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Park S, Yoon YJ, Hong Y, Yu J, Cho JM, Jeong YJ, Yu H, Jeong H, Lee H, Hwang S, Koh WG, Yang JY, Hyun KA, Jung HI, Lim JY. CD9-enriched extracellular vesicles from chemically reprogrammed basal progenitors of salivary glands mitigate salivary gland fibrosis. Bioact Mater 2025; 47:229-247. [PMID: 39925710 PMCID: PMC11803853 DOI: 10.1016/j.bioactmat.2025.01.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 12/07/2024] [Accepted: 01/16/2025] [Indexed: 02/11/2025] Open
Abstract
Extracellular vesicles (EVs) derived from stem cells offer promising potential for cell-free therapy. However, refining their cargo for precise disease targeting and delivery remains challenging. This study employed chemical reprogramming via dual inhibition of transforming growth factor beta (TGFβ) and bone morphogenetic protein (BMP) to expand salivary gland basal progenitor cells (sgBPCs). CD9-enriched (CD9+) EVs were then isolated from the sgBPC secretome concentrate using a dual microfluidic chip. Notably, CD9+ EVs demonstrated superior uptake by salivary epithelial cells compared to CD9-depleted (CD9-) EVs and total EVs. In vivo studies using a salivary gland (SG) obstruction mouse model and ex vivo studies in SG fibrosis organoids revealed that CD9+ EVs significantly enhanced anti-fibrotic effects over CD9- EVs and control treatments. The presence of miR-3162 and miR-1290 in CD9+ EVs supported their anti-fibrotic properties by downregulating ACVR1 expression. The chemical reprogramming culture method effectively expanded sgBPCs, enabling consistent and scalable EV production. Utilizing microfluidic chip-isolated CD9+ EVs and ductal delivery presents a targeted and efficient approach for anti-fibrotic SG regeneration.
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Affiliation(s)
- Sunyoung Park
- School of Mechanical Engineering, Yonsei University, 50 Yonsei-ro, Seoul, 03722, Republic of Korea
- The DABOM Inc., 50 Yonsei-ro, Seoul, 03722, Republic of Korea
| | - Yeo-Jun Yoon
- Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Yongpyo Hong
- Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Jianning Yu
- School of Mechanical Engineering, Yonsei University, 50 Yonsei-ro, Seoul, 03722, Republic of Korea
- Department of Biomedical Laboratory Science, Yonsei University, 1 Yeonsedae-gil, Wonju, Gangwon-do, 26493, Republic of Korea
| | - Jae-Min Cho
- Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Ye Jin Jeong
- Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Haeun Yu
- School of Mechanical Engineering, Yonsei University, 50 Yonsei-ro, Seoul, 03722, Republic of Korea
| | - Hyorim Jeong
- The DABOM Inc., 50 Yonsei-ro, Seoul, 03722, Republic of Korea
| | - Hyunjin Lee
- The DABOM Inc., 50 Yonsei-ro, Seoul, 03722, Republic of Korea
| | - Seungyeon Hwang
- Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
| | - Won-Gun Koh
- Department of Chemical and Biomolecular Engineering, Yonsei University, 50 Yonsei-ro, Seoul, 03722, Republic of Korea
| | - Ji Yeong Yang
- School of Mechanical Engineering, Yonsei University, 50 Yonsei-ro, Seoul, 03722, Republic of Korea
- The DABOM Inc., 50 Yonsei-ro, Seoul, 03722, Republic of Korea
| | - Kyung-A Hyun
- School of Mechanical Engineering, Yonsei University, 50 Yonsei-ro, Seoul, 03722, Republic of Korea
- Korea Electronics Technology Institute (KETI), Seongnam, Gyeonggi-do, 13509, Republic of Korea
| | - Hyo-Il Jung
- School of Mechanical Engineering, Yonsei University, 50 Yonsei-ro, Seoul, 03722, Republic of Korea
- The DABOM Inc., 50 Yonsei-ro, Seoul, 03722, Republic of Korea
| | - Jae-Yol Lim
- Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea
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Moreira MS, Mota ME, Ariga SKK, Jaguar GC, Marques MM. Mesenchymal stem cell therapies evidence in the treatment of irradiated salivary glands: A scoping review. J Clin Exp Dent 2024; 16:e1547-e1554. [PMID: 39822783 PMCID: PMC11733895 DOI: 10.4317/jced.62242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Accepted: 11/08/2024] [Indexed: 01/19/2025] Open
Abstract
Background Radiotherapy is one of the main treatments for head and neck cancer; however, due to its non-selectivity the glandular tissue can be affected. This scoping review aimed to identify the evidence about mesenchymal stem cell therapies for irradiated salivary gland regeneration. Material and Methods Two independent reviewers performed a literature search in MEDLINE/PubMed, Scopus, and Web of Science. The inclusion criteria were: 1) studies evaluation regeneration of irradiated salivary glands by stem cell therapies (cell-based or cell-free), (2) in vivo studies. Results The search resulted in 13 included studies. In general, both therapies demonstrated increased salivary levels, with mucin and amylase increased and structural protection of acinar cells. The cell-free therapy based on labial glands stem cell extract demonstrated a higher number of parasympathetic nerves. Conclusions Stem cell therapies (cell-free and cell-based) appear promising strategies for recovering saliva production in patients presenting irradiation-induced hyposalivation, with positive results toward regeneration of the form and function of the glands. However, due to the scarcity and heterogenicity of these pre-clinical studies, it is not possible to indicate which is the more indicated therapy. Key words:Mesenchymal stem cells, extracellular vesicles, exosomes, salivary glands, stem cell biology, hyposalivation, radiotherapy.
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Affiliation(s)
- Maria Stella Moreira
- Department of Stomatology, A.C. Camargo Cancer Center, São Paulo, SP, Brazil
- Department of Stomatology, School of Dentistry, University of São Paulo, São Paulo, SP, Brazil
| | - Maria Emília Mota
- Department of Stomatology, School of Dentistry, University of São Paulo, São Paulo, SP, Brazil
| | - Suely Kunimi Kubo Ariga
- School of Medicine, Emergency Medicine Laboratory, University of São Paulo, São Paulo, SP, Brazil
| | | | - Márcia Martins Marques
- Department of Stomatology, School of Dentistry, University of São Paulo, São Paulo, SP, Brazil
- AALZ, Sigmund Freud University, Vienna, Austria
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Starska-Kowarska K. Role of Mesenchymal Stem/Stromal Cells in Head and Neck Cancer-Regulatory Mechanisms of Tumorigenic and Immune Activity, Chemotherapy Resistance, and Therapeutic Benefits of Stromal Cell-Based Pharmacological Strategies. Cells 2024; 13:1270. [PMID: 39120301 PMCID: PMC11311692 DOI: 10.3390/cells13151270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 07/11/2024] [Accepted: 07/26/2024] [Indexed: 08/10/2024] Open
Abstract
Head and neck cancer (HNC) entails a heterogenous neoplastic disease that arises from the mucosal epithelium of the upper respiratory system and the gastrointestinal tract. It is characterized by high morbidity and mortality, being the eighth most common cancer worldwide. It is believed that the mesenchymal/stem stromal cells (MSCs) present in the tumour milieu play a key role in the modulation of tumour initiation, development and patient outcomes; they also influence the resistance to cisplatin-based chemotherapy, the gold standard for advanced HNC. MSCs are multipotent, heterogeneous and mobile cells. Although no MSC-specific markers exist, they can be recognized based on several others, such as CD73, CD90 and CD105, while lacking the presence of CD45, CD34, CD14 or CD11b, CD79α, or CD19 and HLA-DR antigens; they share phenotypic similarity with stromal cells and their capacity to differentiate into other cell types. In the tumour niche, MSC populations are characterized by cell quiescence, self-renewal capacity, low reactive oxygen species production and the acquisition of epithelial-to-mesenchymal transition properties. They may play a key role in the process of acquiring drug resistance and thus in treatment failure. The present narrative review examines the links between MSCs and HNC, as well as the different mechanisms involved in the development of resistance to current chemo-radiotherapies in HNC. It also examines the possibilities of pharmacological targeting of stemness-related chemoresistance in HNSCC. It describes promising new strategies to optimize chemoradiotherapy, with the potential to personalize patient treatment approaches, and highlights future therapeutic perspectives in HNC.
