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Górski P, Białas AJ, Piotrowski WJ. Aging Lung: Molecular Drivers and Impact on Respiratory Diseases-A Narrative Clinical Review. Antioxidants (Basel) 2024; 13:1480. [PMID: 39765809 PMCID: PMC11673154 DOI: 10.3390/antiox13121480] [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: 10/30/2024] [Revised: 11/18/2024] [Accepted: 11/26/2024] [Indexed: 01/11/2025] Open
Abstract
The aging process significantly impacts lung physiology and is a major risk factor for chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), asthma, and non-IPF interstitial lung fibrosis. This narrative clinical review explores the molecular and biochemical hallmarks of aging, such as oxidative stress, telomere attrition, genomic instability, epigenetic modifications, proteostasis loss, and impaired macroautophagy, and their roles in lung senescence. Central to this process are senescent cells, which, through the senescence-associated secretory phenotype (SASP), contribute to chronic inflammation and tissue dysfunction. The review highlights parallels between lung aging and pathophysiological changes in respiratory diseases, emphasizing the role of cellular senescence in disease onset and progression. Despite promising research into modulating aging pathways with interventions like caloric restriction, mTOR inhibitors, and SIRT1 activators, clinical evidence for efficacy in reversing or preventing age-related lung diseases remains limited. Understanding the interplay between aging-related mechanisms and environmental factors, such as smoking and pollution, is critical for developing targeted therapies. This review underscores the need for future studies focusing on therapeutic strategies to mitigate aging's detrimental effects on lung health and improve outcomes for patients with chronic respiratory conditions.
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Affiliation(s)
- Paweł Górski
- Department of Pneumology, Medical University of Lodz, 90-419 Lodz, Poland; (A.J.B.); (W.J.P.)
| | - Adam J. Białas
- Department of Pneumology, Medical University of Lodz, 90-419 Lodz, Poland; (A.J.B.); (W.J.P.)
- Department of Pulmonary Rehabilitation, Regional Medical Center for Lung Diseases and Rehabilitation, Blessed Rafal Chylinski Memorial Hospital for Lung Diseases, 91-520 Lodz, Poland
| | - Wojciech J. Piotrowski
- Department of Pneumology, Medical University of Lodz, 90-419 Lodz, Poland; (A.J.B.); (W.J.P.)
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Nabavizadeh SS, Shadi M, Khorraminejad-Shirazi M, Daneshi S, Tavanafar S, Naseri R, Abbaspour A, Alaei-Jahromi K, Talaei-Khozani T. Moldable Alginate/Hydroxyapatite Hydrogel Loaded with Metformin Enhanced Regeneration of the Rabbit Mandibular Defects. J Maxillofac Oral Surg 2024; 23:1391-1404. [PMID: 39618445 PMCID: PMC11607265 DOI: 10.1007/s12663-023-02094-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 12/06/2023] [Indexed: 01/05/2025] Open
Abstract
BACKGROUND Moldable hydrogel-based techniques loaded with osteoinductive agents such as metformin have become a promising field for reconstructing critical-sized bone defects, particularly in those with irregular shapes. Here, we used metformin incorporated in an alginate/hydroxyapatite hydrogel to accelerate the repair of the rabbit critical-sized mandibular defect. METHODS Cytotoxicity and osteoinduction of the metformin-loaded alginate/hydroxyapatite hydrogel were evaluated by culturing the osteosarcoma cell line (MG63). Moreover, in vivo bone formation was assessed in a rabbit bone defect model using computed tomography and histomorphometric analysis to compare the effects of alginate/hydroxyapatite hydrogel with or without metformin. RESULTS The data showed that the scaffolds were not cytotoxic and enhanced osteogenic characteristics of the cells, as manifested by augmented alkaline phosphatase activity and calcium deposition. In vivo studies indicated that all the treated groups exhibited more osteogenesis with a significant increase in bone-specific cell population and less residual scaffold remnant at the defect sites compared with the control group, which was significantly prominent in the group treated with alginate/hydroxyapatite/metformin. Moreover, computed tomography scan analysis also confirmed better bone filling in all the treated groups, especially in the defects treated with alginate/hydroxyapatite/metformin hydrogel. CONCLUSIONS Both In vitro and in vivo experiments revealed that locally loaded metformin with the easy size- and shape-adapted alginate/hydroxyapatite hydrogel has proper biocompatibility and osteogenesis properties. Moreover, our study highlighted the synergistic effect of metformin and hydroxyapatite on osteogenesis.
