spindle-shaped, capable of differentiating into adipocyte and osteocyte, and expressed CD73 and CD90. The viability of MSCs was reduced upon exposure to nicotine in a concentration- and time-dependent manner. The growth curve showed that nicotine reduced the proliferation of MSCs, and treated cells needed more time to double. In addition, the expressions of GATA4 and troponin were downregulated in nicotine-treated cells on day 3. However, these two cardiac markers were overexpressed on day 7. Conclusion: Nicotine decreased normal growth and reduced the expression of cardiac markers in MSCs. This aspect is of eminent importance to smokers with cardiovascular disease who are candidates for stem cell therapy.
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Affiliation(s)
- Maryam Gheisari
- Department of Biochemistry, Shiraz Branch, Islamic Azad University, Shiraz, Iran
| | - Shadi Nosrati
- Department of Biochemistry, Shiraz Branch, Islamic Azad University, Shiraz, Iran
| | - Shahrokh Zare
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahintaj Dara
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Samaneh Zolghadri
- Department of Biology, Jahrom Branch, Islamic Azad University, Jahrom, Iran
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Heikkinen J, Tanner T, Bergmann U, Palosaari S, Lehenkari P. Cigarette smoke and nicotine effect on human mesenchymal stromal cell wound healing and osteogenic differentiation capacity. Tob Induc Dis 2024; 22:TID-22-54. [PMID: 38496254 PMCID: PMC10943629 DOI: 10.18332/tid/185281] [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: 01/06/2024] [Revised: 02/22/2024] [Accepted: 02/23/2024] [Indexed: 03/19/2024] Open
Abstract
INTRODUCTION Mesenchymal stromal cells (MSCs) play a crucial role in promoting tissue regeneration and healing, particularly in bone tissue. Both smoking and nicotine use are known to delay and inhibit the healing process in patients. This study aims at delineating these cellular effects by comparing the impact of nicotine alone to cigarette smoke with equivalent nicotine content, and shedding light on potential differences in the healing process. METHODS We examined how cigarette smoke and nicotine affect the migration, proliferation, and osteogenic differentiation of human patient-derived MSCs in vitro, as well as the secretion of cytokines IL-6 and IL-8. We measured nicotine concentration of the cigarette smoke extract (CSE) to clarify the role of the nicotine in the effect of the cigarette smoke. RESULTS MSCs exposed to nicotine-concentration-standardized CSE exhibited impaired wound healing capability, and at high concentrations, increased cell death. At lower concentrations, CSE dose-dependently impaired migration, proliferation, and osteogenic differentiation, and increased IL-8 secretion. Nicotine impaired proliferation and decreased PINP secretion. While there was a trend for elevated IL-6 levels by nicotine in undifferentiated MSCs, these changes were not statistically significant. Exposure of MSCs to equivalent concentrations of nicotine consistently elicited stronger responses by CSE and had a more pronounced effect on all studied parameters. Our results suggest that the direct effect of cigarette smoke on MSCs contributes to impaired MSC function, that adds to the nicotine effects. CONCLUSIONS Cigarette smoke extract reduced the migration, proliferation, and osteogenic differentiation in MSCs in vitro, while nicotine alone reduced proliferation. Cigarette smoke impairs the osteogenic and regenerative ability of MSCs in a direct cytotoxic manner. Cytotoxic effect of nicotine alone impairs regenerative ability of MSCs, but it only partly explains cytotoxic effects of cigarette smoke. Direct effect of cigarette smoke, and partly nicotine, on MSCs could contribute to the smoking-related negative impact on long-term bone health, especially in bone healing.
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Affiliation(s)
- Janne Heikkinen
- Research Unit of Translational Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland
| | - Tarja Tanner
- Research Unit of Oral Health Sciences, University of Oulu, Oulu, Finland
- Dental Training Clinic, Oulu, Finland
| | - Ulrich Bergmann
- Proteomics and Protein Analysis, Biocenter Oulu, University of Oulu, Oulu, Finland
| | - Sanna Palosaari
- Research Unit of Translational Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland
- Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Petri Lehenkari
- Research Unit of Translational Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland
- Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
- Division of Orthopedic Surgery, Oulu University Hospital, Oulu, Finland
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Upadhyaya P, Milillo C, Bruno A, Anaclerio F, Buccolini C, Dell’Elice A, Angilletta I, Gatta M, Ballerini P, Antonucci I. Nicotine-induced Genetic and Epigenetic Modifications in Primary Human Amniotic Fluid Stem Cells. Curr Pharm Des 2024; 30:1995-2006. [PMID: 38867535 PMCID: PMC11348467 DOI: 10.2174/0113816128305232240607084420] [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: 11/08/2024] [Revised: 04/29/2024] [Accepted: 05/08/2024] [Indexed: 06/14/2024]
Abstract
BACKGROUND Smoking during pregnancy has been linked to adverse health outcomes in offspring, but the underlying mechanisms are not fully understood. To date, the effect of maternal smoking has been tested in primary tissues and animal models, but the scarcity of human tissues limits experimental studies. Evidence regarding smoking-related molecular alteration and gene expression profiles in stem cells is still lacking. METHODS We developed a cell culture model of human amniotic fluid stem cells (hAFSCs) of nicotine (NIC) exposure to examine the impact of maternal smoking on epigenetic alterations of the fetus. RESULTS NIC 0.1 μM (equivalent to "light" smoking, i.e., 5 cigarettes/day) did not significantly affect cell viability; however, significant alterations in DNA methylation and N6-methyladenosine (m6A) RNA methylation in hAFSCs occurred. These epigenetic changes may influence the gene expression and function of hAFSCs. Furthermore, NIC exposure caused time-dependent alterations of the expression of pluripotency genes and cell surface markers, suggesting enhanced cell stemness and impaired differentiation potential. Furthermore, NICtreated cells showed reduced mRNA levels of key adipogenic markers and hypomethylation of the promoter region of the imprinted gene H19 during adipogenic differentiation, potentially suppressing adipo/lipogenesis. Differential expression of 16 miRNAs, with predicted target genes involved in various metabolic pathways and linked to pathological conditions, including cognitive delay and fetal growth retardation, has been detected. CONCLUSION Our findings highlight multi-level effects of NIC on hAFSCs, including epigenetic modifications, altered gene expression, and impaired cellular differentiation, which may contribute to long-term consequences of smoking in pregnancy and its potential impact on offspring health and development.
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Affiliation(s)
- Prabin Upadhyaya
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
| | - Cristina Milillo
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
- Department of Psychological, Health and Territorial Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
| | - Annalisa Bruno
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
- Department of Innovative Technologies in Medicine & Dentistry, “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
| | - Federico Anaclerio
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
- Department of Psychological, Health and Territorial Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
| | - Carlotta Buccolini
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
- Department of Psychological, Health and Territorial Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
| | - Anastasia Dell’Elice
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
- Department of Psychological, Health and Territorial Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
| | - Ilaria Angilletta
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
- Department of Psychological, Health and Territorial Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
| | - Marco Gatta
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
- Department of Innovative Technologies in Medicine & Dentistry, “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
| | - Patrizia Ballerini
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
- Department of Innovative Technologies in Medicine & Dentistry, “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
| | - Ivana Antonucci
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
- Department of Psychological, Health and Territorial Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
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11
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Ye S, Si W, Qin W, Yang L, Luo Z, Li Z, Xie Y, Pan H, Li X, Huang Z, Zhu M, Chen D. Atractylodes lancea volatile oils target ADAR2-miR-181a-5p signaling to mesenchymal stem cell chondrogenic differentiation. Anat Rec (Hoboken) 2023; 306:3006-3020. [PMID: 35446511 DOI: 10.1002/ar.24930] [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: 09/20/2021] [Revised: 02/17/2022] [Accepted: 03/20/2022] [Indexed: 11/07/2022]
Abstract
Atractylodeslancea Rhizoma (Rhizoma atractylodis [RA]) has long been recommended for the treatment of arthritis in traditional Chinese medicine, but its mechanism of action is still unclear. RA contains a large amount of Atractylodes lancea volatile oils (Atr). In this study, we investigated whether Atr can promote mesenchymal stem cells (MSCs) chondrogenic differentiation. The Atr were extracted from RA by steam distillation method, and the effect of Atr on MSCs was detected by the CCK8 assay. The optimal concentration of Atr for MSCs cultivation was 3 μg/ml. The differentially expressed miR-181a-5p was screened by miRNA microarray assay, and its mimics and inhibitors were transfected into MSCs. It was found that the inhibitor of miR-181a-5p could upregulate cartilage-specific genes such as SOX9, COL2A1, and ACAN. Meanwhile, we also found that the expression of gene editing enzyme ADAR2 was significantly increased in the chondrogenic differentiation of MSCs induced by Atr, and the bases of precursor sequence of miR-181a-5p were changed from A to G. After ADAR2 deletion, the expression of cartilage-specific genes was significantly down-regulated and the precursor sequence bases of miR-181a-5p were not changed. Bioinformatics analysis revealed that the predicted target gene of miR-181a-5p was yingyang1 (YY1), and the targeting relationship was verified by dual-luciferase reporter assay. After deleting YY1, the expression of cartilage-specific genes was significantly down-regulated. In conclusion, our study demonstrated that Atr can promote chondrogenic differentiation of MSC through regulation of the ADAR2-miR-181a-5p signaling pathway. This may provide a new insight into the possible mechanism of traditional Chinese medicine (Atr) in treating inflammatory joint diseases.