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Affiliation(s)
- Katarzyna Starska-Kowarska
- Department of Physiology, Pathophysiology and Clinical Immunology, Department of Clinical Physiology, Medical University of Lodz, Żeligowskiego 7/9, 90-752 Lodz, Poland; ; Tel.: +48-42-2725237
- Department of Otorhinolaryngology, EnelMed Center Expert, Lodz, Drewnowska 58, 91-001 Lodz, Poland
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Li H, Wang G, Zhao G, Liu H, Liu L, Cao Y, Li C. TGF-β1 maintains the developmental potential of embryonic submandibular gland epithelia separated with mesenchyme. Heliyon 2024; 10:e33506. [PMID: 39040362 PMCID: PMC11261778 DOI: 10.1016/j.heliyon.2024.e33506] [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: 03/06/2023] [Revised: 06/11/2024] [Accepted: 06/21/2024] [Indexed: 07/24/2024] Open
Abstract
Objective The objective of this study was to investigate the impact of transforming growth factor β1 (TGF-β1) on epithelial development using an ex vivo model of submandibular gland (SMG) epithelial-mesenchymal separation. Materials and methods The ex vivo model was established by separating E13 mouse SMG epithelia and mesenchyme, culturing them independently for 24 h, recombining them, and observing branching morphogenesis. Microarray analysis was performed to evaluate the transcriptome of epithelia treated with and without 1 ng/ml TGF-β1. Differential gene expression, pathway enrichment, and protein-protein interaction networks were analyzed. Quantitative real-time polymerase chain reaction, Western blot, and immunofluorescence were employed to validate the mRNA and protein levels. Results Recombined SMGs using separated epithelia and mesenchyme that were cultured for 24 h showed a significant inhibition of epithelial development compared to SMGs recombined immediately after separation. The level of TGF-β1 decreased in the SMG epithelia after epithelia-mesenchyme separation. Epithelia that were separated from mesenchyme for 24 h and pretreated with 1 ng/ml TGF-β1 continued to develop after recombination with mesenchyme, while epithelia without 1 ng/ml TGF-β1 treatment did not. Microarray analysis suggested pathway enrichment related to epithelial development and an upregulation of Sox2 in the 1 ng/ml TGF-β1-treated epithelia. Further experiments validated the phosphorylation of SMAD2 and SMAD3, upregulation of SOX2 and genes associated with epithelial development, including Prol1, Dcpp1, Bhlha15, Smgc, and Bpifa2. Additionally, 1 ng/ml TGF-β1 inhibited epithelial apoptosis by improving the BCL2/BAX ratio and reducing cleaved caspase 3. Conclusions The addition of 1 ng/ml TGF-β1 maintained the developmental potential of embryonic SMG epithelia separated from mesenchyme for 24 h. This suggests that 1 ng/ml TGF-β1 may partially compensate for the role of mesenchyme during the separation phase, although its compensation is limited in extent.
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Affiliation(s)
- Honglin Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
- Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Guanru Wang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
- Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Guile Zhao
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
- Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Huabing Liu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
- Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Liu Liu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
- Department of Conservative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Yubin Cao
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Chunjie Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
- Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
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Carlander ALF, Gundestrup AK, Jansson PM, Follin B, Hoeeg C, Kousholt BS, Larsen RT, Jakobsen KK, Rimborg S, Fischer-Nielsen A, Grønhøj C, Buchwald CV, Lynggaard CD. Mesenchymal Stromal/Stem Cell Therapy Improves Salivary Flow Rate in Radiation-Induced Salivary Gland Hypofunction in Preclinical in vivo Models: A Systematic Review and Meta-Analysis. Stem Cell Rev Rep 2024; 20:1078-1092. [PMID: 38430363 PMCID: PMC11087340 DOI: 10.1007/s12015-024-10700-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2024] [Indexed: 03/03/2024]
Abstract
BACKGROUND Mesenchymal stromal/stem cells (MSCs) have been suggested for salivary gland (SG) restoration following radio-induced salivary gland damage. This study aimed to determine the safety and effectiveness of MSC therapy on radio-induced SG damage and hypofunction in preclinical in vivo studies. METHODS PubMed and EMBASE were systematically searched for preclinical in vivo interventional studies evaluating efficacy and safety of MSC treatment following radio-induced salivary gland damage published before 10th of January 2022. The primary endpoint was salivary flow rate (SFR) evaluated in a meta-analysis. The study protocol was published and registered on PROSPERO ( www.crd.ac.uk/prospero ), registration number CRD42021227336. RESULTS A total of 16 preclinical in vivo studies were included for qualitative analysis (858 experimental animals) and 13 in the meta-analysis (404 experimental animals). MSCs originated from bone marrow (four studies), adipose tissue (10 studies) and salivary gland tissue (two studies) and were administered intravenously (three studies), intra-glandularly (11 studies) or subcutaneously (one study). No serious adverse events were reported. The overall effect on SFR was significantly increased with a standardized mean difference (SMD) of 6.99 (95% CI: 2.55-11.42). Studies reported improvements in acinar tissue, vascular areas and paracrine factors. CONCLUSION In conclusion, this systematic review and meta-analysis showed a significant effect of MSC therapy for restoring SG functioning and regenerating SG tissue following radiotherapy in preclinical in vivo studies without serious adverse events. MSC therapy holds significant therapeutic potential in the treatment of radio-induced xerostomia, but comprehensive, randomized, clinical trials in humans are required to ascertain their efficacy in a clinical setting.
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Affiliation(s)
- Amanda-Louise Fenger Carlander
- Department of Otolaryngology and Audiology, Head and Neck Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
- Department of Otolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, Copenhagen University hospital, Copenhagen, Denmark.
| | - Anders Kierkegaard Gundestrup
- Department of Otolaryngology and Audiology, Head and Neck Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Per Marcus Jansson
- Department of Otolaryngology and Audiology, Head and Neck Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Bjarke Follin
- Cardiology Stem Cell Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Cecilie Hoeeg
- Cardiology Stem Cell Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Birgitte Saima Kousholt
- Department of Clinical Medicine, Aarhus University Group for Understanding Systematic Reviews and Meta analyses in Translational Preclinical Science, Aarhus University, Copenhagen, Denmark
| | - Rasmus Tolstrup Larsen
- Department of Occupational Therapy and Physiotherapy, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Section of Social Medicine, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Kathrine Kronberg Jakobsen
- Department of Otolaryngology and Audiology, Head and Neck Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Susie Rimborg
- The Royal Danish Library, Copenhagen University Library, Copenhagen, Denmark
| | - Anne Fischer-Nielsen
- Department of Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Christian Grønhøj
- Department of Otolaryngology and Audiology, Head and Neck Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Christian von Buchwald
- Department of Otolaryngology and Audiology, Head and Neck Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Charlotte Duch Lynggaard
- Department of Otolaryngology and Audiology, Head and Neck Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
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Xiao XY, Zhang NN, Long YZ, Huang GL. Repair mechanism of radiation-induced salivary gland injury by hypoxia-pretreated human urine-derived stem cell exosomes. Oral Dis 2024; 30:1234-1241. [PMID: 36546840 DOI: 10.1111/odi.14476] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 12/07/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVE To explore the protective effect of human urine-derived stem cell exosomes (hUSC-Exos) on radiation-induced salivary gland (SG) injuries in Sprague Dawley rats. METHODS Fresh adult urine was collected, and primary hUSCs were isolated and identified. The hUSCs were hypoxia-pretreated with 1% oxygen for 24 h and then transferred to a normoxic culture environment for 24 h. The hUSC-Exos were collected and identified for exosomes. A radiation-induced injury model was established in the rats, and exosomes were introduced by local injection in the SG and tail vein. The submandibular gland was excised for morphological observation 1 week later. Immunohistochemical detection of the glandular tissue was conducted by α-smooth muscle actin (a-SMA), stem cell growth factor receptor (c-Kit) staining, and periodic acid-Schiff staining. Qualitative polymerase chain reaction and western blot analysis were adopted to detect the gene and protein expression of Wnt3a, GSK3β, and Axin. RESULTS In both the normoxic and hypoxic hUSC-Exo groups, microvesicular structures with bilayer membranes of approximately 80 nm in diameter were detected, and the expressions of CD9 and CD63 were detected by nanoflow cytometry. Compared with the control group, in the radiation-induced injury model group, the expression of a-SMA was significantly higher, the expression of c-Kit was significantly lower, and the expressions of Wnt3a, GSK3β, and Axin were significantly upregulated; the differences were statistically significant (p < 0.05). Compared with the model group, in the normoxic and hypoxic hUSC-Exo groups, the expression of a-SMA was significantly decreased, the expression of c-Kit was significantly increased, and the expressions of Wnt3a, GSK3β, and Axin were significantly upregulated; the differences were statistically significant (p < 0.05). CONCLUSION Hypoxia-pretreated hUSC-Exos could repair radiation-induced SG injuries by activating the Wnt3a/GSK3β pathway to suppress the expressions of a-SMA and c-Kit.