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Affiliation(s)
- Sara S Nabavizadeh
- Department of Otolaryngology, Otolaryngology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mehri Shadi
- Anatomy Department, Shiraz Medical School, Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammadhossein Khorraminejad-Shirazi
- Student Research Committee, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Cell and Molecular Medicine Student Research Group, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sajad Daneshi
- Tissue Engineering Lab, Department of Anatomical Sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saeid Tavanafar
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Birjand University of Medical Sciences, Birjand, Iran
| | - Reyhaneh Naseri
- Student Research Committee, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Alireza Abbaspour
- Student Research Committee, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Keivan Alaei-Jahromi
- Student Research Committee, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Radiology Department, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tahereh Talaei-Khozani
- Anatomy Department, Shiraz Medical School, Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Tissue Engineering Lab, Dept. of Anatomy, Shiraz University of Medical Sciences, Shiraz, Iran
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Dwivedi J, Wal P, Dash B, Ovais M, Sachan P, Verma V. Diabetic Pneumopathy- A Novel Diabetes-associated Complication: Pathophysiology, the Underlying Mechanism and Combination Medication. Endocr Metab Immune Disord Drug Targets 2024; 24:1027-1052. [PMID: 37817659 DOI: 10.2174/0118715303265960230926113201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 07/03/2023] [Accepted: 07/20/2023] [Indexed: 10/12/2023]
Abstract
BACKGROUND The "diabetic lung" has been identified as a possible target organ in diabetes, with abnormalities in ventilation control, bronchomotor tone, lung volume, pulmonary diffusing capacity, and neuroadrenergic bronchial innervation. OBJECTIVE This review summarizes studies related to diabetic pneumopathy, pathophysiology and a number of pulmonary disorders including type 1 and type 2 diabetes. METHODS Electronic searches were conducted on databases such as Pub Med, Wiley Online Library (WOL), Scopus, Elsevier, ScienceDirect, and Google Scholar using standard keywords "diabetes," "diabetes Pneumopathy," "Pathophysiology," "Lung diseases," "lung infection" for review articles published between 1978 to 2023 very few previous review articles based their focus on diabetic pneumopathy and its pathophysiology. RESULTS Globally, the incidence of diabetes mellitus has been rising. It is a chronic, progressive metabolic disease. The "diabetic lung" may serve as a model of accelerated ageing since diabetics' rate of respiratory function deterioration is two to three-times higher than that of normal, non-smoking people. CONCLUSION Diabetes-induced pulmonary dysfunction has not gained the attention it deserves due to a lack of proven causality and changes in cellular properties. The mechanism underlying a particular lung illness can still only be partially activated by diabetes but there is evidence that hyperglycemia is linked to pulmonary fibrosis in diabetic people.
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Affiliation(s)
- Jyotsana Dwivedi
- PSIT- Pranveer Singh Institute of Technology (Pharmacy), Kanpur, India
| | - Pranay Wal
- PSIT- Pranveer Singh Institute of Technology (Pharmacy), Kanpur, India
| | - Biswajit Dash
- Department of Pharmaceutical Technology, ADAMAS University, West Bengal, India
| | | | - Pranjal Sachan
- PSIT- Pranveer Singh Institute of Technology (Pharmacy), Kanpur, India
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Skrivergaard S, Krøyer Rasmussen M, Sahebekhtiari N, Feveile Young J, Therkildsen M. Satellite cells sourced from bull calves and dairy cows differs in proliferative and myogenic capacity - Implications for cultivated meat. Food Res Int 2023; 173:113217. [PMID: 37803537 DOI: 10.1016/j.foodres.2023.113217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 06/29/2023] [Accepted: 06/30/2023] [Indexed: 10/08/2023]
Abstract
Cultivated meat produced with primary muscle satellite cells (SCs) will need a continuous supply of isolated cell material from relevant animal donors. Factors such as age, sex, and breed, along with the sustainability and availability of donor animals, could determine the most appropriate donor type for an efficient production. In this study, we focus on the proliferation and differentiation of bovine SCs isolated from bull calf and dairy cow muscle samples. The proliferative performance of bull calf SCs was significantly better than SCs from dairy cows, however a dynamic differentiation assay revealed that the degree of fusion and formation of myotubes were similar between donor types. Furthermore, the proliferation of SCs from both donor types was enhanced using an in-house developed serum-free media compared to 10% FBS, which also delayed myogenic differentiation and increased final cell population density. Using gene chip transcriptomics, we identified several differentially expressed genes between the two donor types, which could help explain the observed cellular differences. This data also revealed a high biological variance between the three replicate animals within donor type, which seemed to be decreased when using our in-house serum-free media. With the use of the powerful imaging modalities of Cytation 5, we developed a novel high contrast brightfield-enabled label-free myotube quantification method along with a more efficient end-point fusion analysis using Phalloidin-staining. The results give new insights into the bovine SC biology and potential use of bull calves and dairy cows as relevant donor animals for cultivated beef cell sourcing. The newly developed differentiation assays will further enhance future research within the field of cultivated meat and SC biology.