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Affiliation(s)
- Shanyu Ye
- Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
- Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Wenwen Si
- Shenzhen BaoAn Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Wei Qin
- Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lin Yang
- Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ziwei Luo
- Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhen Li
- Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yulu Xie
- School of Chinese Herbal Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hao Pan
- Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xinrong Li
- Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Zifeng Huang
- Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Meiling Zhu
- Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Dongfeng Chen
- Department of Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
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12
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Pavlovic D, Miloradovic D, Stojanovic MD, Harrell CR, Polosa R, Rust S, Volti GL, Caruso M, Jakovljevic V, Djonov V, Volarevic V. Cigarette smoke attenuates mesenchymal stem cell-based suppression of immune cell-driven acute liver failure. Toxicol Lett 2023; 385:12-20. [PMID: 37572970 DOI: 10.1016/j.toxlet.2023.08.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 07/22/2023] [Accepted: 08/09/2023] [Indexed: 08/14/2023]
Abstract
Detrimental effects of smoking on mesenchymal stem cell (MSC)-dependent immunosuppression and hepatoprotection are unknown. Herewith, by using α-galactosylceramide (α-GalCer)-induced liver injury, a well-established murine model of fulminant hepatitis, we examined molecular mechanisms which were responsible for negative effects of cigarette smoke on MSC-dependent immunomodulation. MSC which were grown in cigarette smoke-exposed medium (MSCWS-CM) obtained pro-inflammatory phenotype, were not able to optimally produce hepatoprotective and immunosuppressive cytokines (TGF-β, HGF, IL-10, NO, KYN), and secreted significantly higher amounts of inflammatory cytokines (IFN-γ, TNF-α, IL-17, IL-6) than MSC that were cultured in standard medium never exposed to cigarette smoke (MSCCM). In contrast to MSCCM, which efficiently attenuated α-GalCer-induced hepatitis, MSCWS-CM were not able to prevent hepatocyte injury and liver inflammation. MSCWS-CM had reduced capacity for the suppression of liver-infiltrated inflammatory macrophages, dendritic cells (DCs) and lymphocytes. Although significantly lower number of IL-12-producing macrophages and DCs, TNF-α, IFN-γ or IL-17-producing CD4 + and CD8 +T lymphocytes, NK and NKT cells were noticed in the livers of α-GalCer+MSCCM-treated mice compared to α-GalCer+saline-treated animals, this phenomenon was not observed in α-GalCer-injured mice that received MSCWS-CM. MSCWS-CM could not induce expansion of anti-inflammatory IL-10-producing FoxP3 +CD4 + and CD8 + T regulatory cells and were not able to create immunosuppressive microenvironment in the liver as MSCCM. Similarly as it was observed in mice, MSCWS-CM were not able to optimally inhibit production of inflammatory and hepatototoxic cytokines in activated human Th1/Th17 and NKT1/NKT17 cells, confirming the hypothesis that cigarette smoke significantly attenuates therapeutic potential of MSC in cell-based immunotherapy of inflammatory liver diseases.
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Affiliation(s)
- Dragica Pavlovic
- Department of Genetics, Center for harm reduction of biological and chemical hazards, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia
| | - Dragana Miloradovic
- Department of Genetics, Center for harm reduction of biological and chemical hazards, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia
| | - Milica Dimitrijevic Stojanovic
- Department of Pathology, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia
| | - Carl Randall Harrell
- Regenerative Processing Plant, LLC, 34176 US Highway 19 N Palm Harbor, Palm Harbor, FL 34684, USA
| | - Riccardo Polosa
- Center of Excellence for the Acceleration of Harm Reduction (CoEHAR), University of Catania, Via S. Sofia, 89, 95123 Catania, Italy; Department of Clinical and Experimental Medicine, University of Catania, Via S. Sofia, 89, 95123 Catania, Italy
| | - Sonja Rust
- ECLAT Srl, University of Catania, Via S. Sofia, 89, 95123 Catania, Italy
| | - Giovanni Li Volti
- Center of Excellence for the Acceleration of Harm Reduction (CoEHAR), University of Catania, Via S. Sofia, 89, 95123 Catania, Italy; Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia, 89, 95123 Catania, Italy
| | - Massimo Caruso
- Center of Excellence for the Acceleration of Harm Reduction (CoEHAR), University of Catania, Via S. Sofia, 89, 95123 Catania, Italy; Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia, 89, 95123 Catania, Italy
| | - Vladimir Jakovljevic
- Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia
| | - Valentin Djonov
- Institute of Anatomy, University of Bern, Baltzerstrasse 2, 3012 Bern, Switzerland
| | - Vladislav Volarevic
- Department of Genetics, Center for harm reduction of biological and chemical hazards, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, 34000 Kragujevac, Serbia; Departments of Genetics and Department of Microbiology and Immunology, Center for harm reduction of biological and chemical hazards, Faculty of Medical Sciences University of Kragujevac, Serbia.
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13
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Hardin LT, Vang D, Thor D, Han X, Mashkoor F, Alpagot T, Ojcius DM, Xiao N. Cigarette smoking exposure disrupts the regenerative potential of dental pulp stem cells. Tob Induc Dis 2023; 21:101. [PMID: 37533959 PMCID: PMC10392041 DOI: 10.18332/tid/168125] [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: 01/31/2023] [Revised: 04/04/2023] [Accepted: 06/12/2023] [Indexed: 08/04/2023] Open
Abstract
INTRODUCTION Smoking is known to alter the regenerative and immunomodulatory properties of many types of mesenchymal stem cells (MSCs). This study investigates the impact of cigarette smoke exposure on the regenerative potential of dental pulp stem cells (DPSCs). METHODS DPSCs were treated with various doses of cigarette smoke condensate (CSC) or nicotine. Cell proliferation and survival were evaluated by a water-soluble tetrazolium salt (WST-1) and a survival assay. DPSC migration, cytokine expression, mutagenesis, and the signaling pathway were also measured during CSC and nicotine treatment. RESULTS Low concentrations of CSC and nicotine did not impair cell proliferation, but higher concentrations reduced cell proliferation. CSC and nicotine could impede DPSC survival and migration in a dose-dependent manner. In addition, the cytokine secretion expression profile was altered with CSC or nicotine treatments. In particular, secretion of IL-6, TNF-α, and IL-10 significantly increased, while TGF-β1 levels showed different patterns after exposure to CSC or nicotine, as shown by ELISA and quantitative PCR. Nicotine treatment increased AKT (also known as protein kinase B) and extracellular signal-regulated kinase (ERK) phosphorylation. Finally, CSC induced higher levels of mutagenicity than nicotine, as shown by the Ames test. CONCLUSIONS These findings suggest that cigarette smoke exposure alters the regenerative abilities of DPSCs in various ways. Future studies are warranted to further characterize the underlying molecular mechanisms of smoking-mediated damage to DPSCs, which will guide the personalized stem cell treatment plan for smoking patients.
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Affiliation(s)
- Leyla Tahrani Hardin
- Department of Biomedical Sciences, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, United States
| | - David Vang
- Department of Biomedical Sciences, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, United States
| | - Der Thor
- Department of Biomedical Sciences, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, United States
| | - Xiaoyuan Han
- Department of Biomedical Sciences, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, United States
| | - Fatima Mashkoor
- Department of Oral and Maxillofacial Surgery, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, United States
| | - Tamer Alpagot
- Department of Periodontics, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, United States
| | - David M. Ojcius
- Department of Biomedical Sciences, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, United States
| | - Nan Xiao
- Department of Biomedical Sciences, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, United States
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14
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Helsper S, Yuan X, Bagdasarian FA, Athey J, Li Y, Borlongan CV, Grant SC. Multinuclear MRI Reveals Early Efficacy of Stem Cell Therapy in Stroke. Transl Stroke Res 2023; 14:545-561. [PMID: 35900719 PMCID: PMC10733402 DOI: 10.1007/s12975-022-01057-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 04/28/2022] [Accepted: 06/16/2022] [Indexed: 10/16/2022]
Abstract
Compromised adult human mesenchymal stem cells (hMSC) can impair cell therapy efficacy and further reverse ischemic recovery. However, in vitro assays require extended passage to characterize cells, limiting rapid assessment for therapeutic potency. Multinuclear magnetic resonance imaging and spectroscopy (MRI/S) provides near real-time feedback on disease progression and tissue recovery. Applied to ischemic stroke, 23Na MRI evaluates treatment efficacy within 24 h after middle cerebral artery occlusion, showing recovery of sodium homeostasis and lesion reduction in specimens treated with hMSC while 1H MRS identifies reduction in lactate levels. This combined metric was confirmed by evaluating treatment groups receiving healthy or compromised hMSC versus vehicle (sham saline injection) over 21 days. Behavioral tests to assess functional recovery and cell analysis for immunomodulatory and macrophage activity to detect hMSC potency confirm MR findings. Clinically, these MR metrics may prove critical to early evaluations of therapeutic efficacy and overall stroke recovery.
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Affiliation(s)
- Shannon Helsper
- The National High Magnetic Field Laboratory, Florida State University, 1800 E. Paul Dirac Dr, Tallahassee, FL, 32310, USA
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, 32310, USA
| | - Xuegang Yuan
- The National High Magnetic Field Laboratory, Florida State University, 1800 E. Paul Dirac Dr, Tallahassee, FL, 32310, USA
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, 32310, USA
| | - F Andrew Bagdasarian
- The National High Magnetic Field Laboratory, Florida State University, 1800 E. Paul Dirac Dr, Tallahassee, FL, 32310, USA
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, 32310, USA
| | - Jacob Athey
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, 32310, USA
| | - Yan Li
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, 32310, USA
| | - Cesario V Borlongan
- Center of Excellence for Aging & Brain Repair, University of South Florida, Tampa, FL, 33612, USA
| | - Samuel C Grant
- The National High Magnetic Field Laboratory, Florida State University, 1800 E. Paul Dirac Dr, Tallahassee, FL, 32310, USA.
- Department of Chemical and Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, 32310, USA.