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Affiliation(s)
| | - Ni-Ni Zhang
- Department of Dentofacial Surgery, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China
| | - Yuan-Zhu Long
- School Stomatol, Key Lab Oral Disease Research, Zunyi Medical University, Zunyi, China
| | - Gui-Lin Huang
- Department of Dentofacial Surgery, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China
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Girard N. Surgical Treatment of Facial Abscesses and Jaw Osteomyelitis of Dental Origin Using Extraoral Tooth Extraction in the Domestic Rabbit: A Case Series. J Vet Dent 2024; 41:93-105. [PMID: 37050862 DOI: 10.1177/08987564231168985] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2023]
Abstract
The treatment of facial abscesses of dental origin is difficult as jaw osteomyelitis in rabbits is mainly associated with a thick caseous pus that is particularly difficult to drain. Precise identification of the teeth involved in the infected site with the use of cone beam computed tomography (CBCT) was expected to ensure a favorable surgical treatment plan without a long-term local antibiotic strategy or local marsupialization. The first part of the study compared multi-planar reconstruction (MPR) and 3D reconstruction complemented by a maximum intensity projection filter (MIP). The surgical part of the study included rabbits with documentation of the treatment outcome for a period greater than one month after surgery and having had at least one post-operative CBCT demonstrating the achievement of surgical extraction. MPR is significantly more efficient than MIP techniques for alveolar bone (P < 10-7), spongious bone (P < 10-10) and apical elongation (P < 10-5) parameters. Nineteen of 20 surgical sites gave radiological confirmation of the success of the surgical plan. Eighteen of 20 of the abscess sites were clinically healed within one month. Seven out of 20 of the abscess sites presented evidence of one dental structure regrowth following the CBCT recheck. Two out of these seven cases presented with a concomitant persistent chronic facial fistula. Both cases healed after second-stage surgery to extract the tooth structure. The mean number of teeth extracted was 2.85, and seven of the 20 procedures included one incisor.
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Affiliation(s)
- Nicolas Girard
- Azurvet Veterinary Referal Center, Saint Laurent du Var, France
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Zayed HM, Kheir El Din NH, Abu-Seida AM, Abo Zeid AA, Ezzatt OM. Gingival-derived mesenchymal stem cell therapy regenerated the radiated salivary glands: functional and histological evidence in murine model. Stem Cell Res Ther 2024; 15:46. [PMID: 38365799 PMCID: PMC10874004 DOI: 10.1186/s13287-024-03659-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 02/07/2024] [Indexed: 02/18/2024] Open
Abstract
BACKGROUND Radiotherapy in head and neck cancer management causes degeneration of the salivary glands (SG). This study was designed to determine the potential of gingival mesenchymal stem cells (GMSCs) as a cell-based therapy to regenerate irradiated parotid SG tissues and restore their function using a murine model. METHODS Cultured isolated cells from gingival tissues of 4 healthy guinea pigs at passage 3 were characterized as GMSCSs using flow cytometry for surface markers and multilineage differentiation capacity. Twenty-one Guinea pigs were equally divided into three groups: Group I/Test, received single local irradiation of 15 Gy to the head and neck field followed by intravenous injection of labeled GMSCs, Group II/Positive control, which received the same irradiation dose followed by injection of phosphate buffer solution (PBS), and Group III/Negative control, received (PBS) injection only. Body weight and salivary flow rate (SFR) were measured at baseline, 11 days, 8-, 13- and 16-weeks post-irradiation. At 16 weeks, parotid glands were harvested for assessment of gland weight and histological and immunohistochemical analysis. RESULTS The injected GMSCs homed to degenerated glands, with subsequent restoration of the normal gland histological acinar and tubular structure associated with a significant increase in cell proliferation and reduction in apoptotic activity. Subsequently, a significant increase in body weight and SFR, as well as an increase in gland weight at 16 weeks in comparison with the irradiated non-treated group were observed. CONCLUSION The study provided a new potential therapeutic strategy for the treatment of xerostomia by re-engineering radiated SG using GMSCs.
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Affiliation(s)
- Hagar M Zayed
- Department of Oral Medicine, Periodontology and Oral Diagnosis, Faculty of Dentistry, Ain Shams University, 20 Organization of African Union St., Cairo, 1156, Egypt
- Central Lab of Stem Cells and Biomaterial Applied Research (CLSBAR), Faculty of Dentistry, Ain-Shams University, Cairo, Egypt
| | - Nevine H Kheir El Din
- Department of Oral Medicine, Periodontology and Oral Diagnosis, Faculty of Dentistry, Ain Shams University, 20 Organization of African Union St., Cairo, 1156, Egypt
| | - Ashraf M Abu-Seida
- Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, Cairo University, Cairo, 13736, Egypt
| | - Asmaa A Abo Zeid
- Department of Histology, and Cell Biology, Faculty of Medicine, Ain Shams University, Cairo, 11591, Egypt
| | - Ola M Ezzatt
- Department of Oral Medicine, Periodontology and Oral Diagnosis, Faculty of Dentistry, Ain Shams University, 20 Organization of African Union St., Cairo, 1156, Egypt.
- Central Lab of Stem Cells and Biomaterial Applied Research (CLSBAR), Faculty of Dentistry, Ain-Shams University, Cairo, Egypt.
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Rose SC, Larsen M, Xie Y, Sharfstein ST. Salivary Gland Bioengineering. Bioengineering (Basel) 2023; 11:28. [PMID: 38247905 PMCID: PMC10813147 DOI: 10.3390/bioengineering11010028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 11/19/2023] [Accepted: 11/30/2023] [Indexed: 01/23/2024] Open
Abstract
Salivary gland dysfunction affects millions globally, and tissue engineering may provide a promising therapeutic avenue. This review delves into the current state of salivary gland tissue engineering research, starting with a study of normal salivary gland development and function. It discusses the impact of fibrosis and cellular senescence on salivary gland pathologies. A diverse range of cells suitable for tissue engineering including cell lines, primary salivary gland cells, and stem cells are examined. Moreover, the paper explores various supportive biomaterials and scaffold fabrication methodologies that enhance salivary gland cell survival, differentiation, and engraftment. Innovative engineering strategies for the improvement of vascularization, innervation, and engraftment of engineered salivary gland tissue, including bioprinting, microfluidic hydrogels, mesh electronics, and nanoparticles, are also evaluated. This review underscores the promising potential of this research field for the treatment of salivary gland dysfunction and suggests directions for future exploration.
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Affiliation(s)
- Stephen C. Rose
- Department of Nanoscale Science and Engineering, College of Nanotechnology, Science, and Engineering, University at Albany, SUNY, 257 Fuller Road, Albany, NY 12203, USA (Y.X.)
| | - Melinda Larsen
- Department of Biological Sciences and The RNA Institute, University at Albany, SUNY, 1400 Washington Ave., Albany, NY 12222, USA;
| | - Yubing Xie
- Department of Nanoscale Science and Engineering, College of Nanotechnology, Science, and Engineering, University at Albany, SUNY, 257 Fuller Road, Albany, NY 12203, USA (Y.X.)
| | - Susan T. Sharfstein
- Department of Nanoscale Science and Engineering, College of Nanotechnology, Science, and Engineering, University at Albany, SUNY, 257 Fuller Road, Albany, NY 12203, USA (Y.X.)
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Strojan P, Plavc G, Kokalj M, Mitrovic G, Blatnik O, Lezaic L, Socan A, Bavec A, Tesic N, Hartman K, Svajger U. Post-radiation xerostomia therapy with allogeneic mesenchymal stromal stem cells in patients with head and neck cancer: study protocol for phase I clinical trial. Radiol Oncol 2023; 57:538-549. [PMID: 38038413 PMCID: PMC10690747 DOI: 10.2478/raon-2023-0052] [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: 09/04/2023] [Accepted: 09/25/2023] [Indexed: 12/02/2023] Open
Abstract
BACKGROUND Xerostomia is a common side effect of radiotherapy in patients with head and neck tumors that negatively affects quality of life. There is no known effective standard treatment for xerostomia. Here, we present the study protocol used to evaluate the safety and preliminary efficacy of allogeneic mesenchymal stromal stem cells (MSCs) derived from umbilical cord tissue. PATIENTS AND METHODS Ten oropharyngeal cancer patients with post-radiation xerostomia and no evidence of disease recurrence 2 or more years after (chemo)irradiation (intervention group) and 10 healthy volunteers (control group) will be enrolled in this nonrandomized, open-label, phase I exploratory study. MSCs from umbilical cord tissue will be inserted under ultrasound guidance into both parotid glands and both submandibular glands of the patients. Toxicity of the procedure will be assessed according to CTCAE v5.0 criteria at days 0, 1, 5, 28, and 120. Efficacy will be assessed by measuring salivary flow and analyzing its composition, scintigraphic evaluation of MSC grafting, retention, and migration, and questionnaires measuring subjective xerostomia and quality of life. In addition, the radiological, functional, and morphological characteristics of the salivary tissue will be assessed before, at 4 weeks, and at 4 months after the procedure. In the control group subjects, only salivary flow rate and salivary composition will be determined. DISCUSSION The use of allogeneic MSCs from umbilical cord tissue represents an innovative approach for the treatment of xerostomia after radiation. Due to the noninvasive collection procedure, flexibility of cryobanking, and biological advantages, xerostomia therapy using allogeneic MSCs from umbilical cord tissue may have an advantage over other similar therapies.