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Teale MA, Schneider S, Eibl D, van den Bos C, Neubauer P, Eibl R. Mesenchymal and induced pluripotent stem cell-based therapeutics: a comparison. Appl Microbiol Biotechnol 2023:10.1007/s00253-023-12583-4. [PMID: 37246986 DOI: 10.1007/s00253-023-12583-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 05/07/2023] [Accepted: 05/08/2023] [Indexed: 05/30/2023]
Abstract
Stem cell-based cell therapeutics and especially those based on human mesenchymal stem cells (hMSCs) and induced pluripotent stem cells (hiPSCs) are said to have enormous developmental potential in the coming years. Their applications range from the treatment of orthopedic disorders and cardiovascular diseases to autoimmune diseases and even cancer. However, while more than 27 hMSC-derived therapeutics are currently commercially available, hiPSC-based therapeutics have yet to complete the regulatory approval process. Based on a review of the current commercially available hMSC-derived therapeutic products and upcoming hiPSC-derived products in phase 2 and 3, this paper compares the cell therapy manufacturing process between these two cell types. Moreover, the similarities as well as differences are highlighted and the resulting impact on the production process discussed. Here, emphasis is placed on (i) hMSC and hiPSC characteristics, safety, and ethical aspects, (ii) their morphology and process requirements, as well as (iii) their 2- and 3-dimensional cultivations in dependence of the applied culture medium and process mode. In doing so, also downstream processing aspects are covered and the role of single-use technology is discussed. KEY POINTS: • Mesenchymal and induced pluripotent stem cells exhibit distinct behaviors during cultivation • Single-use stirred bioreactor systems are preferred for the cultivation of both cell types • Future research should adapt and modify downstream processes to available single-use devices.
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Affiliation(s)
- Misha A Teale
- Centre for Biochemical Engineering and Cell Cultivation Techniques, Institute of Chemistry and Biotechnology, Zurich University of Applied Sciences, Grüentalstrasse 14, 8820, Wädenswil, Switzerland.
| | - Samuel Schneider
- Centre for Biochemical Engineering and Cell Cultivation Techniques, Institute of Chemistry and Biotechnology, Zurich University of Applied Sciences, Grüentalstrasse 14, 8820, Wädenswil, Switzerland
| | - Dieter Eibl
- Centre for Biochemical Engineering and Cell Cultivation Techniques, Institute of Chemistry and Biotechnology, Zurich University of Applied Sciences, Grüentalstrasse 14, 8820, Wädenswil, Switzerland
| | | | - Peter Neubauer
- Institute of Biotechnology, Chair of Bioprocess Engineering, Technical University of Berlin, ACK24, Ackerstraße 76, 13355, Berlin, Germany
| | - Regine Eibl
- Centre for Biochemical Engineering and Cell Cultivation Techniques, Institute of Chemistry and Biotechnology, Zurich University of Applied Sciences, Grüentalstrasse 14, 8820, Wädenswil, Switzerland
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Mirghaderi SP, Valizadeh Z, Shadman K, Lafosse T, Oryadi-Zanjani L, Yekaninejad MS, Nabian MH. Cell therapy efficacy and safety in treating tendon disorders: a systemic review of clinical studies. J Exp Orthop 2022; 9:85. [PMID: 36042110 PMCID: PMC9428081 DOI: 10.1186/s40634-022-00520-9] [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: 05/06/2022] [Accepted: 08/10/2022] [Indexed: 11/18/2022] Open
Abstract
PURPOSE Despite substantial animal evidence, cell therapy in humans remains in its infancy. The purpose of this study was to examine the potential therapeutic effects and safety of cell therapy in the treatment of tendon disorders. METHODS According to the PRISMA guideline, a systematic review was performed on clinical studies concerning cell therapy in tendon disorders. A comprehensive search including the 5 databases of MEDLINE, Embase, Scopus, Web of Science, and Cochrane Library until December 2021 was carried out and associated with hand searching. The quality of the eligible studies was assessed using the tools suggested by Cochrane recommendations. Qualitative synthesis was performed in 2 tables and discussed separately for rotator cuff, elbow, patella, Achilles, and gluteal tendons. RESULTS Through 6017 records, 22 studies were included in the qualitative synthesis, including 658 patients. All the studies administered autologous cells, except one that used allogenic adipose-derived mesenchymal stem cells (Allogenic AD-MSC). Almost all studies demonstrated the safety of cell injection in their follow-up period with no serious side effects or immunologic reactions, with only a few related minor adverse events in some cases. The included studies showed the effectiveness of cell injection in tendinopathies of different sites, rotator cuff, elbow, patella, Achilles, and gluteal tendons. Among the rotator cuff studies, 4 comparative studies claimed that cell therapy is a more efficient treatment with a lower retear rate and pain level compared to the control group. However, one study found no differences between the groups. No controlled study has been performed on elbow tendinopathies, but 5 case series demonstrated the effectiveness of cell injection in elbow tendon disorders. For Achilles tendinopathies, only one randomized controlled trial (RCT) found that both cell therapy and control groups showed significant pain reduction and functional improvement with no statistical differences at the 6 months follow-up, but the cell therapy group had improved faster at earlier follow-ups. Patellar tendinopathy was studied in 2 RCTs, one did not show a significant difference and the other showed superior improvement compared to controls. CONCLUSION Cell therapy showed promising results and the available evidence suggests that it is safe at several sites of tendon disease. Based on available evidence, cell therapy should be suggested in specific conditions at each site. To approve cell therapy for tendon diseases, randomized clinical trials are required with a large sample size and long-term follow-ups. LEVEL OF EVIDENCE IV.