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15
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Gao J, Liang Y, Chen J, Shen H, Liu H. CXCR4 enhances the inhibitory effects of bone mesenchymal stem cells on lung cell apoptosis in a rat model of smoking-induced COPD. Apoptosis 2023; 28:639-652. [PMID: 36719470 PMCID: PMC9888343 DOI: 10.1007/s10495-022-01800-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/04/2022] [Indexed: 02/01/2023]
Abstract
Chronic obstructive pulmonary disease is the 3rd leading cause of death worldwide, and the available treatments are unsatisfactory, resulting in a major economic burden. As cellular therapy is commonly used for lung disease, we investigated a treatment with CXCR4-overexpressing BMSCs in a COPD model. We extracted and purified Bone marrow mesenchymal stem cells (BMSCs) from SD rats. COPD apoptosis model was established by cigarette smoke exposure. BMSCs (1 × 106 cells per injection)were transplanted in vivo twice a month during model establishment, and alveolar rupture in the lung was assessed. Lung cell apoptosis was assessed by terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) analysis, and the concentrations of apoptotic proteins in the lungs were detected by Western blotting. We successfully isolated BMSCs and established CXCR4-overexpressing BMSCs. qRT‒PCR and Western blotting detection both reveal that CXCR4 mRNA level and protein both significantly higher expression in CXCR4-BMSCs than the pBABE-BMSCs. Continuous cigarette smoke exposure caused alveolar septal rupture: In the model group, the alveolar mean linear intercept in the first month was significantly lower than that in the third month (p < 0.05). In the third month, the alveolar mean linear intercept values of the control and CXCR4-BMSC groups were lower than those of the model group (control group p < 0.01, CXCR4-BMSC group p < 0.05), and TUNEL staining revealed that the apoptosis rates of the control and CXCR4-BMSC groups were significantly lower than those of the model group (p < 0.01). Furthermore, the levels of the apoptotic proteins cleaved caspase-8, cleaved caspase-3 and cleaved PARP-1 were higher in the model group than in the control group (p < 0.05) and significantly lower in the CXCR4-BMSC group than in the model group (p < 0.05). The transplantation of CXCR4-overexpressing BMSCs during COPD model generation significantly inhibited apoptosis via the extrinsic apoptosis pathway. CXCR4 enhances the inhibitory effects of bone mesenchymal stem cells on lung cell apoptosis in a rat model of smoking-induced COPD.
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Affiliation(s)
- Jiansheng Gao
- First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Yuli Liang
- First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Jiabao Chen
- First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Huihui Shen
- First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Hua Liu
- First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China.
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16
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Boronat-Toscano A, Vañó I, Monfort-Ferré D, Menacho M, Valldosera G, Caro A, Espina B, Mañas MJ, Marti M, Espin E, Saera-Vila A, Serena C. Smoking Suppresses the Therapeutic Potential of Adipose Stem Cells in Crohn’s Disease Patients through Epigenetic Changes. Cells 2023; 12:cells12071021. [PMID: 37048094 PMCID: PMC10093550 DOI: 10.3390/cells12071021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/21/2023] [Accepted: 03/25/2023] [Indexed: 03/29/2023] Open
Abstract
Patients with Crohn’s disease (CD) who smoke are known to have a worse prognosis than never-smokers and a higher risk for post-surgical recurrence, whereas patients who quit smoking after surgery have significantly lower post-operative recurrence. The hypothesis was that smoking induces epigenetic changes that impair the capacity of adipose stem cells (ASCs) to suppress the immune system. It was also questioned whether this impairment remains in ex-smokers with CD. ASCs were isolated from non-smokers, smokers and ex-smokers with CD and their interactions with immune cells were studied. The ASCs from both smokers and ex-smokers promoted macrophage polarization to an M1 pro-inflammatory phenotype, were not able to inhibit T- and B-cell proliferation in vitro and enhanced the gene and protein expression of inflammatory markers including interleukin-1b. Genome-wide epigenetic analysis using two different bioinformatic approaches revealed significant changes in the methylation patterns of genes that are critical for wound healing, immune and metabolic response and p53-mediated DNA damage response in ASCs from smokers and ex-smokers with CD. In conclusion, cigarette smoking induces a pro-inflammatory epigenetic signature in ASCs that likely compromises their therapeutic potential.
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17
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Río C, Jahn AK, Martin-Medina A, Calvo Bota AM, De Francisco Casado MT, Pont Antona PJ, Gigirey Castro O, Carvajal ÁF, Villena Portella C, Gómez Bellvert C, Iglesias A, Calvo Benito J, Gayà Puig A, Ortiz LA, Sala-Llinàs E. Mesenchymal Stem Cells from COPD Patients Are Capable of Restoring Elastase-Induced Emphysema in a Murine Experimental Model. Int J Mol Sci 2023; 24:ijms24065813. [PMID: 36982887 PMCID: PMC10054868 DOI: 10.3390/ijms24065813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/15/2023] [Accepted: 03/17/2023] [Indexed: 03/22/2023] Open
Abstract
COPD is a chronic lung disease that affects millions of people, declining their lung function and impairing their life quality. Despite years of research and drug approvals, we are still not capable of halting progression or restoring normal lung function. Mesenchymal stem cells (MSC) are cells with extraordinary repair capacity, and MSC-based therapy brings future hope for COPD treatment, although the best source and route of administration are unclear. MSC from adipose tissue (AD-MSC) represents an option for autologous treatment; however, they could be less effective than donor MSC. We compared in vitro behavior of AD-MSC from COPD and non-COPD individuals by migration/proliferation assay, and tested their therapeutic potential in an elastase mouse model. In addition, we tested intravenous versus intratracheal routes, inoculating umbilical cord (UC) MSC and analyzed molecular changes by protein array. Although COPD AD-MSC have impaired migratory response to VEGF and cigarette smoke, they were as efficient as non-COPD in reducing elastase-induced lung emphysema. UC-MSC reduced lung emphysema regardless of the administration route and modified the inflammatory profile in elastase-treated mice. Our data demonstrate equal therapeutic potential of AD-MSC from COPD and non-COPD subjects in the pre-clinical model, thus supporting their autologous use in disease.
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Affiliation(s)
- Carlos Río
- Inflammation, Repair and Cancer of Respiratory Diseases (i-Respire), Fundació Institut d’ Investigació Sanitària Illes Balears (IdISBa), 07120 Palma, Spain
| | - Andreas K. Jahn
- Inflammation, Repair and Cancer of Respiratory Diseases (i-Respire), Fundació Institut d’ Investigació Sanitària Illes Balears (IdISBa), 07120 Palma, Spain
| | - Aina Martin-Medina
- Inflammation, Repair and Cancer of Respiratory Diseases (i-Respire), Fundació Institut d’ Investigació Sanitària Illes Balears (IdISBa), 07120 Palma, Spain
| | - Alba Marina Calvo Bota
- Inflammation, Repair and Cancer of Respiratory Diseases (i-Respire), Fundació Institut d’ Investigació Sanitària Illes Balears (IdISBa), 07120 Palma, Spain
| | | | - Pere Joan Pont Antona
- Estabulary, Scientific-Technical Services, Universitat de les Illes Balears (UIB), 07122 Palma, Spain
| | | | | | - Cristina Villena Portella
- Inflammation, Repair and Cancer of Respiratory Diseases (i-Respire), Fundació Institut d’ Investigació Sanitària Illes Balears (IdISBa), 07120 Palma, Spain
- CIBERES Pulmonary Biobank Consortium, Hospital Universitari Son Espases, 07120 Palma, Spain
| | | | - Amanda Iglesias
- Inflammation, Repair and Cancer of Respiratory Diseases (i-Respire), Fundació Institut d’ Investigació Sanitària Illes Balears (IdISBa), 07120 Palma, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Javier Calvo Benito
- Banc de Teixits, Blood and Tissue Bank of the Balearic Islands (FBSTIB), 07120 Palma, Spain
- Cell Therapy and Tissue Engineering Group (TERCIT), Institut d’ Investigació Sanitària Illes Balears (IdISBa), 07004 Palma, Spain
| | - Antoni Gayà Puig
- Banc de Teixits, Blood and Tissue Bank of the Balearic Islands (FBSTIB), 07120 Palma, Spain
- Cell Therapy and Tissue Engineering Group (TERCIT), Institut d’ Investigació Sanitària Illes Balears (IdISBa), 07004 Palma, Spain
| | - Luis A. Ortiz
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Ernest Sala-Llinàs
- Inflammation, Repair and Cancer of Respiratory Diseases (i-Respire), Fundació Institut d’ Investigació Sanitària Illes Balears (IdISBa), 07120 Palma, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Department of Pulmonary Medicine, Hospital Universitari Son Espases, 07120 Palma, Spain
- Correspondence: ; Tel.: +34-871-206-507
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18
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Park SR, Kim SK, Kim SR, Yu WJ, Lee SJ, Lee HY. Effects of smoking on the tissue regeneration-associated functions of human endometrial stem cells via a novel target gene SERPINB2. Stem Cell Res Ther 2022; 13:404. [PMID: 35932085 PMCID: PMC9356492 DOI: 10.1186/s13287-022-03061-1] [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: 03/23/2022] [Accepted: 07/19/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Smokers directly inhale mainstream cigarette smoke, which contains numerous known and potential toxic substances, and thus, smoking is expected to have broad harmful effects that cause tissue injury and dysfunction. Interestingly, many studies have suggested that the recent decline in female fertility and increased rate of spontaneous abortion could be associated with increased smoking rates. Indeed, women that smoked for 10 years or more were reported to have a ~ 20% higher infertility rate than women that had never smoked. However, the reasons for the underlying harmful aspects of smoking on female fertility remain a matter of debate. Importantly, a previous study revealed that resident endometrial stem cell deficiency significantly limits the cyclic regeneration potential of endometrium, which, in turn, decreases successful pregnancy outcomes. In this context, we postulated that exposure to mainstream cigarette smoke extracts might decrease female fertility by inhibiting the functions of resident endometrial stem cells. METHODS We investigated whether cigarette mainstream smoke exposure directly inhibits various tissue regeneration-associated functions of endometrial stem cells, such as self-renewal, migration, pluripotency, and differentiation capacity in vitro. Next, we determined whether SERPINB2 mediates cigarette smoke-induced suppressive effects on various tissue regeneration-associated functions by depleting SERPINB2 expression with specific shRNA targeting SERPINB2. Mice were injected intraperitoneally with low (0.5 mg/kg) or high (1 mg/kg) doses of cigarette smoke extract (10 times for two weeks), and endometrial stem cells were then isolated from mice uterine tissues. RESULTS We found that exposure to cigarette smoke extracts remarkably suppressed various tissue regeneration-associated functions of endometrial stem cells, such as self-renewal, migration, multilineage differentiation ability, and pluripotency in vitro and in vivo by activating the SERPINB2 gene. Indeed, cigarette smoke-induced inhibitory effects on various endometrial stem cell functions were significantly abolished by SERPINB2 knockdown. CONCLUSIONS These findings provide valuable information on the harmful effects of cigarette smoking on resident endometrial stem cells and hopefully will facilitate the developments of promising therapeutic strategies for subfertile or infertile women that smoke cigarettes.