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Affiliation(s)
- Primoz Strojan
- Institute of Oncology Ljubljana, Ljubljana, Slovenia
- University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia
| | - Gaber Plavc
- Institute of Oncology Ljubljana, Ljubljana, Slovenia
- University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia
| | - Marko Kokalj
- Institute of Oncology Ljubljana, Ljubljana, Slovenia
| | | | - Olga Blatnik
- Institute of Oncology Ljubljana, Ljubljana, Slovenia
| | - Luka Lezaic
- University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia
- University Medical Centre Ljubljana, Department of Nuclear Medicine, Ljubljana, Slovenia
| | - Aljaz Socan
- University Medical Centre Ljubljana, Department of Nuclear Medicine, Ljubljana, Slovenia
| | - Aljosa Bavec
- University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia
| | - Natasa Tesic
- Blood Transfusion Center of Slovenia, Ljubljana, Slovenia
| | | | - Urban Svajger
- Blood Transfusion Center of Slovenia, Ljubljana, Slovenia
- University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia
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11
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Zhang H, Wan X, Tian J, An Z, Liu L, Zhao X, Zhou Y, Zhang L, Ge C, Song X. The therapeutic efficacy and clinical translation of mesenchymal stem cell-derived exosomes in cardiovascular diseases. Biomed Pharmacother 2023; 167:115551. [PMID: 37783149 DOI: 10.1016/j.biopha.2023.115551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 09/08/2023] [Accepted: 09/18/2023] [Indexed: 10/04/2023] Open
Abstract
Exosomes, mainly derived from mesenchymal stem cells, provide a good reference for cardiac function repair and clinical application in cardiac and vascular diseases by regulating cardiomyocyte viability, inflammatory levels, angiogenesis, and ventricular remodeling after a heart injury. This review presents the cardioprotective efficacy of mesenchymal stem cell-originated exosomes and explores the underlying molecular mechanisms. Furthermore, we expound on several efficient approaches to transporting exosomes into the heart in clinical application and comment on the advantages and disadvantages of each method.
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Affiliation(s)
- Huan Zhang
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China
| | - Xueqi Wan
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China
| | - Jinfan Tian
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China
| | - Ziyu An
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China
| | - Libo Liu
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China; The Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong 271000, PR China
| | - Xin Zhao
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China
| | - Yuquan Zhou
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China
| | - Lijun Zhang
- Department of Radiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China
| | - Changjiang Ge
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China.
| | - Xiantao Song
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China.
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12
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Prescher H, Froimson JR, Hanson SE. Deconstructing Fat to Reverse Radiation Induced Soft Tissue Fibrosis. Bioengineering (Basel) 2023; 10:742. [PMID: 37370673 PMCID: PMC10295516 DOI: 10.3390/bioengineering10060742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 06/06/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Adipose tissue is composed of a collection of cells with valuable structural and regenerative function. Taken as an autologous graft, these cells can be used to address soft tissue defects and irregularities, while also providing a reparative effect on the surrounding tissues. Adipose-derived stem or stromal cells are primarily responsible for this regenerative effect through direct differentiation into native cells and via secretion of numerous growth factors and cytokines that stimulate angiogenesis and disrupt pro-inflammatory pathways. Separating adipose tissue into its component parts, i.e., cells, scaffolds and proteins, has provided new regenerative therapies for skin and soft tissue pathology, including that resulting from radiation. Recent studies in both animal models and clinical trials have demonstrated the ability of autologous fat grafting to reverse radiation induced skin fibrosis. An improved understanding of the complex pathologic mechanism of RIF has allowed researchers to harness the specific function of the ASCs to engineer enriched fat graft constructs to improve the therapeutic effect of AFG.
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Affiliation(s)
| | | | - Summer E. Hanson
- Section of Plastic & Reconstructive Surgery, University of Chicago Medical Center, Chicago, IL 60615, USA
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13
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Phan TV, Oo Y, Ahmed K, Rodboon T, Rosa V, Yodmuang S, Ferreira JN. Salivary gland regeneration: from salivary gland stem cells to three-dimensional bioprinting. SLAS Technol 2023; 28:199-209. [PMID: 37019217 DOI: 10.1016/j.slast.2023.03.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 03/13/2023] [Accepted: 03/28/2023] [Indexed: 04/05/2023]
Abstract
Hyposalivation and severe dry mouth syndrome are the most common complications in patients with head and neck cancer (HNC) after receiving radiation therapy. Conventional treatment for hyposalivation relies on the use of sialogogues such as pilocarpine; however, their efficacy is constrained by the limited number of remnant acinar cells after radiation. After radiotherapy, the salivary gland (SG) secretory parenchyma is largely destroyed, and due to the reduced stem cell niche, this gland has poor regenerative potential. To tackle this, researchers must be able to generate highly complex cellularized 3D constructs for clinical transplantation via technologies, including those that involve bioprinting of cells and biomaterials. A potential stem cell source with promising clinical outcomes to reserve dry mouth is adipose mesenchymal stem cells (AdMSC). MSC-like cells like human dental pulp stem cells (hDPSC) have been tested in novel magnetic bioprinting platforms using nanoparticles that can bind cell membranes by electrostatic interaction, as well as their paracrine signals arising from extracellular vesicles. Both magnetized cells and their secretome cues were found to increase epithelial and neuronal growth of in vitro and ex vivo irradiated SG models. Interestingly, these magnetic bioprinting platforms can be applied as a high-throughput drug screening system due to the consistency in structure and functions of their organoids. Recently, exogenous decellularized porcine ECM was added to this magnetic platform to stimulate an ideal environment for cell tethering, proliferation, and/or differentiation. The combination of these SG tissue biofabrication strategies will promptly allow for in vitro organoid formation and establishment of cellular senescent organoids for aging models, but challenges remain in terms of epithelial polarization and lumen formation for unidirectional fluid flow. Current magnetic bioprinting nanotechnologies can provide promising functional and aging features to in vitro craniofacial exocrine gland organoids, which can be utilized for novel drug discovery and/or clinical transplantation.
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Affiliation(s)
- Toan V Phan
- Avatar Biotechnologies for Oral Health and Healthy Longevity Research Unit, Department of Research Affairs, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand; International Graduate Program in Oral Biology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Yamin Oo
- Avatar Biotechnologies for Oral Health and Healthy Longevity Research Unit, Department of Research Affairs, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Khurshid Ahmed
- Avatar Biotechnologies for Oral Health and Healthy Longevity Research Unit, Department of Research Affairs, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand; Department of Industrial Biotechnology, Faculty of Agro-Industry, Prince of Songkla University, Songkhla, Thailand
| | - Teerapat Rodboon
- Avatar Biotechnologies for Oral Health and Healthy Longevity Research Unit, Department of Research Affairs, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand; Department of Clinical Pathology, Faculty of Medicine, Navamindradhiraj University, Bangkok, Thailand
| | - Vinicius Rosa
- Faculty of Dentistry, National University of Singapore, Singapore, Singapore; Centre for Advanced 2D Materials, National University of Singapore, Singapore, Singapore; Department of Materials Science and Engineering, College of Design and Engineering, National University of Singapore, Singapore, Singapore; ORCHIDS: Oral Care Health Innovations and Designs Singapore, National University of Singapore, Singapore, Singapore
| | - Supansa Yodmuang
- Avatar Biotechnologies for Oral Health and Healthy Longevity Research Unit, Department of Research Affairs, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand; Department of Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Joao N Ferreira
- Avatar Biotechnologies for Oral Health and Healthy Longevity Research Unit, Department of Research Affairs, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.
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14
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Muallah D, Matschke J, Kappler M, Kroschwald LM, Lauer G, Eckert AW. Dental Pulp Stem Cells for Salivary Gland Regeneration-Where Are We Today? Int J Mol Sci 2023; 24:ijms24108664. [PMID: 37240009 DOI: 10.3390/ijms24108664] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 05/02/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
Xerostomia is the phenomenon of dry mouth and is mostly caused by hypofunction of the salivary glands. This hypofunction can be caused by tumors, head and neck irradiation, hormonal changes, inflammation or autoimmune disease such as Sjögren's syndrome. It is associated with a tremendous decrease in health-related quality of life due to impairment of articulation, ingestion and oral immune defenses. Current treatment concepts mainly consist of saliva substitutes and parasympathomimetic drugs, but the outcome of these therapies is deficient. Regenerative medicine is a promising approach for the treatment of compromised tissue. For this purpose, stem cells can be utilized due to their ability to differentiate into various cell types. Dental pulp stem cells are adult stem cells that can be easily harvested from extracted teeth. They can form tissues of all three germ layers and are therefore becoming more and more popular for tissue engineering. Another potential benefit of these cells is their immunomodulatory effect. They suppress proinflammatory pathways of lymphocytes and could therefore probably be used for the treatment of chronic inflammation and autoimmune disease. These attributes make dental pulp stem cells an interesting tool for the regeneration of salivary glands and the treatment of xerostomia. Nevertheless, clinical studies are still missing. This review will highlight the current strategies for using dental pulp stem cells in the regeneration of salivary gland tissue.