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Affiliation(s)
- Seyed Peyman Mirghaderi
- Center of Orthopedic Trans-Disciplinary Applied Research (COTAR), Tehran University of Medical Sciences, Tehran, Iran
- Students’ Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Valizadeh
- Center of Orthopedic Trans-Disciplinary Applied Research (COTAR), Tehran University of Medical Sciences, Tehran, Iran
- Students’ Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Kimia Shadman
- Center of Orthopedic Trans-Disciplinary Applied Research (COTAR), Tehran University of Medical Sciences, Tehran, Iran
- Students’ Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Thibault Lafosse
- Alps Surgery Institute: Hand, Upper Limb, Brachial Plexus, and Microsurgery Unit (PBMA), Clinique Générale d’Annecy, Annecy, France
| | - Leila Oryadi-Zanjani
- Center of Orthopedic Trans-Disciplinary Applied Research (COTAR), Tehran University of Medical Sciences, Tehran, Iran
- Department of Orthopedic and Trauma Surgery, Shariati Hospital and School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mir Saeed Yekaninejad
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Nabian
- Center of Orthopedic Trans-Disciplinary Applied Research (COTAR), Tehran University of Medical Sciences, Tehran, Iran
- Department of Orthopedic and Trauma Surgery, Shariati Hospital and School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Dave JR, Chandekar SS, Behera S, Desai KU, Salve PM, Sapkal NB, Mhaske ST, Dewle AM, Pokare PS, Page M, Jog A, Chivte PA, Srivastava RK, Tomar GB. Human gingival mesenchymal stem cells retain their growth and immunomodulatory characteristics independent of donor age. SCIENCE ADVANCES 2022; 8:eabm6504. [PMID: 35749495 PMCID: PMC9232118 DOI: 10.1126/sciadv.abm6504] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 05/06/2022] [Indexed: 05/28/2023]
Abstract
Aging has been reported to deteriorate the quantity and quality of mesenchymal stem cells (MSCs), which affect their therapeutic use in regenerative medicine. A dearth of age-related stem cell research further restricts their clinical applications. The present study explores the possibility of using MSCs derived from human gingival tissues (GMSCs) for studying their ex vivo growth characteristics and differentiation potential with respect to donor age. GMSCs displayed decreased in vitro adipogenesis and in vitro and in vivo osteogenesis with age, but in vitro neurogenesis remained unaffected. An increased expression of p53 and SIRT1 with donor age was correlated to their ability of eliminating tumorigenic events through apoptosis or autophagy, respectively. Irrespective of donor age, GMSCs displayed effective immunoregulation and regenerative potential in a mouse model of LPS-induced acute lung injury. Thus, we suggest the potential of GMSCs for designing cell-based immunomodulatory therapeutic approaches and their further extrapolation for acute inflammatory conditions such as acute respiratory distress syndrome and COVID-19.