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Affiliation(s)
- Se-Ra Park
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Republic of Korea.,Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, 406-840, Republic of Korea
| | - Seong-Kwan Kim
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Republic of Korea.,Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, 406-840, Republic of Korea
| | - Soo-Rim Kim
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Republic of Korea.,Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, 406-840, Republic of Korea
| | - Wook-Joon Yu
- Developmental and Reproductivoxicology Research Group, Korea Institute of Toxicology, Deajeon, 34114, Republic of Korea
| | - Seung-Jin Lee
- Developmental and Reproductivoxicology Research Group, Korea Institute of Toxicology, Deajeon, 34114, Republic of Korea
| | - Hwa-Yong Lee
- Division of Science Education, Kangwon National University, Chuncheon, 24341, Republic of Korea.
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19
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Nishino K, Tamai K, Orita K, Hashimoto Y, Nakamura H. Heated Tobacco Products Impair Cell Viability, Osteoblastic Differentiation, and Bone Fracture-Healing. J Bone Joint Surg Am 2021; 103:2024-2031. [PMID: 34730563 DOI: 10.2106/jbjs.20.02227] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND The negative impact of cigarette smoking on bone union has been well documented. However, the impact of heated tobacco product (HTP) use on bone fracture-healing remains unclear. The present study investigated the effect of HTPs on preosteoblast viability, osteoblastic differentiation, and fracture-healing and compared the effects with those of conventional combustible cigarettes. METHODS Cigarette smoke extracts (CSEs) were generated from combustible cigarettes (cCSE) and HTPs (hCSE). CSE concentrations were standardized by assessing optical density. Preosteoblast (MC3T3-E1) cells were incubated with normal medium, cCSE, or hCSE. The cell viability was assessed via MTT assay. After osteoblastic differentiation of CSE-exposed cells, alkaline phosphatase (ALP) activity was assessed. To assess the in vivo effects of CSEs, a femoral midshaft osteotomy was performed in a rat model; thereafter, saline solution, cCSE, or hCSE was injected intraperitoneally, and bone union was assessed on the basis of micro-computed tomography (μCT) and biomechanical analysis 4 weeks later. RESULTS MC3T3-E1 cell viability was reduced in a time and concentration-dependent manner when treated with either cCSE or hCSE. ALP activity after osteoblastic differentiation of cCSE-treated cells was significantly lower than that of both untreated and hCSE-treated cells (mean and standard deviation, 452.4 ± 48.8 [untreated], 326.2 ± 26.2 [cCSE-treated], and 389.9 ± 26.6 [hCSE-treated] mol/L/min; p = 0.002). Moreover, the levels of osteoblastic differentiation in untreated and hCSE-treated cells differed significantly (p < 0.05). In vivo assessment of the femoral midshaft cortical region revealed that both cCSE and hCSE administration significantly decreased bone mineral content 4 weeks after surgery compared with levels observed in untreated animals (107.0 ± 11.9 [untreated], 94.5 ± 13.0 [cCSE-treated], and 89.0 ± 10.1 mg/cm3 [hCSE-treated]; p = 0.049). Additionally, cCSE and hCSE-exposed femora had significantly lower bone volumes than unexposed femora. Biomechanical analyses showed that both cCSE and hCSE administration significantly decreased femoral maximum load and elastic modulus (p = 0.015 and 0.019). CONCLUSIONS HTP use impairs cell viability, osteoblastic differentiation, and bone fracture-healing at levels comparable with those associated with combustible cigarette use. CLINICAL RELEVANCE HTP use negatively affects bone fracture-healing to a degree similar to that of combustible cigarettes. Orthopaedic surgeons should recommend HTP smoking cessation to improve bone union.
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Affiliation(s)
- Kazuya Nishino
- Department of Orthopedics, Osaka City University Graduate School of Medicine, Osaka, Japan
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20
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Kükrek H, Aitzetmüller M, Vodiškar M, Moog P, Machens HG, Duscher D. Erythropoetin can partially restore cigarette smoke induced effects on Adipose derived Stem Cells. Clin Hemorheol Microcirc 2021; 77:27-36. [PMID: 32651309 DOI: 10.3233/ch-200852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
INTRODUCTION Adipose derived Stem Cells (ASCs) have been proven to play a key role in tissue regeneration. However, exposure to large amounts of cigarette smoke can drastically diminish their function. Erythropoetin (EPO), can modulate cellular response to injury. Therefore, we investigated the ability of EPO to restore the regenerative function and differentiation capacity of ASCs. MATERIAL AND METHODS Human ASCs were isolated from abdominoplasty samples using standard isolation procedures. Cell identity was established by means of Fluorescence Activated Cell Scanning. Subsequently, isolated ASCs were cultivated with cigarette smoke extract both with and without EPO. Parameters investigated included cellular metabolic activity, adipogenic and osteogenic differentiation capacity, and in vitro wound closure capacity. For further enhancing wound closure, EPO was combined with Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) or Stromal Derived Factor-1 alpha (SDF-1 a). RESULTS Cigarette smoke reduces adipogenic differentiation, the osteogenic differentiation capacity as well as the in vitro wound healing ability of human derived ASCs. EPO did not change metabolic activity of ASCs significantly. The addition of EPO could partially restore their function. The combination of EPO with GM-CSF or SDF-1 did not result in a synergistic effect regarding wound healing ability. CONCLUSION Exposure to cigarette smoke significantly reduced the regenerative potential of ASCs. Treatment of ASCs exposed to cigarette smoke with EPO has the potential to partially restore their function.
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Affiliation(s)
- Haydar Kükrek
- Department for Plastic and Hand Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Matthias Aitzetmüller
- Department for Plastic and Hand Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Mateja Vodiškar
- Department for Plastic and Hand Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Philipp Moog
- Department for Plastic and Hand Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Hans-Günther Machens
- Department for Plastic and Hand Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Dominik Duscher
- Department for Plastic and Hand Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
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21
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Nguyen B, Alpagot T, Oh H, Ojcius D, Xiao N. Comparison of the effect of cigarette smoke on mesenchymal stem cells and dental stem cells. Am J Physiol Cell Physiol 2021; 320:C175-C181. [PMID: 33175571 DOI: 10.1152/ajpcell.00217.2020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The persistent prevalence of cigarette smoking continues to contribute to preventable disease and death in the United States. Although much is known about the deleterious systemic effects of cigarette smoke and nicotine, some clinically relevant areas, such as the impact of cigarette smoke and nicotine on stem cells and the subsequent implications in regenerative medicine, still remain unclear. This review focuses on recent studies on the effect of cigarette smoke and one of its deleterious components, nicotine, on mesenchymal stem cells, with an emphasis on dental stem cells.
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Affiliation(s)
- Brandon Nguyen
- Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, California
| | - Tamer Alpagot
- Department of Periodontics, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, California
| | - Heesoo Oh
- Department of Orthodontics, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, California
| | - David Ojcius
- Department of Biomedical Sciences, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, California
| | - Nan Xiao
- Department of Biomedical Sciences, Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, California
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Abstract
Buerger’s disease or Thromboangiitis Obliterans (TAO) is a nonatherosclerotic segmental vascular disease which affects small and medium arteries and veins in the upper and lower extremities. Based on pathological findings, TAO can be considered as a distinct form of vasculitis that is most prevalent in young male smokers. There is no definitive cure for this disease as therapeutic modalities are limited in number and efficacy. Surgical bypass has limited utility and 24% of patients will ultimately require amputation. Recently, studies have shown that therapeutic angiogenesis and immunomodulatory approaches through the delivery of stem cells to target tissues are potential options for ischemic lesion treatment. In this review, we summarize the current knowledge of TAO treatment and provide an overview of stem cell-based treatment modalities.
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23
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Rodriguez-Fontan F, Reeves B, Tuaño K, Colakoglu S, D' Agostino L, Banegas R. Tobacco use and neurogenesis: A theoretical review of pathophysiological mechanism affecting the outcome of peripheral nerve regeneration. J Orthop 2020; 22:59-63. [PMID: 32280170 PMCID: PMC7138932 DOI: 10.1016/j.jor.2020.03.026] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 03/22/2020] [Indexed: 02/07/2023] Open
Abstract
Peripheral nerve injury often requires medical intervention. Unfortunately, many patients never have a full recovery, despite a multi-disciplinary approach, including operative intervention and physical and/or occupational therapy. Outcomes are multifactorial, but are largely affected by the original injury severity, and patient comorbidities. A lcoholism, diabetes mellitus and ageing may detrimentally affect the outcomes of nerve injury; however little is known about tobacco's potential impact on nerve regeneration. Tobacco has known immunomodulatory effects, which suggests that it might affect peripheral nerve regeneration and functional recovery following injury. This review characterizes the effects of tobacco use on the complex cellular and chemokine interactions in peripheral nerve regeneration.