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Affiliation(s)
- David Muallah
- Department of Oral and Maxillofacial Surgery, University Hospital Hamburg-Eppendorf, Martinistraße 52, 20251 Hamburg, Germany
| | - Jan Matschke
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine "Carl Gustav Carus", Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany
| | - Matthias Kappler
- Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany
| | - Lysann Michaela Kroschwald
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine "Carl Gustav Carus", Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany
- Center for Translational Bone, Joint and Soft Tissue Research, University Hospital "Carl Gustav Carus", Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany
| | - Günter Lauer
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine "Carl Gustav Carus", Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany
| | - Alexander W Eckert
- Department of Cranio Maxillofacial Surgery, Paracelsus Medical University, Breslauer Straße 201, 90471 Nuremberg, Germany
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15
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Marinkovic M, Tran ON, Wang H, Abdul-Azees P, Dean DD, Chen XD, Yeh CK. Autologous mesenchymal stem cells offer a new paradigm for salivary gland regeneration. Int J Oral Sci 2023; 15:18. [PMID: 37165024 PMCID: PMC10172302 DOI: 10.1038/s41368-023-00224-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 02/20/2023] [Accepted: 03/29/2023] [Indexed: 05/12/2023] Open
Abstract
Salivary gland (SG) dysfunction, due to radiotherapy, disease, or aging, is a clinical manifestation that has the potential to cause severe oral and/or systemic diseases and compromise quality of life. Currently, the standard-of-care for this condition remains palliative. A variety of approaches have been employed to restore saliva production, but they have largely failed due to damage to both secretory cells and the extracellular matrix (niche). Transplantation of allogeneic cells from healthy donors has been suggested as a potential solution, but no definitive population of SG stem cells, capable of regenerating the gland, has been identified. Alternatively, mesenchymal stem cells (MSCs) are abundant, well characterized, and during SG development/homeostasis engage in signaling crosstalk with the SG epithelium. Further, the trans-differentiation potential of these cells and their ability to regenerate SG tissues have been demonstrated. However, recent findings suggest that the "immuno-privileged" status of allogeneic adult MSCs may not reflect their status post-transplantation. In contrast, autologous MSCs can be recovered from healthy tissues and do not present a challenge to the recipient's immune system. With recent advances in our ability to expand MSCs in vitro on tissue-specific matrices, autologous MSCs may offer a new therapeutic paradigm for restoration of SG function.
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Affiliation(s)
- Milos Marinkovic
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Research Service, South Texas Veterans Health Care System, San Antonio, TX, USA
| | - Olivia N Tran
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Hanzhou Wang
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Parveez Abdul-Azees
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Research Service, South Texas Veterans Health Care System, San Antonio, TX, USA
| | - David D Dean
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX, USA
| | - Xiao-Dong Chen
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
- Research Service, South Texas Veterans Health Care System, San Antonio, TX, USA.
- Department of Biomedical Engineering, University of Texas at San Antonio, San Antonio, TX, USA.
| | - Chih-Ko Yeh
- Department of Comprehensive Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
- Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA.
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16
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Guan Z, Zhang J, Jiang N, Tian M, Wang H, Liang B. Efficacy of mesenchymal stem cell therapy in rodent models of radiation-induced xerostomia and oral mucositis: a systematic review. Stem Cell Res Ther 2023; 14:82. [PMID: 37046350 PMCID: PMC10099931 DOI: 10.1186/s13287-023-03301-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 03/27/2023] [Indexed: 04/14/2023] Open
Abstract
BACKGROUND Radiation-induced xerostomia and oral mucositis are serious complications of radiation therapy for head and neck cancers. Current treatment options have limited efficacy. Mesenchymal stem cell (MSC) therapy has shown promising results in supporting the restoration of glandular secretion function and the regeneration of damaged tissues. This study aim to (1) assess the quality of evidence for MSCs treatment in rodent models of radiation-induced oral complications and (2) determine whether MSCs can improve the therapeutic effect of radiation-induced oral mucositis. METHODS Intervention studies using MSCs in rodent models were comprehensively retrieved in the Pubmed, Medline, Embase, Web of Science, and Cochrane library databases on June 1, 2022. The quality of all in vivo experiments was assessed using SYRCLE, and this article is written following the PRISMA guidelines. RESULTS A total of 12 studies were included in this systematic review. The study found that in animal models of radiation-induced xerostomia, MSCs could increase salivary protein secretion, improve SFR, shorten the salivary lag time, anti-apoptosis, etc. In animal models of radiation-induced oral mucositis, MSCs improve the micromorphology and macromorphology of RIOM. Moreover, the effect of MSCs on the modification of ulcer duration and latency may be related to the time of MSCs transplantation but further studies are needed. CONCLUSION The results of our systematic review suggest that MSCs appeared to be effective in the treatment of radiation-induced xerostomia and oral mucositis.
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Affiliation(s)
- Zirui Guan
- The Second Hospital of Jilin University, Changchun City, 130022, Jilin Province, People's Republic of China
| | - Jiaxin Zhang
- School of Nursing, Jilin University, Changchun City, 130021, Jilin Province, People's Republic of China
| | - Nan Jiang
- School of Nursing, Jilin University, Changchun City, 130021, Jilin Province, People's Republic of China
| | - Mingyan Tian
- The Second Hospital of Jilin University, Changchun City, 130022, Jilin Province, People's Republic of China
| | - Hongyong Wang
- The Second Hospital of Jilin University, Changchun City, 130022, Jilin Province, People's Republic of China.
| | - Bing Liang
- School of Nursing, Jilin University, Changchun City, 130021, Jilin Province, People's Republic of China.
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17
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Sheykhbahaei N, Bayramzadeh F, Koopaie M. Transdifferentiation of periodontal ligament stem cells into acinar cells using an indirect co-culture system. Cell Tissue Bank 2023; 24:241-251. [PMID: 35982342 DOI: 10.1007/s10561-022-10029-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 07/13/2022] [Indexed: 11/29/2022]
Abstract
Serous Acinar Cells (ACs) are mature and functional secretory epithelial cells that develop and complete through other stem cells at the end of the ductal system. So, the regeneration of the salivary gland damaged by radiation does not occur without cell therapy. Todays, an accessible tissue like the Periodontal Ligament (PDL) of the tooth was considered to easily extract the Mesenchymal Stem Cells (MSCs). In-vitro differentiation of stem cells before transplantation to damaged tissue reduces the risk of tumorigenesis. This study was conducted to evaluate the feasibility of differentiation of PDLSCs into salivary acinar cells by a co-culture system. PDLSCs were isolated from adult human PDL tissue and co-cultured with rat parotid ACs using an indirect co-culture system. The transdifferentiation of PDLSCs was evaluated by PCR of Aquaporin 5 (AQP5) and Carbonic anhydrase 6 (CA6) genes, then quantitative real-time PCR was used to measure the gene expression levels. The data were analyzed by ANOVA. Specific bond with the correct size on 6% acrylamide gel and TBE5X buffer showed the expression of AQP5 and CA6 in PDLSCs co-cultured with acinar cells. RT-PCR revealed co-cultured PDLSCs with or without KGF (Keratinocyte Growth Factor) showed significantly increased expression of AQP5 genes in compared to the initial PDLSCs. Expression of AQP5 and CA6, indicating successful transdifferentiation of PDLSCs into ACs, in co-culture system for 3 weeks.
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Affiliation(s)
- Nafiseh Sheykhbahaei
- Oral and Maxillofacial Medicine, School of Dentistry, Tehran University of Medical Science, North Kargar St, P.O. BOX: 14395-433, Tehran, 14399-55991, Iran
| | | | - Maryam Koopaie
- Oral and Maxillofacial Medicine, School of Dentistry, Tehran University of Medical Science, North Kargar St, P.O. BOX: 14395-433, Tehran, 14399-55991, Iran.