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Affiliation(s)
- Jay R. Dave
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Sayali S. Chandekar
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Shubhanath Behera
- National Centre for Cell Science, Savitribai Phule Pune University Campus, Pune, 411007 Maharashtra, India
| | - Kaushik U. Desai
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Pradnya M. Salve
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Neha B. Sapkal
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Suhas T. Mhaske
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Ankush M. Dewle
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Parag S. Pokare
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
| | - Megha Page
- Department of Dentistry, Deenanath Mangeshkar Hospital and Research Centre, Pune, 411004 Maharashtra, India
| | - Ajay Jog
- Department of Dentistry, Deenanath Mangeshkar Hospital and Research Centre, Pune, 411004 Maharashtra, India
| | - Pankaj A. Chivte
- Saraswati Danwantri Dental College and Hospital, Parbhani, 431401 Maharashtra, India
| | - Rupesh K. Srivastava
- Department of Biotechnology, All India Institute of Medical Science, New Delhi 110029, India
| | - Geetanjali B. Tomar
- Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Pune, 411007 Maharashtra, India
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ABSTRACTS (BY NUMBER). Tissue Eng Part A 2022. [DOI: 10.1089/ten.tea.2022.29025.abstracts] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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Tracy EP, Stielberg V, Rowe G, Benson D, Nunes SS, Hoying JB, Murfee WL, LeBlanc AJ. State of the field: cellular and exosomal therapeutic approaches in vascular regeneration. Am J Physiol Heart Circ Physiol 2022; 322:H647-H680. [PMID: 35179976 PMCID: PMC8957327 DOI: 10.1152/ajpheart.00674.2021] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/07/2022] [Accepted: 02/09/2022] [Indexed: 01/19/2023]
Abstract
Pathologies of the vasculature including the microvasculature are often complex in nature, leading to loss of physiological homeostatic regulation of patency and adequate perfusion to match tissue metabolic demands. Microvascular dysfunction is a key underlying element in the majority of pathologies of failing organs and tissues. Contributing pathological factors to this dysfunction include oxidative stress, mitochondrial dysfunction, endoplasmic reticular (ER) stress, endothelial dysfunction, loss of angiogenic potential and vascular density, and greater senescence and apoptosis. In many clinical settings, current pharmacologic strategies use a single or narrow targeted approach to address symptoms of pathology rather than a comprehensive and multifaceted approach to address their root cause. To address this, efforts have been heavily focused on cellular therapies and cell-free therapies (e.g., exosomes) that can tackle the multifaceted etiology of vascular and microvascular dysfunction. In this review, we discuss 1) the state of the field in terms of common therapeutic cell population isolation techniques, their unique characteristics, and their advantages and disadvantages, 2) common molecular mechanisms of cell therapies to restore vascularization and/or vascular function, 3) arguments for and against allogeneic versus autologous applications of cell therapies, 4) emerging strategies to optimize and enhance cell therapies through priming and preconditioning, and, finally, 5) emerging strategies to bolster therapeutic effect. Relevant and recent clinical and animal studies using cellular therapies to restore vascular function or pathologic tissue health by way of improved vascularization are highlighted throughout these sections.
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Affiliation(s)
- Evan Paul Tracy
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
| | - Virginia Stielberg
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
| | - Gabrielle Rowe
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
| | - Daniel Benson
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
- Department of Bioengineering, University of Louisville, Louisville, Kentucky
| | - Sara S Nunes
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Heart & Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada
| | - James B Hoying
- Advanced Solutions Life Sciences, Manchester, New Hampshire
| | - Walter Lee Murfee
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida
| | - Amanda Jo LeBlanc
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
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Montazeri-Najafabady N, Dabbaghmanesh MH, Nasimi N, Sohrabi Z, Estedlal A, Asmarian N. Importance of TP53 codon 72 and intron 3 duplication 16 bp polymorphisms and their haplotypes in susceptibility to sarcopenia in Iranian older adults. BMC Geriatr 2022; 22:103. [PMID: 35123410 PMCID: PMC8818191 DOI: 10.1186/s12877-022-02765-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 01/13/2022] [Indexed: 12/13/2022] Open
Abstract
Abstract
Background
Sarcopenia is described as age-related progressive skeletal muscle failure that results in marked reduction in the patient’s independence and life quality. In this study, we explored the association of TP53 exon 4 Arg72pro (rs1042522) and Intron 3 16-bp Del/Ins (rs17878362) polymorphisms and their haplotypes with sarcopenia, anthropometric, body composition and biochemical parameters.
Methods
A total of 254 older individuals (65 sarcopenic and 189 healthy) were recruited in this research and genotyped by PCR–RFLP. Linear regression was applied to find the correlation between TP53 polymorphism, and biochemical and anthropometric parameters. The correlation between TP53 polymorphism and haplotypes and the risk of sarcopenia was investigated by logistic regression.