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Affiliation(s)
- Francisco Rodriguez-Fontan
- Department of Orthopedics, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
- Universidad de Buenos Aires, Facultad de Medicina, Buenos Aires, Argentina
| | - Bradley Reeves
- University of Colorado, School of Medicine, Anschutz Medical Campus, Aurora, CO, USA
| | - Krystle Tuaño
- Division of Plastic and Reconstructive Surgery, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Salih Colakoglu
- Division of Plastic and Reconstructive Surgery, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
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Effect of Breast Cancer and Adjuvant Therapy on Adipose-Derived Stromal Cells: Implications for the Role of ADSCs in Regenerative Strategies for Breast Reconstruction. Stem Cell Rev Rep 2020; 17:523-538. [PMID: 32929604 DOI: 10.1007/s12015-020-10038-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/04/2020] [Indexed: 12/14/2022]
Abstract
Tissue engineering using Adipose Derived Stromal Cells (ADSCs) has emerged as a novel regenerative medicine approach to replace and reconstruct soft tissue damaged or lost as a result of disease process or therapeutic surgical resection. ADSCs are an attractive cell source for soft tissue regeneration due to the fact that they are easily accessible, multipotent, non-immunogenic and pro-angiogenic. ADSC based regenerative strategies have been successfully translated to the clinical setting for the treatment of Crohn's fistulae, musculoskeletal pathologies, wound healing, and cosmetic breast augmentation (fat grafting). ADSCs are particularly attractive as a source for adipose tissue engineering as they exhibit preferential differentiation to adipocytes and support maintenance of mature adipose graft volume. The potential for reconstruction with an autologous tissue sources and a natural appearance and texture is particularly appealing in the setting of breast cancer; up to 40% of patients require mastectomy for locoregional control and current approaches to post-mastectomy breast reconstruction (PMBR) are limited by the potential for complications at the donor and reconstruction sites. Despite their potential, the use of ADSCs in breast cancer patients is controversial due to concerns regarding oncological safety. These concerns relate to the regeneration of tissue at a site where a malignancy has been treated and the impact this may have on stimulating local disease recurrence or dissemination. Pre-clinical data suggest that ADSCs exhibit pro-oncogenic characteristics and are involved in stimulating progression, and growth of tumour cells. However, there have been conflicting reports on the oncologic outcome, in terms of locoregional recurrence, for breast cancer patients in whom ADSC enhanced fat grafting was utilised as an alternative to reconstruction for small volume defects. A further consideration which may impact the successful translation of ADSC based regenerative strategies for post cancer reconstruction is the potential effects of cancer therapy. This review aims to address the effect of malignant cells, adjuvant therapies and patient-specific factors that may influence the success of regenerative strategies using ADSCs for post cancer tissue regeneration.
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Abstract
Although stem cell therapy has tremendous therapeutic potential, clinical translation of stem cell therapy has yet to be fully realized. Recently, patient comorbidities and lifestyle choices have emerged to be important factors in the efficacy of stem cell therapy. Tobacco usage is an important risk factor for numerous diseases, and nicotine exposure specifically has become increasing more prevalent with the rising use of electronic cigarettes. This review describes the effects of nicotine exposure on the function of various stem cells. We place emphasis on the differential effects of nicotine exposure in vitro and as well as in preclinical models. Further research on the effects of nicotine on stem cells will deepen our understanding of how lifestyle choices can impact the outcome of stem cell therapies.
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Affiliation(s)
- Alex Hp Chan
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USA.,Stanford Cardiovascular Institute, Stanford University, Stanford, CA 94305, USA.,Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA
| | - Ngan F Huang
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA 94305, USA.,Stanford Cardiovascular Institute, Stanford University, Stanford, CA 94305, USA.,Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA
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26
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YİĞENOĞLU TN, BAŞCI S, ŞAHİN D, BAKIRTAŞ M, KILINC A, UNCU ULU B, BATGİ H, İSKENDER D, OZCAN N, KIZIL ÇAKIR M, DAL S, HACIBEKİROĞLU T, ALTUNTAŞ F. The effect of smoking on stem cell mobilization in allogeneic donors. JOURNAL OF HEALTH SCIENCES AND MEDICINE 2020. [DOI: 10.32322/jhsm.729505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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27
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Cai X, Gao L, Cucchiarini M, Madry H. Association of Nicotine with Osteochondrogenesis and Osteoarthritis Development: The State of the Art of Preclinical Research. J Clin Med 2019; 8:jcm8101699. [PMID: 31623196 PMCID: PMC6832988 DOI: 10.3390/jcm8101699] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Revised: 10/02/2019] [Accepted: 10/10/2019] [Indexed: 12/27/2022] Open
Abstract
The deleterious effects of nicotine on various health conditions have been well documented. Although many orthopedic diseases are adversely affected by nicotine, little is known about its preclinical effects on chondrogenesis or osteogenesis, cartilage formation, osteoarthritis (OA), and osteochondral repair. A systematic review was conducted examining the current scientific evidence on the effects of nicotine on chondrogenesis or osteogenesis in vitro, possible consequences of prenatal nicotine exposure (PNE) on cartilage and OA susceptibility in the offspring, and whether nicotine affects OA development and osteochondral repair in vivo, always focusing on their underlying mechanisms. The data reveal dose-dependent effects on articular chondrocytes and on the chondrogenesis and osteogenesis of medicinal signaling cells in vitro, with lower doses often resulting in positive effects and higher doses causing negative effects. PNE negatively affects articular cartilage development and induces OA in the offspring without or with nicotine exposure. In contrast, protective effects on OA development were only reported in monosodium iodoacetate-induced small animal models. Finally, nicotine repressed MSC-based osteochondral repair in vivo. Future studies need to investigate dose-dependent clinical effects of smoking on cartilage quality in offspring, OA susceptibility and progression, and osteochondral repair more in detail, thus identifying possible thresholds for its pathological effects.
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Affiliation(s)
- Xiaoyu Cai
- Center of Experimental Orthopaedics, Saarland University Medical Center and Saarland University, 66421 Homburg/Saar, Germany.
| | - Liang Gao
- Center of Experimental Orthopaedics, Saarland University Medical Center and Saarland University, 66421 Homburg/Saar, Germany.
| | - Magali Cucchiarini
- Center of Experimental Orthopaedics, Saarland University Medical Center and Saarland University, 66421 Homburg/Saar, Germany.
| | - Henning Madry
- Center of Experimental Orthopaedics, Saarland University Medical Center and Saarland University, 66421 Homburg/Saar, Germany.
- Department of Orthopaedic Surgery, Saarland University Medical Center and Saarland University, 66421 Homburg/Saar, Germany.
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28
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Forner L, Berkowicz A, Dickmeiss E, Hyldegaard O, Jansen EC, Fischer-Nielsen A. Only minor stem cell mobilization in head and neck irradiated patients treated with hyperbaric oxygen. Diving Hyperb Med 2019; 49:175-185. [PMID: 31523792 DOI: 10.28920/dhm49.3.175-185] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 05/10/2019] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Hyperbaric oxygen, (HBO) is used to treat several conditions including late radiation tissue injury. Previous studies have suggested that HBO mobilizes bone marrow derived stem/progenitor cells (SPC) to the peripheral blood, however possible cumulative effects were highly variable. METHODS We have investigated a possible HBO-induced mobilization of SPCs by determining CD34+CD45dim cell numbers, as well as SPCs in general. The latter were characterized by high aldehyde dehydrogenase (ALDH) activity by use of the Aldefluor® assay. We included ten patients admitted for HBO treatment of radiation tissue injury. Six patients completed the 29-30 HBO treatment exposures. We also investigated possible HBO-induced effects on platelet activation as measured by flow cytometry and functional analyses. RESULTS We found a weak and insignificant tendency toward mobilization of CD34+CD45dim cells after a single HBO exposure versus before. Additionally, we found an additive effect of 15 HBO exposures on the increase in CD34+CD45dim cells relative to the pre-1st-HBO values. These changes were significantly more than zero but less than a doubling. We could not demonstrate a significant effect of HBO on the content of Aldefluor® positive SPCs in peripheral blood. There was no significant effect on platelet activation overall. However, in patients with increased expression of activation markers at baseline, we found a decrease after one exposure although this was not reflected in functional tests. CONCLUSION We found a minor statistically significant mobilizing effect of HBO treatment on the bone marrow derived stem/progenitor cell content in peripheral blood after 15 treatments (n = 10 patients), but no effect after 30 treatments (n = 6 patients). However, because of the low number of patients we cannot confidentially prove or disprove the null hypothesis. The possibility that HBO treatment reduces the number of activated platelets could not be demonstrated nor excluded.