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18
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Kano F, Hashimoto N, Liu Y, Xia L, Nishihara T, Oki W, Kawarabayashi K, Mizusawa N, Aota K, Sakai T, Azuma M, Hibi H, Iwasaki T, Iwamoto T, Horimai N, Yamamoto A. Therapeutic benefits of factors derived from stem cells from human exfoliated deciduous teeth for radiation-induced mouse xerostomia. Sci Rep 2023; 13:2706. [PMID: 36792628 PMCID: PMC9932159 DOI: 10.1038/s41598-023-29176-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 01/31/2023] [Indexed: 02/17/2023] Open
Abstract
Radiation therapy for head and neck cancers is frequently associated with adverse effects on the surrounding normal tissue. Irreversible damage to radiation-sensitive acinar cells in the salivary gland (SG) causes severe radiation-induced xerostomia (RIX). Currently, there are no effective drugs for treating RIX. We investigated the efficacy of treatment with conditioned medium derived from stem cells from human exfoliated deciduous teeth (SHED-CM) in a mouse RIX model. Intravenous administration of SHED-CM, but not fibroblast-CM (Fibro-CM), prevented radiation-induced cutaneous ulcer formation (p < 0.0001) and maintained SG function (p < 0.0001). SHED-CM treatment enhanced the expression of multiple antioxidant genes in mouse RIX and human acinar cells and strongly suppressed radiation-induced oxidative stress. The therapeutic effects of SHED-CM were abolished by the superoxide dismutase inhibitor diethyldithiocarbamate (p < 0.0001). Notably, quantitative liquid chromatography-tandem mass spectrometry shotgun proteomics of SHED-CM and Fibro-CM identified eight proteins activating the endogenous antioxidant system, which were more abundant in SHED-CM than in Fibro-CM (p < 0.0001). Neutralizing antibodies against those activators reduced antioxidant activity of SHED-CM (anti-PDGF-D; p = 0.0001, anti-HGF; p = 0.003). Our results suggest that SHED-CM may provide substantial therapeutic benefits for RIX primarily through the activation of multiple antioxidant enzyme genes in the target tissue.
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Affiliation(s)
- Fumiya Kano
- grid.267335.60000 0001 1092 3579Department of Tissue Regeneration, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8504 Japan
| | - Noboru Hashimoto
- grid.267335.60000 0001 1092 3579Department of Tissue Regeneration, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8504 Japan
| | - Yao Liu
- grid.267335.60000 0001 1092 3579Department of Tissue Regeneration, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8504 Japan
| | - Linze Xia
- grid.267335.60000 0001 1092 3579Department of Tissue Regeneration, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8504 Japan
| | - Takaaki Nishihara
- grid.267335.60000 0001 1092 3579Department of Tissue Regeneration, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8504 Japan
| | - Wakana Oki
- grid.267335.60000 0001 1092 3579Department of Tissue Regeneration, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8504 Japan
| | - Keita Kawarabayashi
- grid.267335.60000 0001 1092 3579Department of Pediatric Dentistry, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Noriko Mizusawa
- grid.267335.60000 0001 1092 3579Department of Oral Bioscience, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Keiko Aota
- grid.267335.60000 0001 1092 3579Department of Oral Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Takayoshi Sakai
- grid.136593.b0000 0004 0373 3971Department of Oral-Facial Disorders, Osaka University Graduate School of Dentistry, Osaka, Japan
| | - Masayuki Azuma
- grid.267335.60000 0001 1092 3579Department of Oral Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Hideharu Hibi
- grid.27476.300000 0001 0943 978XDepartment of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tomonori Iwasaki
- grid.267335.60000 0001 1092 3579Department of Pediatric Dentistry, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Tsutomu Iwamoto
- grid.265073.50000 0001 1014 9130Department of Pediatric Dentistry/Special Needs Dentistry, Division of Oral Health Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | | | - Akihito Yamamoto
- Department of Tissue Regeneration, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8504, Japan.
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19
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Cell-Free Therapies: The Use of Cell Extracts to Mitigate Irradiation-Injured Salivary Glands. BIOLOGY 2023; 12:biology12020305. [PMID: 36829582 PMCID: PMC9953449 DOI: 10.3390/biology12020305] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 02/06/2023] [Accepted: 02/07/2023] [Indexed: 02/17/2023]
Abstract
Radiotherapy is a standard treatment for head and neck cancer patients worldwide. However, millions of patients who received radiotherapy consequently suffer from xerostomia because of irreversible damage to salivary glands (SGs) caused by irradiation (IR). Current treatments for IR-induced SG hypofunction only provide temporary symptom alleviation but do not repair the damaged SG, thus resulting in limited treatment efficacy. Therefore, there has recently been a growing interest in regenerative treatments, such as cell-free therapies. This review aims to summarize cell-free therapies for IR-induced SG, with a particular emphasis on utilizing diverse cell extract (CE) administrations. Cell extract is a group of heterogeneous mixtures containing multifunctional inter-cellular molecules. This review discusses the current knowledge of CE's components and efficacy. We propose optimal approaches to improve cell extract treatment from multiple perspectives (e.g., delivery routes, preparation methods, and other details regarding CE administration). In addition, the advantages and limitations of CE treatment are systematically discussed by comparing it to other cell-free (such as conditioned media and exosomes) and cell-based therapies. Although a comprehensive identification of the bioactive factors within CEs and their mechanisms of action have yet to be fully understood, we propose cell extract therapy as an effective, practical, user-friendly, and safe option to conventional therapies in IR-induced SG.
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Kim JM, Choi ME, Jeon EJ, Park JM, Kim S, Park JE, Oh SW, Choi JS. Cell-derived vesicles from adipose-derived mesenchymal stem cells ameliorate irradiation-induced salivary gland cell damage. Regen Ther 2022; 21:453-459. [PMID: 36313393 PMCID: PMC9587124 DOI: 10.1016/j.reth.2022.09.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 09/08/2022] [Accepted: 09/16/2022] [Indexed: 11/07/2022] Open
Abstract
Introduction Salivary gland (SG) damage is commonly caused by aging, irradiation, and some medications, and currently, no damage modifying agent is available. However, cell therapy based on mesenchymal stem cells (MSCs) has been proposed as a therapeutic modality for irradiated SGs. Therefore, we administered cell-derived vesicles (CDVs) of adipose-derived mesenchymal stem cells (ADMSCs) to irradiated SG cells to investigate their radioprotective effects in vitro. Methods The artificial CDVs were obtained from ADMSC by tangential flow filtration (TFF) purification and ultracentrifugation. Cultured human SG epithelial cells were exposed to 2, 5 or 15 Gy of 4 MV X-rays produced by a linear accelerator. The effects of ADMSC-CDVs on SG epithelial cells damaged by irradiation were tested by proliferation activity, transepithelial electrical resistance (TEER), and amylase activity. Results Exposure to penetrating radiation inhibited the proliferation of SG epithelial cells, but the radiation intensity required to reduce the proliferation of human submandibular gland epithelial cells (hSMGECs) was greater than required for other SG cells. ADMSC-CDVs restored the proliferative ability of SG epithelial cells reduced by irradiation, and the proliferation capacities of irradiated human parotid gland epithelial cells (hPGECs) and human sublingual gland epithelial cells (hSLGECs) were increased by administering ADMSC-CDVs to non-irradiated SG epithelial cells. Furthermore, amylase activity in irradiated hPGECs, hSMGECs, and hSLGECs was lower than in non-irradiated controls. However, amylase ability was restored in all by ADMSC-CDV treatment. Also, TEER was diminished by irradiation in hPGECs, hSMGECs, and hSLGECs and restored by ADMSC-CDV administration. Conclusion Overall, our findings demonstrate that ADMSC-CDVs have potent radioprotective effects on irradiated SG cells.
ADMSC-CDVs restored the proliferation and amylase activity of SG cells damaged by irradiation. Reduced TEER in irradiated SG epithelial cells was restored by ADMSC-CDVs. ADMSC-CDVs have potent radioprotective effects on irradiated SG cells.
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Key Words
- ADMSCs, Adipose-derived mesenchymal stem cells
- Adipose-derived mesenchymal stem cells (ADMSCs)
- CDVs, Cell-derived vesicles
- Cell-derived vesicles (CDVs)
- Irradiation
- MSCs, Mesenchymal stem cells
- SG, Salivary gland
- Salivary gland
- TEER, Transepithelial electrical resistance
- TFF, Tangential flow filtration
- hPGECs, human parotid gland epithelial cells
- hPL, human platelet lysate
- hSLGECs, human sublingual gland epithelial cells
- hSMGECs, human submandibular gland epithelial cells
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Affiliation(s)
- Jeong Mi Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, Inha University College of Medicine, 27 Inhang-ro, Jung-gu, Incheon 22332, Republic of Korea
- Department of Biomedical Science, Program in Biomedical Science & Engineering, Inha University, 100 Inharo, Michuholgu, Incheon 22212, Republic of Korea
| | - Mi Eun Choi
- Department of Otorhinolaryngology-Head and Neck Surgery, Inha University College of Medicine, 27 Inhang-ro, Jung-gu, Incheon 22332, Republic of Korea
| | - Eun Jeong Jeon
- Department of Otorhinolaryngology-Head and Neck Surgery, Inha University College of Medicine, 27 Inhang-ro, Jung-gu, Incheon 22332, Republic of Korea
- Department of Biomedical Science, Program in Biomedical Science & Engineering, Inha University, 100 Inharo, Michuholgu, Incheon 22212, Republic of Korea
| | - Jin-Mi Park
- Department of Otorhinolaryngology-Head and Neck Surgery, Inha University College of Medicine, 27 Inhang-ro, Jung-gu, Incheon 22332, Republic of Korea
| | - Sungryeal Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, Inha University College of Medicine, 27 Inhang-ro, Jung-gu, Incheon 22332, Republic of Korea
| | - Jeong Eun Park
- Biodrone Research Institute, MDimune Inc., Seoul 04790, Republic of Korea
| | - Seung Wook Oh
- Biodrone Research Institute, MDimune Inc., Seoul 04790, Republic of Korea
| | - Jeong-Seok Choi
- Department of Otorhinolaryngology-Head and Neck Surgery, Inha University College of Medicine, 27 Inhang-ro, Jung-gu, Incheon 22332, Republic of Korea
- Department of Biomedical Science, Program in Biomedical Science & Engineering, Inha University, 100 Inharo, Michuholgu, Incheon 22212, Republic of Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, 100 Inharo, Michuhol-gu, Incheon 22212, Republic of Korea
- Corresponding author. Department of Otorhinolaryngology, Inha University College of Medicine, 27 Inhang-ro, Jung-gu, Incheon, 22332, Republic of Korea. Fax: +82 32 890 3580.