Results
Arg/Pro genotype carriers was at a lower (ORadj = 0.175, 95% CI = 0.068 – 0.447; P < 0.001) risk of sarcopenia compared to the Arg/Arg group. In haplotypes analysis, Arg-Ins (ORadj: 0.484, 95% CI = 0.231 – 1.011, P = 0.043) and Pro-Ins (ORadj: 0.473, 95% CI = 0.210 – 1.068, P = 0.022) haplotypes showed decreased risk of developing sarcopenia. Moreover, in the case of codon 72 polymorphism, skeletal muscle mass, appendicular lean mass (ALM), skeletal muscle mass index (SMI), hand grip strength and Triglycerides, for Intron 3 16-bp Del/Ins polymorphism, albumin, calcium, cholesterol, and LDL were different, and for the haplotypes, skeletal muscle mass, SMI, ALM, HDL and triglycerides were significantly different between groups.
Conclusions
We suggested that the Arg/Pro genotype of the codon 72 polymorphism in exon 4 of TP53, and Arginine-Insertion and Proline-Insertion haplotypes might decrease the risk of sarcopenia in Iranian older adults.
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Guo X, Wang J, Zou W, Wei W, Guan X, Liu J. Exploring microenvironment strategies to delay mesenchymal stem cell senescence. Stem Cells Dev 2021; 31:38-52. [PMID: 34913751 DOI: 10.1089/scd.2021.0254] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have recently emerged as an important candidate for cell therapy and tissue regeneration. However, some limitations in translational research and therapies still exist, such as insufficient cell supply, inadequate differentiation potential, and decreased immune capacity, all of which result from replicative senescence during long-term in vitro culture. In vitro, stem cells lack a protective microenvironment owing to the absence of physical and biochemical cues compared with the in vivo niche, which provides dynamic physicochemical and biological cues. This difference results in accelerated aging after long-term in vitro culture. Therefore, it remains a great challenge to delay replicative senescence in culture. Constructing a microenvironment to delay replicative senescence of MSCs by maintaining their phenotypes, properties, and functions is a feasible strategy to solve this problem and has made measurable progress both in preclinical studies and clinical trials. Here, we review the current knowledge on the characteristics of senescent MSCs, explore the molecular mechanisms of MSCs senescence, describe the niche of MSCs, and discuss some current microenvironment strategies to delay MSCs replicative senescence that can broaden their range of therapeutic applications.
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Affiliation(s)
- Xunhui Guo
- First Affiliated Hospital of Dalian Medical University, 74710, Stem Cell Clinical Research Center, Dalian, China;
| | - Jiayi Wang
- First Affiliated Hospital of Dalian Medical University, 74710, Stem Cell Clinical Research Center, Dalian, Dalian, China;
| | - Wei Zou
- Liaoning Normal University, 66523, College of Life Sciences, Dalian, China;
| | - Wenjuan Wei
- First Affiliated Hospital of Dalian Medical University, 74710, Dalian, China, 116011;
| | - Xin Guan
- First Affiliated Hospital of Dalian Medical University, 74710, Dalian, China, 116011;
| | - Jing Liu
- First Affiliated Hospital of Dalian Medical University, 74710, Dalian, China, 116011;
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Shang G, Han L, Wang Z, Song M, Wang D, Tan Y, Li Y, Li Y, Zhang W, Zhong M. Pim1 knockout alleviates sarcopenia in aging mice via reducing adipogenic differentiation of PDGFRα + mesenchymal progenitors. J Cachexia Sarcopenia Muscle 2021; 12:1741-1756. [PMID: 34435457 PMCID: PMC8718082 DOI: 10.1002/jcsm.12770] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 07/01/2021] [Accepted: 07/10/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Sarcopenia widely exists in elderly people and triggers numerous age-related events. The essential pathologic change lies in the increased intramuscular adipose tissue after aging with no exception to non-obese objects. Pim1 appears to be associated with adipogenic differentiation in recent studies, inspiring us to explore whether it regulates adipogenesis in aging muscles and affects sarcopenia. METHODS Wild-type and Pim1 knockout C57/BL6J mice were randomized into young and old groups. Histo-pathological and molecular biological methods were applied to assess the intramuscular adipose tissue content, the atrophy and regeneration, and the expressions of Pim1 and adipogenic transcription factors. PDGFRα+ mesenchymal progenitors were separated and their replicative aging model were established. Different time of adipogenic induction and different amounts of Pim1 inhibitor were applied, after which the adipogenic potency were evaluated. The expressions of Pim1 and adipogenic transcription factors were measured through western blotting. RESULTS The aging mice demonstrated decreased forelimb grip strength (P = 0.0003), hanging impulse (P < 0.0001), exhaustive running time (P < 0.0001), tetanic force (P = 0.0298), lean mass (P = 0.0008), and