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Affiliation(s)
- Lone Forner
- Corresponding author: Dr Lone Forner, Department of Oral and Maxillofacial Surgery, Centre for Head and Orthopedics and Department of Anaesthesia, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark, .,Department of Oral and Maxillofacial Surgery, Centre for Head and Orthopedics and Department of Anaesthesia, Copenhagen University Hospital, Copenhagen, Denmark.,Department of Anaesthesia, Centre for Head and Orthopedics, Copenhagen University Hospital, Copenhagen, Denmark
| | - Adela Berkowicz
- Cell Therapy Facility, Department of Clinical Immunology, Centre of Diagnostic Investigation, Copenhagen University Hospital, Copenhagen, Denmark
| | - Ebbe Dickmeiss
- Cell Therapy Facility, Department of Clinical Immunology, Centre of Diagnostic Investigation, Copenhagen University Hospital, Copenhagen, Denmark
| | - Ole Hyldegaard
- Department of Anaesthesia, Centre for Head and Orthopedics, Copenhagen University Hospital, Copenhagen, Denmark
| | - Erik C Jansen
- Department of Anaesthesia, Centre for Head and Orthopedics, Copenhagen University Hospital, Copenhagen, Denmark
| | - Anne Fischer-Nielsen
- Cell Therapy Facility, Department of Clinical Immunology, Centre of Diagnostic Investigation, Copenhagen University Hospital, Copenhagen, Denmark
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29
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Worley JR, Parker GC. Effects of environmental stressors on stem cells. World J Stem Cells 2019; 11:565-577. [PMID: 31616535 PMCID: PMC6789190 DOI: 10.4252/wjsc.v11.i9.565] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 07/12/2019] [Accepted: 09/04/2019] [Indexed: 02/06/2023] Open
Abstract
Environmental toxicants are ubiquitous, and many are known to cause harmful health effects. However, much of what we know or think we know concerning the targets and long-term effects of exposure to environmental stressors is sadly lacking. Toxicant exposure may have health effects that are currently mischaracterized or at least mechanistically incompletely understood. While much of the recent excitement about stem cells (SCs) focuses on their potential as therapeutic agents, they also offer a valuable resource to give us insight into the mechanisms and risks of toxicant effects. Not only as a response to the increasing ethical pressure to reduce animal testing, SC studies allow us valuable insight into the true effects of human exposure to environmental stressors under controlled conditions. We present a review of the history of publications on the effects of environmental stressors on SCs, followed by a consolidation of the literature over the past five years on a subset of key environmental stressors of importance to human health and their effects on both embryonic and tissue SCs. The review will make constructive suggestions as to areas of toxicant research where further studies are needed, as well as making indications of the potential utility for advancing knowledge and directing research on environmental toxicology.
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Affiliation(s)
- Jessica R Worley
- Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI 48202, United States
| | - Graham C Parker
- Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI 48202, United States
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30
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Widholz B, Tsitlakidis S, Reible B, Moghaddam A, Westhauser F. Pooling of Patient-Derived Mesenchymal Stromal Cells Reduces Inter-Individual Confounder-Associated Variation without Negative Impact on Cell Viability, Proliferation and Osteogenic Differentiation. Cells 2019; 8:cells8060633. [PMID: 31238494 PMCID: PMC6628337 DOI: 10.3390/cells8060633] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 06/07/2019] [Accepted: 06/21/2019] [Indexed: 01/16/2023] Open
Abstract
Patient-derived mesenchymal stromal cells (MSCs) play a key role in bone tissue engineering. Various donor-specific factors were identified causing significant variability in the biological properties of MSCs impairing quality of data and inter-study comparability. These limitations might be overcome by pooling cells of different donors. However, the effects of pooling on osteogenic differentiation, proliferation and vitality remain unknown and have, therefore, been evaluated in this study. MSCs of 10 donors were cultivated and differentiated into osteogenic lineage individually and in a pooled setting, containing MSCs of each donor in equal parts. Proliferation was evaluated in expansion (assessment of generation time) and differentiation (quantification of dsDNA content) conditions. Vitality was visualized by a fluorescence-microscopy-based live/dead assay. Osteogenic differentiation was assessed by quantification of alkaline phosphatase (ALP) activity and extracellular calcium deposition. Compared to the individual setting, generation time of pooled MSCs was shorter and proliferation was increased during differentiation with significantly lower variances. Calcium deposition was comparable, while variances were significantly higher in the individual setting. ALP activity showed high variance in both groups, but increased comparably during the incubation period. In conclusion, MSC pooling helps to compensate donor-dependent variability and does not negatively influence MSC vitality, proliferation and osteogenic differentiation.
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Affiliation(s)
- Benedikt Widholz
- Center of Orthopedics, Traumatology, and Spinal Cord Injury, Heidelberg University Hospital, Schlierbacher Landstraße 200a, 69118 Heidelberg, Germany.
| | - Stefanos Tsitlakidis
- Center of Orthopedics, Traumatology, and Spinal Cord Injury, Heidelberg University Hospital, Schlierbacher Landstraße 200a, 69118 Heidelberg, Germany.
| | - Bruno Reible
- Center of Orthopedics, Traumatology, and Spinal Cord Injury, Heidelberg University Hospital, Schlierbacher Landstraße 200a, 69118 Heidelberg, Germany.
| | - Arash Moghaddam
- Center of Orthopedics, Traumatology, and Spinal Cord Injury, Heidelberg University Hospital, Schlierbacher Landstraße 200a, 69118 Heidelberg, Germany.
- ATORG - Aschaffenburg Trauma and Orthopedic Research Group, Center for Trauma Surgery, Orthopedics, and Sports Medicine, Klinikum Aschaffenburg-Alzenau, Am Hasenkopf 1, 63739 Aschaffenburg, Germany.
| | - Fabian Westhauser
- Center of Orthopedics, Traumatology, and Spinal Cord Injury, Heidelberg University Hospital, Schlierbacher Landstraße 200a, 69118 Heidelberg, Germany.
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Aspera-Werz RH, Chen T, Ehnert S, Zhu S, Fröhlich T, Nussler AK. Cigarette Smoke Induces the Risk of Metabolic Bone Diseases: Transforming Growth Factor Beta Signaling Impairment via Dysfunctional Primary Cilia Affects Migration, Proliferation, and Differentiation of Human Mesenchymal Stem Cells. Int J Mol Sci 2019; 20:2915. [PMID: 31207955 PMCID: PMC6628373 DOI: 10.3390/ijms20122915] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 05/27/2019] [Accepted: 06/12/2019] [Indexed: 12/18/2022] Open
Abstract
It is well established that smoking has detrimental effects on bone integrity and is a preventable risk factor for metabolic bone disorders. Following orthopedic surgeries, smokers frequently show delayed fracture healing associated with many complications, which results in prolonged hospital stays. One crucial factor responsible for fracture repair is the recruitment and differentiation of mesenchymal stem cells (MSCs) at early stages, a mechanism mediated by transforming growth factor β (TGF-β). Although it is known that smokers frequently have decreased TGF-β levels, little is known about the actual signaling occurring in these patients. We investigated the effect of cigarette smoke on TGF-β signaling in MSCs to evaluate which step in the pathway is affected by cigarette smoke extract (CSE). Single-cell-derived human mesenchymal stem cell line (SCP-1 cells) were treated with CSE concentrations associated with smoking up to 20 cigarettes a day. TGF-β signaling was analyzed using an adenovirus-based reporter assay system. Primary cilia structure and downstream TGF-β signaling modulators (Smad2, Smad3, and Smad4) were analyzed by Western blot and immunofluorescence staining. CSE exposure significantly reduced TGF-β signaling. Intriguingly, we observed that protein levels of phospho-Smad2/3 (active forms) as well as nuclear translocation of the phospho-Smad3/4 complex decreased after CSE exposure, phenomena that affected signal propagation. CSE exposure reduced the activation of TGF-β modulators under constitutive activation of TGF-β receptor type I (ALK5), evidencing that CSE affects signaling downstream of the ALK5 receptor but not the binding of the cytokine to the receptor itself. CSE-mediated TGF-β signaling impaired MSC migration, proliferation, and differentiation and ultimately affected endochondral ossification. Thus, we conclude that CSE-mediated disruption of TGF-β signaling in MSCs is partially responsible for delayed fracture healing in smokers.
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Affiliation(s)
- Romina H Aspera-Werz
- Siegfried Weller Research Institute, Department of Trauma and Reconstructive Surgery, Eberhard Karls University Tübingen, BG Trauma Center Tübingen, 72076 Tübingen, Germany.
| | - Tao Chen
- Siegfried Weller Research Institute, Department of Trauma and Reconstructive Surgery, Eberhard Karls University Tübingen, BG Trauma Center Tübingen, 72076 Tübingen, Germany.
| | - Sabrina Ehnert
- Siegfried Weller Research Institute, Department of Trauma and Reconstructive Surgery, Eberhard Karls University Tübingen, BG Trauma Center Tübingen, 72076 Tübingen, Germany.
| | - Sheng Zhu
- Siegfried Weller Research Institute, Department of Trauma and Reconstructive Surgery, Eberhard Karls University Tübingen, BG Trauma Center Tübingen, 72076 Tübingen, Germany.
| | - Theresa Fröhlich
- Siegfried Weller Research Institute, Department of Trauma and Reconstructive Surgery, Eberhard Karls University Tübingen, BG Trauma Center Tübingen, 72076 Tübingen, Germany.
| | - Andreas K Nussler
- Siegfried Weller Research Institute, Department of Trauma and Reconstructive Surgery, Eberhard Karls University Tübingen, BG Trauma Center Tübingen, 72076 Tübingen, Germany.
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Aedo G, Miranda M, Chávez MN, Allende ML, Egaña JT. A Reliable Preclinical Model to Study the Impact of Cigarette Smoke in Development and Disease. ACTA ACUST UNITED AC 2019; 80:e78. [PMID: 31058471 DOI: 10.1002/cptx.78] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The World Health Organization has estimated that, worldwide, cigarette smoking has caused more than 100 million deaths in the last century, a number that is expected to increase in the future. Understanding cigarette smoke toxicity is key for research and development of proper public health policies. The current challenge is to establish a reliable preclinical model to evaluate the effects of cigarette smoke. In this work, we describe a simple method that allows for quantifying the toxic effects of cigarette smoke using zebrafish. Here, viability of larvae and adult fish, as well as the effects of cigarette smoke extracts on vascular development and tissue regeneration, can be easily assayed. © 2019 by John Wiley & Sons, Inc.