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21
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Chibly AM, Aure MH, Patel VN, Hoffman MP. Salivary gland function, development, and regeneration. Physiol Rev 2022; 102:1495-1552. [PMID: 35343828 PMCID: PMC9126227 DOI: 10.1152/physrev.00015.2021] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 11/27/2021] [Accepted: 03/17/2022] [Indexed: 02/08/2023] Open
Abstract
Salivary glands produce and secrete saliva, which is essential for maintaining oral health and overall health. Understanding both the unique structure and physiological function of salivary glands, as well as how they are affected by disease and injury, will direct the development of therapy to repair and regenerate them. Significant recent advances, particularly in the OMICS field, increase our understanding of how salivary glands develop at the cellular, molecular, and genetic levels: the signaling pathways involved, the dynamics of progenitor cell lineages in development, homeostasis, and regeneration, and the role of the extracellular matrix microenvironment. These provide a template for cell and gene therapies as well as bioengineering approaches to repair or regenerate salivary function.
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Affiliation(s)
- Alejandro M Chibly
- Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
| | - Marit H Aure
- Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
| | - Vaishali N Patel
- Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
| | - Matthew P Hoffman
- Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
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22
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Dai S, Wen Y, Luo P, Ma L, Liu Y, Ai J, Shi C. Therapeutic implications of exosomes in the treatment of radiation injury. BURNS & TRAUMA 2022; 10:tkab043. [PMID: 35071650 PMCID: PMC8778593 DOI: 10.1093/burnst/tkab043] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 11/11/2021] [Indexed: 12/28/2022]
Abstract
Radiotherapy is one of the main cancer treatments, but it may damage normal tissue and cause various side effects. At present, radioprotective agents used in clinics have side effects such as nausea, vomiting, diarrhea and hypotension, which limit their clinical application. It has been found that exosomes play an indispensable role in radiation injury. Exosomes are lipid bilayer vesicles that carry various bioactive substances, such as proteins, lipids and microRNA (miRNA), that play a key role in cell-to-cell communication and affect tissue injury and repair. In addition, studies have shown that radiation can increase the uptake of exosomes in cells and affect the composition and secretion of exosomes. Here, we review the existing studies and discuss the effects of radiation on exosomes and the role of exosomes in radiation injury, aiming to provide new insights for the treatment of radiation injury.
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Affiliation(s)
| | | | | | | | | | - Junhua Ai
- Correspondence. Junhua Ai, ; Chunmeng Shi,
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23
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Alginate Hydrogel Microtubes for Salivary Gland Cell Organization and Cavitation. Bioengineering (Basel) 2022; 9:bioengineering9010038. [PMID: 35049747 PMCID: PMC8773299 DOI: 10.3390/bioengineering9010038] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 12/25/2021] [Accepted: 12/28/2021] [Indexed: 12/14/2022] Open
Abstract
Understanding the different regulatory functions of epithelial and mesenchymal cell types in salivary gland development and cellular organization is essential for proper organoid formation and salivary gland tissue regeneration. Here, we demonstrate a biocompatible platform using pre-formed alginate hydrogel microtubes to facilitate direct epithelial–mesenchymal cell interaction for 3D salivary gland cell organization, which allows for monitoring cellular organization while providing a protective barrier from cell-cluster loss during medium changes. Using mouse salivary gland ductal epithelial SIMS cells as the epithelial model cell type and NIH 3T3 fibroblasts or primary E16 salivary mesenchyme cells as the stromal model cell types, self-organization from epithelial–mesenchymal interaction was examined. We observed that epithelial and mesenchymal cells undergo aggregation on day 1, cavitation by day 4, and generation of an EpCAM-expressing epithelial cell layer as early as day 7 of the co-culture in hydrogel microtubes, demonstrating the utility of hydrogel microtubes to facilitate heterotypic cell–cell interactions to form cavitated organoids. Thus, pre-formed alginate microtubes are a promising co-culture method for further understanding epithelial and mesenchymal interaction during tissue morphogenesis and for future practical applications in regenerative medicine.
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24
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Egg White Alginate as a Novel Scaffold Biomaterial for 3D Salivary Cell Culturing. Biomimetics (Basel) 2021; 7:biomimetics7010005. [PMID: 35076454 PMCID: PMC8788534 DOI: 10.3390/biomimetics7010005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/23/2021] [Accepted: 12/24/2021] [Indexed: 12/12/2022] Open
Abstract
Saliva production by salivary glands play a crucial role in oral health. The loss of salivary gland function could lead to xerostomia, a condition also known as dry mouth. Significant reduction in saliva production could lead to further complications such as difficulty in speech, mastication, and increased susceptibility to dental caries and oral infections and diseases. While some palliative treatments are available for xerostomia, there are no curative treatments to date. This study explores the use of Egg White Alginate (EWA), as an alternative scaffold to Matrigel® for culturing 3D salivary gland cells. A protocol for an optimized EWA was established by comparing cell viability using 1%, 2%, and 3% alginate solution. The normal salivary simian virus 40-immortalized acinar cell (NS-SV-AC) and the submandibular gland-human-1 (SMG-hu-1) cell lines were also used to compare the spheroid formation and cell viability properties of both scaffold biomaterials; cell viability was observed over 10 days using a Live–Dead Cell Assay. Cell viability and spheroid size in 2% EWA was significantly greater than 1% and 3%. It is evident that EWA can support salivary cell survivability as well as form larger spheroids when compared to cells grown in Matrigel®. However, further investigations are necessary as it is unclear if cultured cells were proliferating or aggregating.
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25
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Abd El-Haleem MR, Amer MG, Fares AE, Kamel AHM. Evaluation of the Radioprotective Effect of Silver Nanoparticles on Irradiated Submandibular Gland of Adult Albino Rats. A Histological and Sialochemical Study. BIONANOSCIENCE 2021. [DOI: 10.1007/s12668-021-00917-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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26
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Kaboodkhani R, Mehrabani D, Karimi-Busheri F. Achievements and Challenges in Transplantation of Mesenchymal Stem Cells in Otorhinolaryngology. J Clin Med 2021; 10:2940. [PMID: 34209041 PMCID: PMC8267672 DOI: 10.3390/jcm10132940] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/25/2021] [Accepted: 06/28/2021] [Indexed: 12/15/2022] Open
Abstract
Otorhinolaryngology enrolls head and neck surgery in various tissues such as ear, nose, and throat (ENT) that govern different activities such as hearing, breathing, smelling, production of vocal sounds, the balance, deglutition, facial animation, air filtration and humidification, and articulation during speech, while absence of these functions can lead to high morbidity and even mortality. Conventional therapies for head and neck damaged tissues include grafts, transplants, and artificial materials, but grafts have limited availability and cause morbidity in the donor site. To improve these limitations, regenerative medicine, as a novel and rapidly growing field, has opened a new therapeutic window in otorhinolaryngology by using cell transplantation to target the healing and replacement of injured tissues. There is a high risk of rejection and tumor formation for transplantation of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs); mesenchymal stem cells (MSCs) lack these drawbacks. They have easy expansion and antiapoptotic properties with a wide range of healing and aesthetic functions that make them a novel candidate in otorhinolaryngology for craniofacial defects and diseases and hold immense promise for bone tissue healing; even the tissue sources and types of MSCs, the method of cell introduction and their preparation quality can influence the final outcome in the injured tissue. In this review, we demonstrated the anti-inflammatory and immunomodulatory properties of MSCs, from different sources, to be safely used for cell-based therapies in otorhinolaryngology, while their achievements and challenges have been described too.