percentage of gastrocnemius weight in body weight (P < 0.0001), which were improved by Pim1 knockout (P = 0.0015, P = 0.0222, P < 0.0001, P = 0.0444, P = 0.0004, and P = 0.0003, respectively). To elucidate the mechanisms, analyses showed that Pim1 knockout decreased the fat mass (P = 0.0005) and reduced the intramuscular adipose tissue content (P = 0.0008) by inhibiting the C/EBPδ pathway (P = 0.0067) in aging mice, resulting in increased cross-sectional area of all and fast muscle fibres (P = 0.0017 and 0.0024 respectively), decreased levels of MuRF 1 and atrogin 1 (P = 0.0001 and 0.0329 respectively), and decreased content of Pax7 at the basal state (P = 0.0055). In vitro, senescent PDGFRα+ mesenchymal progenitors showed significantly increased the intracellular adipose tissue content (OD510) compared with young cells after 6 days of adipogenic induction (P < 0.0001). The Pim1 expression was elevated during adipogenic differentiation, and Pim1 inhibition significantly reduced the OD510 in senescent cells (P = 0.0040) by inhibiting the C/EBPδ pathway (P = 0.0047). CONCLUSIONS Pim1 knockout exerted protective effects in sarcopenia by inhibiting the adipogenic differentiation of PDGFRα+ mesenchymal progenitors induced by C/EBPδ activation and thus reducing the intramuscular adipose tissue content in aging mice. These results provide a potential target for the treatment of sarcopenia.
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Affiliation(s)
- Guo‐kai Shang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanShandongChina
| | - Lu Han
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanShandongChina
- Department of General Practice, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanShandongChina
| | - Zhi‐hao Wang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanShandongChina
- Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of MedicineShandong University; Shandong key Laboratory of Cardiovascular ProteomicsJinanShandongChina
| | - Ming Song
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanShandongChina
| | - Di Wang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanShandongChina
| | - Yan‐min Tan
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanShandongChina
| | - Yi‐hui Li
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanShandongChina
- Department of Critical Care Medicine, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanShandongChina
| | - Yu‐lin Li
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanShandongChina
| | - Wei Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanShandongChina
| | - Ming Zhong
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of MedicineShandong UniversityJinanShandongChina
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Kardeh S, Khorraminejad-Shirazi M, Faezi-Marian S. Cellular senescence and skin tissue engineering: mTOR as a potential pharmacological target for increasing proliferative capacity of keratinocytes. Burns 2020; 47:744-746. [PMID: 33277093 DOI: 10.1016/j.burns.2020.10.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 10/12/2020] [Indexed: 01/18/2023]
Affiliation(s)
- Sina Kardeh
- Cellular and Molecular Medicine Student Research Group, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Mohammadhossein Khorraminejad-Shirazi
- Cellular and Molecular Medicine Student Research Group, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shima Faezi-Marian
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
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Preconditioned and Genetically Modified Stem Cells for Myocardial Infarction Treatment. Int J Mol Sci 2020; 21:ijms21197301. [PMID: 33023264 PMCID: PMC7582407 DOI: 10.3390/ijms21197301] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 09/25/2020] [Accepted: 09/25/2020] [Indexed: 02/07/2023] Open
Abstract
Ischemic heart disease and myocardial infarction remain leading causes of mortality worldwide. Existing myocardial infarction treatments are incapable of fully repairing and regenerating the infarcted myocardium. Stem cell transplantation therapy has demonstrated promising results in improving heart function following myocardial infarction. However, poor cell survival and low engraftment at the harsh and hostile environment at the site of infarction limit the regeneration potential of stem cells. Preconditioning with various physical and chemical factors, as well as genetic modification and cellular reprogramming, are strategies that could potentially optimize stem cell transplantation therapy for clinical application. In this review, we discuss the most up-to-date findings related to utilizing preconditioned stem cells for myocardial infarction treatment, focusing mainly on preconditioning with hypoxia, growth factors, drugs, and biological agents. Furthermore, genetic manipulations on stem cells, such as the overexpression of specific proteins, regulation of microRNAs, and cellular reprogramming to improve their efficiency in myocardial infarction treatment, are discussed as well.