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Affiliation(s)
- Geraldine Aedo
- Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.,FONDAP Advanced Center for Chronic Disease, Center for Molecular Studies of the Cell, Facultad de Ciencias Químicas y Farmacéuticas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Miguel Miranda
- Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.,FONDAP Center for Genome Regulation, Facultad de Ciencias, Universidad de Chile, Santiago, Chile.,Facultad de Medicina Veterinaria y Agronomía, Universidad de las Américas, Santiago, Chile
| | - Myra N Chávez
- FONDAP Advanced Center for Chronic Disease, Center for Molecular Studies of the Cell, Facultad de Ciencias Químicas y Farmacéuticas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.,FONDAP Center for Genome Regulation, Facultad de Ciencias, Universidad de Chile, Santiago, Chile
| | - Miguel L Allende
- FONDAP Center for Genome Regulation, Facultad de Ciencias, Universidad de Chile, Santiago, Chile
| | - José T Egaña
- Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
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33
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Zhao G, Mo J, Zheng T, Li Y, Wu X, Huang J, Liu G, Huang Z, Yu B. Puberty exposure to cigarette smoke extract impairs adult spermatogenesis in the mouse. Reprod Toxicol 2019; 83:8-13. [DOI: 10.1016/j.reprotox.2018.10.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 09/26/2018] [Accepted: 10/31/2018] [Indexed: 02/08/2023]
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Assadollahi V, Mohammadi E, Fathi F, Hassanzadeh K, Erfan MBK, Soleimani F, Banafshi O, Yosefi F, Allahvaisi O. Effects of cigarette smoke condensate on proliferation and pluripotency gene expression in mouse embryonic stem cells. J Cell Biochem 2018; 120:4071-4080. [PMID: 30269371 DOI: 10.1002/jcb.27692] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Accepted: 08/27/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND Embryonic stem cells (ESCs) are derived from the inner cell mass (ICM) of blastocysts. They can be used as valuable experimental models to test the effects of drugs, chemicals, and environmental contaminants such as cigarette smoke condensate (CSC) on preimplantation embryo development. The aim of this study was to evaluate the effect of CSC on ESCs derived from mice with different genetic backgrounds and maternal ages. METHODS The study groups consisted of mouse ESCs (mESCs) obtained from three sources: blastocysts developed from fertilized oocytes of two-month-old (2-C57) and six-month-old (6-C57) C57BL/6 inbred mice and those developed from fertilized oocytes of two-month-old (2-NMRI) NMRI outbred mice. The groups of mESCs were exposed to 0.04, 4, and 40 μg/mL CSC. After exposure, we measured cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and real-time polymerase chain reaction for changes in expressions of Oct4, Sox2, Nanog, Ahr, Bax, Bcl2, TFAM, and POLG. The cell doubling time (DT) of these populations was also determined. RESULTS We observed that CSC changed proliferation and DT in the 2-C57 and 6-C57 cells. There was no change in 2-NMRI cells. Exposure to CSC caused changes in the gene expressions and induced apoptosis in all three cell lines. CONCLUSION Based on the results of the study, it can be concluded that CSC has an effect on the viability, DT and gene expression patterns in mouse ESCs and its effects vary based on the genetic background and maternal age of isolated mouse ESCs.
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Affiliation(s)
- Vahideh Assadollahi
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Ebrahim Mohammadi
- Environmental Health Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.,Department of Occupational Health Engineering, Faculty of Health, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Fardin Fathi
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Kambiz Hassanzadeh
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Mohamad Bager Khadem Erfan
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Farzad Soleimani
- Department of Biology, School of Natural Science, University of Tabriz, Tabriz, Iran
| | - Omid Banafshi
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Fayeg Yosefi
- Social Determinants of Health Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Ozra Allahvaisi
- Department of Anatomy, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
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A Novel In Vivo Model to Study Impaired Tissue Regeneration Mediated by Cigarette Smoke. Sci Rep 2018; 8:10926. [PMID: 30026555 PMCID: PMC6053433 DOI: 10.1038/s41598-018-28687-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 06/13/2018] [Indexed: 12/27/2022] Open
Abstract
Cigarette smoke is associated with several pathologies including chronic respiratory diseases and cancer. In addition, exposure to cigarette smoke is correlated with impaired wound healing, where a significant decrease in the regenerative capacity of smokers is well documented and broadly considered a negative risk factor after trauma or surgery. So far, some in vitro and in vivo models have been described to study how exposure to cigarette smoke diminishes the regenerative potential in different organisms. However, although useful, many of these models are difficult and expensive to implement and do not allow high-throughput screening approaches. In order to establish a reliable and accessible model, we have evaluated the effects of cigarette smoke extract (CSE) on zebrafish development and regeneration. In this work, zebrafish embryos and larvae were exposed to low doses of aqueous CSE showing severe developmental abnormalities in a dose-dependent manner. Furthermore, when adult zebrafish were subjected to caudal fin amputation, we observed a significant decrease in the regenerative capacity of animals exposed to CSE. The effect was exacerbated in male and aged fish compared to female or young organisms. The establishment of a zebrafish model to assess the consequences of cigarette smoke and its effects on animal physiology could provide a new tool to study the underlying mechanisms involved in impaired tissue regeneration, and aid the development of novel approaches to treat complications associated with cigarette smoke toxicity.
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Sreekumar V, Aspera-Werz R, Ehnert S, Strobel J, Tendulkar G, Heid D, Schreiner A, Arnscheidt C, Nussler AK. Resveratrol protects primary cilia integrity of human mesenchymal stem cells from cigarette smoke to improve osteogenic differentiation in vitro. Arch Toxicol 2018; 92:1525-1538. [PMID: 29264620 DOI: 10.1007/s00204-017-2149-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 12/14/2017] [Indexed: 12/21/2022]
Abstract
Several studies have explored the negative effects of cigarette smoke on bone healing; however, the complex pathogenesis still remains unclear. One crucial and primary factor determining effective fracture repair is the recruitment and differentiation of mesenchymal stem cells (MSCs) into bone-forming cells. Recently, primary cilia, microtubule-based sensory organelles, have been shown to be critical in lineage commitment and differentiation of MSCs. Our present study indicates that exposure to cigarette smoke extract (CSE 0.1-10%) impaired osteogenic differentiation of human mesenchymal stem cell line (SCP-1) and interestingly, also affected primary cilia distribution and integrity in these cells during the differentiation. Furthermore, significant amounts of free radicals generated by CSE could be causative of primary cilia loss since treatment with 0.01% of hydrogen peroxide, a prime free radical in CSE, destroyed primary cilia in these cells. The debilitated differentiation of CSE-exposed SCP-1 cells also correlated with the significantly reduced expression of transcription factor and target genes of primary cilia-specific hedgehog signalling, a key player in osteogenic differentiation. As a treatment strategy, co-incubation of the CSE-exposed SCP-1 cells with the antioxidant resveratrol (1 µM) had a protective effect as it significantly reduced free radical production, protected the primary cilia and enhanced osteogenic differentiation. The current study shows for the first time that cigarette smoke affects primary cilia in human MSCs during osteogenic differentiation and treatment with resveratrol could reverse the effects and enhance differentiation, thus opening up potential therapeutic alternatives to treat fracture healing in smokers, in particularly, when delayed fracture healing is assumed.
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Affiliation(s)
- Vrinda Sreekumar
- Department of Traumatology, BG Trauma Clinic, Siegfried Weller Institute for Trauma Research, Eberhard Karls Universität Tübingen, Tübingen, Germany
| | - Romina Aspera-Werz
- Department of Traumatology, BG Trauma Clinic, Siegfried Weller Institute for Trauma Research, Eberhard Karls Universität Tübingen, Tübingen, Germany
| | - Sabrina Ehnert
- Department of Traumatology, BG Trauma Clinic, Siegfried Weller Institute for Trauma Research, Eberhard Karls Universität Tübingen, Tübingen, Germany
| | - Julius Strobel
- Department of Traumatology, BG Trauma Clinic, Siegfried Weller Institute for Trauma Research, Eberhard Karls Universität Tübingen, Tübingen, Germany
| | - Gauri Tendulkar
- Department of Traumatology, BG Trauma Clinic, Siegfried Weller Institute for Trauma Research, Eberhard Karls Universität Tübingen, Tübingen, Germany
| | - Daniel Heid
- Department of Traumatology, BG Trauma Clinic, Siegfried Weller Institute for Trauma Research, Eberhard Karls Universität Tübingen, Tübingen, Germany
| | - Anna Schreiner
- Department of Traumatology, BG Trauma Clinic, Siegfried Weller Institute for Trauma Research, Eberhard Karls Universität Tübingen, Tübingen, Germany
| | - Christian Arnscheidt
- Department of Traumatology, BG Trauma Clinic, Siegfried Weller Institute for Trauma Research, Eberhard Karls Universität Tübingen, Tübingen, Germany
| | - Andreas K Nussler
- Department of Traumatology, BG Trauma Clinic, Siegfried Weller Institute for Trauma Research, Eberhard Karls Universität Tübingen, Tübingen, Germany.
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Barwinska D, Traktuev DO, Merfeld-Clauss S, Cook TG, Lu H, Petrache I, March KL. Cigarette Smoking Impairs Adipose Stromal Cell Vasculogenic Activity and Abrogates Potency to Ameliorate Ischemia. Stem Cells 2018; 36:856-867. [PMID: 29589872 DOI: 10.1002/stem.2813] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 02/05/2018] [Accepted: 02/05/2018] [Indexed: 12/17/2022]
Abstract
Cigarette smoking (CS) adversely affects the physiologic function of endothelial progenitor, hematopoietic stem and progenitor cells. However, the effect of CS on the ability of adipose stem/stromal cells (ASC) to promote vasculogenesis and rescue perfusion in the context of ischemia is unknown. To evaluate this, ASC from nonsmokers (nCS-ASC) and smokers (CS-ASC), and their activity to promote perfusion in hindlimb ischemia models, as well as endothelial cell (EC) survival and vascular morphogenesis in vitro were assessed. While nCS-ASC improved perfusion in ischemic limbs, CS-ASC completely lost this therapeutic effect. In vitro vasculogenesis assays revealed that human CS-ASC and ASC from CS-exposed mice showed compromised support of EC morphogenesis into vascular tubes, and the CS-ASC secretome was less potent in supporting EC survival/proliferation. Comparative secretome analysis revealed that CS-ASC produced lower amounts of hepatocyte growth factor (HGF) and stromal cell-derived growth factor 1 (SDF-1). Conversely, CS-ASC secreted the angiostatic/pro-inflammatory factor Activin A, which was not detected in nCS-ASC conditioned media (CM). Furthermore, higher Activin A levels were measured in EC/CS-ASC cocultures than in EC/nCS-ASC cocultures. CS-ASC also responded to inflammatory cytokines with 5.2-fold increase in Activin A secretion, whereas nCS-ASC showed minimal Activin A induction. Supplementation of EC/CS-ASC cocultures with nCS-ASC CM or with recombinant vascular endothelial growth factor, HGF, or SDF-1 did not rescue vasculogenesis, whereas inhibition of Activin A expression or activity improved network formation up to the level found in EC/nCS-ASC cocultures. In conclusion, ASC of CS individuals manifest compromised in vitro vasculogenic activity as well as in vivo therapeutic activity. Stem Cells 2018;36:856-867.