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Granz CL, Gorji A. Dental stem cells: The role of biomaterials and scaffolds in developing novel therapeutic strategies. World J Stem Cells 2020; 12:897-921. [PMID: 33033554 PMCID: PMC7524692 DOI: 10.4252/wjsc.v12.i9.897] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 06/05/2020] [Accepted: 08/16/2020] [Indexed: 02/06/2023] Open
Abstract
Dental stem cells (DSCs) are self-renewable cells that can be obtained easily from dental tissues, and are a desirable source of autologous stem cells. The use of DSCs for stem cell transplantation therapeutic approaches is attractive due to their simple isolation, high plasticity, immunomodulatory properties, and multipotential abilities. Using appropriate scaffolds loaded with favorable biomolecules, such as growth factors, and cytokines, can improve the proliferation, differentiation, migration, and functional capacity of DSCs and can optimize the cellular morphology to build tissue constructs for specific purposes. An enormous variety of scaffolds have been used for tissue engineering with DSCs. Of these, the scaffolds that particularly mimic tissue-specific micromilieu and loaded with biomolecules favorably regulate angiogenesis, cell-matrix interactions, degradation of extracellular matrix, organized matrix formation, and the mineralization abilities of DSCs in both in vitro and in vivo conditions. DSCs represent a promising cell source for tissue engineering, especially for tooth, bone, and neural tissue restoration. The purpose of the present review is to summarize the current developments in the major scaffolding approaches as crucial guidelines for tissue engineering using DSCs and compare their effects in tissue and organ regeneration.
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Affiliation(s)
- Cornelia Larissa Granz
- Epilepsy Research Center, Westfälische Wilhelms-Universität Münster, Münster 48149, Germany
| | - Ali Gorji
- Epilepsy Research Center, Westfälische Wilhelms-Universität Münster, Münster 48149, Germany
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Khorraminejad-Shirazi M, Sani M, Talaei-Khozani T, Dorvash M, Mirzaei M, Faghihi MA, Monabati A, Attar A. AICAR and nicotinamide treatment synergistically augment the proliferation and attenuate senescence-associated changes in mesenchymal stromal cells. Stem Cell Res Ther 2020; 11:45. [PMID: 32014016 PMCID: PMC6998366 DOI: 10.1186/s13287-020-1565-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 01/05/2020] [Accepted: 01/19/2020] [Indexed: 12/11/2022] Open
Abstract
Background Mesenchymal stromal cell (MSC) stemness capacity diminishes over prolonged in vitro culture, which negatively affects their application in regenerative medicine. To slow down the senescence of MSCs, here, we have evaluated the in vitro effects of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator, and nicotinamide (NAM), an activator of sirtuin1 (SIRT1). Methods Human adipose-derived MSCs were cultured to passage (P) 5. Subsequently, the cells were grown in either normal medium alone (control group), the medium supplemented with AICAR (1 mM) and NAM (5 mM), or in the presence of both for 5 weeks to P10. Cell proliferation, differentiation capacity, level of apoptosis and autophagy, morphological changes, total cellular reactive oxygen species (ROS), and activity of mTORC1 and AMPK were compared among different treatment groups. Results MSCs treated with AICAR, NAM, or both displayed an increase in proliferation and osteogenic differentiation, which was augmented in the group receiving both. Treatment with AICAR or NAM led to decreased expression of β-galactosidase, reduced accumulation of dysfunctional lysosomes, and characteristic morphologic features of young MSCs. Furthermore, while NAM administration could significantly reduce the total cellular ROS in aged MSCs, AICAR treatment did not. Moreover, AICAR-treated cells possess a high proliferation capacity; however, they also show the highest level of cellular apoptosis. The observed effects of AICAR and NAM were in light of the attenuated mTORC1 activity and increased AMPK activity and autophagy. Conclusions Selective inhibition of mTORC1 by AICAR and NAM boosts autophagy, retains MSCs’ self-renewal and multi-lineage differentiation capacity, and postpones senescence-associated changes after prolonged in vitro culture. Additionally, co-administration of AICAR and NAM shows an additive or probably a synergistic effect on cellular senescence.
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Affiliation(s)
- Mohammadhossein Khorraminejad-Shirazi
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran.,Cell and Molecular Medicine Student Research Group, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahsa Sani
- Tissue Engineering Department, School of Advanced Medical Science and Technology, Shiraz University of Medical Science, Shiraz, Iran.,Tissue Engineering Lab, Department of Anatomical Sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tahereh Talaei-Khozani
- Tissue Engineering Lab, Department of Anatomical Sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammadreza Dorvash
- Cell and Molecular Medicine Student Research Group, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.,Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Malihe Mirzaei
- Persian BayanGene Research and Training Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Ali Faghihi
- Persian BayanGene Research and Training Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Ahmad Monabati
- Department of Pathology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.,Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Armin Attar
- Department of Cardiovascular Medicine, Shiraz University of Medical Sciences, PO Box 71344-1864, Shiraz, Iran.
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