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Affiliation(s)
- Daria Barwinska
- Department of Cellular and Integrative Physiology.,Krannert Institute of Cardiology.,Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana, USA
| | - Dmitry O Traktuev
- Krannert Institute of Cardiology.,Division of Cardiology.,Department of Medicine, Indiana University, Indianapolis, Indiana, USA.,Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana, USA.,Center for Regenerative Medicine, Department of Medicine University of Florida, Gainesville, Florida, USA
| | - Stephanie Merfeld-Clauss
- Krannert Institute of Cardiology.,Division of Cardiology.,Department of Medicine, Indiana University, Indianapolis, Indiana, USA.,Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana, USA.,Center for Regenerative Medicine, Department of Medicine University of Florida, Gainesville, Florida, USA
| | - Todd G Cook
- Krannert Institute of Cardiology.,Division of Cardiology.,Department of Medicine, Indiana University, Indianapolis, Indiana, USA.,Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana, USA
| | - Hongyan Lu
- Krannert Institute of Cardiology.,Division of Cardiology.,Department of Medicine, Indiana University, Indianapolis, Indiana, USA.,Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana, USA
| | - Irina Petrache
- Department of Medicine, Indiana University, Indianapolis, Indiana, USA.,Department of Medicine, National Jewish Health and University of Colorado, Denver, Colorado, USA
| | - Keith L March
- Department of Cellular and Integrative Physiology.,Krannert Institute of Cardiology.,Division of Cardiology.,Department of Medicine, Indiana University, Indianapolis, Indiana, USA.,Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana, USA.,Center for Regenerative Medicine, Department of Medicine University of Florida, Gainesville, Florida, USA
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Higham A, Bostock D, Booth G, Dungwa JV, Singh D. The effect of electronic cigarette and tobacco smoke exposure on COPD bronchial epithelial cell inflammatory responses. Int J Chron Obstruct Pulmon Dis 2018; 13:989-1000. [PMID: 29615835 PMCID: PMC5870631 DOI: 10.2147/copd.s157728] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background Electronic cigarettes (e-cigs) are used to help smoking cessation. However, these devices contain harmful chemicals, and there are safety concerns. We have investigated the effects of e-cigs on the inflammatory response and viability of COPD bronchial epithelial cells (BECs). Methods BECs from COPD patients and controls were exposed to e-cig vapor extract (ECVE) and the levels of interleukin (IL)-6, C-X-C motif ligand 8 (CXCL8), and lactate dehydrogenase release were measured. We also examined the effect of ECVE pretreatment on polyinosinic:polycytidylic acid (poly I:C)-stimulated cytokine release from BECs. Parallel experiments using Calu-3 cells were performed. Comparisons were made with cigarette smoke extract (CSE). Results ECVE and CSE caused an increase in the release of IL-6 and CXCL8 from Calu-3 cells. ECVE only caused toxicity in BECs and Calu-3 cells. Furthermore, ECVE and CSE dampened poly I:C-stimulated C-X-C motif ligand 10 release from both cell culture models, reaching statistical significance for CSE at an optical density of 0.3. Conclusion ECVE caused toxicity and reduced the antiviral response to poly I:C. This raises concerns over the safety of e-cig use.
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Affiliation(s)
- Andrew Higham
- Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester and University Hospital of South Manchester, NHS Foundation Trust, Manchester, UK.,Medicines Evaluation Unit, University Hospital of South Manchester, Manchester, UK
| | - Declan Bostock
- Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester and University Hospital of South Manchester, NHS Foundation Trust, Manchester, UK
| | - George Booth
- Medicines Evaluation Unit, University Hospital of South Manchester, Manchester, UK
| | - Josiah V Dungwa
- Medicines Evaluation Unit, University Hospital of South Manchester, Manchester, UK
| | - Dave Singh
- Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester and University Hospital of South Manchester, NHS Foundation Trust, Manchester, UK.,Medicines Evaluation Unit, University Hospital of South Manchester, Manchester, UK
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Greenberg JM, Carballosa CM, Cheung HS. Concise Review: The Deleterious Effects of Cigarette Smoking and Nicotine Usage and Mesenchymal Stem Cell Function and Implications for Cell-Based Therapies. Stem Cells Transl Med 2017; 6:1815-1821. [PMID: 28696009 PMCID: PMC5689746 DOI: 10.1002/sctm.17-0060] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 06/14/2017] [Indexed: 12/22/2022] Open
Abstract
Stem cell sources for cell‐based therapeutics are often screened for infectious agents and genetic diseases prior to implantation; however, there are other risk factors that are often overlooked, which may ultimately lead to less efficacious clinical outcomes. One such risk factor is exposure of mesenchymal stem cells (MSCs) to cigarette smoke or nicotine. Recent data have shown that exposure to cigarette smoke or nicotine leads to decreased regenerative potential, namely decreased proliferation, decreased migration, and decreased differentiation potential of exposed MSCs. This review provides a brief introduction into MSCs and their respective niches and a summary regarding the interactions of cigarettes and nicotine with MSCs populations. Specifically, the effects of cigarette smoke and nicotine on the regenerative potential of MSCs (i.e., proliferation, migration, and differentiation) will be covered with an emphasis on considerations for the development of future cell‐based clinical trials and therapies. stemcellstranslationalmedicine2017;6:1815–1821
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Affiliation(s)
- Jordan M Greenberg
- Department of Biomedical Engineering, College of Engineering, University of Miami, Coral Gables, Florida, USA
| | - Carlos M Carballosa
- Department of Biomedical Engineering, College of Engineering, University of Miami, Coral Gables, Florida, USA
| | - Herman S Cheung
- Department of Biomedical Engineering, College of Engineering, University of Miami, Coral Gables, Florida, USA.,Geriatric Research, Education and Clinical Center (GRECC); Miami Veterans Affairs Medical Center, Miami, Florida, USA
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Shin NR, Ko JW, Park SH, Cho YK, Oh SR, Ahn KS, Ryu JM, Kim JC, Seo CS, Shin IS. Protective effect of HwangRyunHaeDok-Tang water extract against chronic obstructive pulmonary disease induced by cigarette smoke and lipopolysaccharide in a mouse model. JOURNAL OF ETHNOPHARMACOLOGY 2017; 200:60-65. [PMID: 28216440 DOI: 10.1016/j.jep.2017.02.027] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 02/02/2017] [Accepted: 02/14/2017] [Indexed: 06/06/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Hwangryunhaedok-tang is an oriental herbal formula treated to cure inflammation and gastric disorders in China, Japan, and Korea. We explored the protective effects of Hwangryunhaedok-tang water extract (HRWE) against airway pathophysiological changes caused by cigarette smoke (CS) and lipopolysaccharide (LPS) in a mouse. MATERIALS AND METHODS We performed quantitative analyses of five marker components, namely geniposide, baicalin, coptisine, plamatine, and berberine, using high-performance liquid chromatography. Animals were received CS exposure (1h per day) for 7 days. LPS was administered intranasally on day 4. Mice were received HRWE at dose of 100 or 200mg/kg for 1h before CS exposure. RESULTS Treatment with HRWE significantly suppressed the increased inflammatory cell count induced by CS and LPS exposure. In addition, reduction in IL-6, TNF-α and IL-1β in broncho-alveolar lavage fluid (BALF) was observed after HRWE treatment. HRWE not only decreased inflammatory cell infiltration in lung, but also decreased the expression of iNOS, NF-κB and matrix metallopeptidase (MMP)-9 in lung tissues. CONCLUSION This study showed that HRWE can attenuate respiratory inflammation caused by CS and LPS exposure. Therefore, HRWE has potential for treating airway inflammatory disease.
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Affiliation(s)
- Na-Rae Shin
- College of Veterinary Medicine (BK21 Plus Project Team), Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 500-757, Republic of Korea
| | - Je-Won Ko
- College of Veterinary Medicine (BK21 Plus Project Team), Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 500-757, Republic of Korea
| | - Sung-Hyeuk Park
- College of Veterinary Medicine (BK21 Plus Project Team), Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 500-757, Republic of Korea
| | - Young-Kwon Cho
- College of Health Sciences, Cheongju University, 298 Daesung-ro, Sangdang-gu, Cheongju-si, Chungbuk 360-764, Republic of Korea
| | - Sei-Ryang Oh
- Natural Medicine Research Center, Korea Research Institute of Bioscience & Biotechnology, 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, Chungbuk 363-883, Republic of Korea
| | - Kyung-Seob Ahn
- Natural Medicine Research Center, Korea Research Institute of Bioscience & Biotechnology, 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, Chungbuk 363-883, Republic of Korea
| | - Jung-Min Ryu
- College of Veterinary Medicine (BK21 Plus Project Team), Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 500-757, Republic of Korea
| | - Jong-Choon Kim
- College of Veterinary Medicine (BK21 Plus Project Team), Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 500-757, Republic of Korea
| | - Chang-Seob Seo
- K-herb Research Center, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, Republic of Korea.
| | - In-Sik Shin
- College of Veterinary Medicine (BK21 Plus Project Team), Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 500-757, Republic of Korea.
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