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Affiliation(s)
- Reza Kaboodkhani
- Otorhinolaryngology Research Center, Department of Otorhinolaryngology, School of Medicine, Shiraz University of Medical Sciences, Shiraz 71936-36981, Iran;
| | - Davood Mehrabani
- Stem Cell Technology Research Center, Shiraz University of Medical Sciences, Shiraz 71348-14336, Iran
- Burn and Wound Healing Research Center, Shiraz University of Medical Sciences, Shiraz 71987-74731, Iran
- Comparative and Experimental Medicine Center, Shiraz University of Medical Sciences, Shiraz 71348-14336, Iran
- Li Ka Shing Center for Health Research and Innovation, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Feridoun Karimi-Busheri
- Department of Oncology, Faculty of Medicine, University of Alberta, Edmonton, AB T6G 1Z2, Canada
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Abstract
PURPOSE Within the context of xerostomia, there is evidence that adipose-derived stem cells (ASCs) can differentiate into salivary gland cells in the appropriate environment. The purpose of this study was to preliminarily investigate whether fat grafting as practiced in the United States would be an effective treatment for xerostomia. METHODS Patients were selected for the study if they were seeking treatment for xerostomia after radiation treatment to the head and neck for cancer treatment. Fat grafting was performed in bilateral parotid and submandibular glands. Visual Analog Scale (VAS) of xerostomia was used both preoperatively and postoperatively to assess the effect upon xerostomia symptoms. RESULTS Nine patients were included in this study. All patients had complaints of long-standing xerostomia. The average preoperative VAS score was 9.1. All patients tolerated all rounds of fat grafting with no complications. The average postoperative VAS score was 6.0. Compared to preoperative scores, all patients had improvement in VAS scores. The decrease in average VAS score postoperatively (9.1 versus 6.0) was statistically significant (P = 0.007). CONCLUSIONS Our study showed that there was improvement in xerostomia symptoms with autologous fat transfer alone. This is a novel finding for fat grafting demonstrating regenerative potential. There has been extensive basic research that has shown that adipose-derived mesenchymal stem cells can have a protective and restorative role after salivary gland radiation damage. Our case series is the first report of fat grafting having a similar reported outcome.Level of Evidence: 4.
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28
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Nanduri LSY, Duddempudi PK, Yang WL, Tamarat R, Guha C. Extracellular Vesicles for the Treatment of Radiation Injuries. Front Pharmacol 2021; 12:662437. [PMID: 34084138 PMCID: PMC8167064 DOI: 10.3389/fphar.2021.662437] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 05/04/2021] [Indexed: 01/02/2023] Open
Abstract
Normal tissue injury from accidental or therapeutic exposure to high-dose radiation can cause severe acute and delayed toxicities, which result in mortality and chronic morbidity. Exposure to single high-dose radiation leads to a multi-organ failure, known as acute radiation syndrome, which is caused by radiation-induced oxidative stress and DNA damage to tissue stem cells. The radiation exposure results in acute cell loss, cell cycle arrest, senescence, and early damage to bone marrow and intestine with high mortality from sepsis. There is an urgent need for developing medical countermeasures against radiation injury for normal tissue toxicity. In this review, we discuss the potential of applying secretory extracellular vesicles derived from mesenchymal stromal/stem cells, endothelial cells, and macrophages for promoting repair and regeneration of organs after radiation injury.
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Affiliation(s)
- Lalitha Sarad Yamini Nanduri
- Department of Radiation Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
| | - Phaneendra K. Duddempudi
- Department of Biochemistry, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
| | - Weng-Lang Yang
- Department of Radiation Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
| | - Radia Tamarat
- Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Fontenay-aux-Roses, France
| | - Chandan Guha
- Department of Radiation Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
- Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
- Department of Urology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
- Institute for Onco-Physics, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY, United States
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29
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Grawish ME, Saeed MA, Sultan N, Scheven BA. Therapeutic applications of dental pulp stem cells in regenerating dental, periodontal and oral-related structures. World J Meta-Anal 2021; 9:176-192. [DOI: 10.13105/wjma.v9.i2.176] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/13/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
Dental pulp stem cells (DPSCs) have emerged as a promising tool with great potential for use in tissue regeneration and engineering. Some of the main advantages of these cells are their multifaceted differentiation capacity, along with their high proliferation rate, a relative simplicity of extraction and culture that enables obtaining patient-specific cell lines for their use in autologous cell therapy. PubMed, Scopus and Google Scholar databases were searched for relevant articles related to the use of DPSCs in regeneration of dentin-pulp complex (DPC), periodontal tissues, salivary gland and craniomaxillofacial bone defects. Few studies were found regarding the use of DPSCs for regeneration of DPC. Scaffold-based combined with DPSCs isolated from healthy pulps was the strategy used for DPC regeneration. Studies involved subcutaneous implantation of scaffolds loaded with DPSCs pretreated with odontogenic media, or performed on human tooth root model as a root slice. Most of the studies were related to periodontal tissue regeneration which mainly utilized DPSCs/secretome. For periodontal tissues, DPSCs or their secretome were isolated from healthy or inflamed pulps and they were used either for preclinical or clinical studies. Regarding salivary gland regeneration, the submandibular gland was the only model used for the preclinical studies and DPSCs or their secretome were isolated only from healthy pulps and they were used in preclinical studies. Likewise, DPSCs have been studied for craniomaxillofacial bone defects in the form of mandibular, calvarial and craniofacial bone defects where DPSCs were isolated only from healthy pulps for preclinical and clinical studies. From the previous results, we can conclude that DPSCs is promising candidate for dental and oral tissue regeneration.
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Affiliation(s)
- Mohammed E Grawish
- Department of Oral Biology, Faculty of Dentistry, Mansoura University, Mansoura 35516, Egypt
- Department of Oral Biology, Faculty of Oral and Dental Medicine, Delta University for Science and Technology, Mansoura 11152, Egypt
| | - Mahmoud A Saeed
- Department of Oral Biology, Faculty of Oral and Dental Medicine, Delta University for Science and Technology, Mansoura 11152, Egypt
| | - Nessma Sultan
- Department of Oral Biology, Faculty of Dentistry, Mansoura University, Mansoura 35516, Egypt
| | - Ben A Scheven
- School of Dentistry, Oral Biology, College of Medical and Dental Sciences, University of Birmingham, Birmingham B5 7EG, United Kingdom
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31
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Grawish ME, Saeed MA, Sultan N, Scheven BA. Therapeutic applications of dental pulp stem cells in regenerating dental, periodontal and oral-related structures. World J Meta-Anal 2021; 9:175-191. [DOI: 10.13105/wjma.v9.i2.175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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32
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Chansaenroj A, Yodmuang S, Ferreira JN. Trends in Salivary Gland Tissue Engineering: From Stem Cells to Secretome and Organoid Bioprinting. TISSUE ENGINEERING PART B-REVIEWS 2021; 27:155-165. [DOI: 10.1089/ten.teb.2020.0149] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Ajjima Chansaenroj
- Exocrine Gland Biology and Regeneration Research Group, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Supansa Yodmuang
- Exocrine Gland Biology and Regeneration Research Group, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
- Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - João N. Ferreira
- Exocrine Gland Biology and Regeneration Research Group, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
- Faculty of Dentistry, National University of Singapore, Singapore, Singapore
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Maurizi E, Adamo D, Magrelli FM, Galaverni G, Attico E, Merra A, Maffezzoni MBR, Losi L, Genna VG, Sceberras V, Pellegrini G. Regenerative Medicine of Epithelia: Lessons From the Past and Future Goals. Front Bioeng Biotechnol 2021; 9:652214. [PMID: 33842447 PMCID: PMC8026866 DOI: 10.3389/fbioe.2021.652214] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 02/23/2021] [Indexed: 12/13/2022] Open
Abstract
This article explores examples of successful and unsuccessful regenerative medicine on human epithelia. To evaluate the applications of the first regenerated tissues, the analysis of the past successes and failures addresses some pending issues and lay the groundwork for developing new therapies. Research should still be encouraged to fill the gap between pathologies, clinical applications and what regenerative medicine can attain with current knowledge.
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Affiliation(s)
| | - Davide Adamo
- Interdepartmental Centre for Regenerative Medicine “Stefano Ferrari”, University of Modena and Reggio Emilia, Modena, Italy
| | | | - Giulia Galaverni
- Interdepartmental Centre for Regenerative Medicine “Stefano Ferrari”, University of Modena and Reggio Emilia, Modena, Italy
| | - Eustachio Attico
- Interdepartmental Centre for Regenerative Medicine “Stefano Ferrari”, University of Modena and Reggio Emilia, Modena, Italy
| | | | | | - Lorena Losi
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | | | | | - Graziella Pellegrini
- Holostem Terapie Avanzate S.r.l., Modena, Italy
- Interdepartmental Centre for Regenerative Medicine “Stefano Ferrari”, University of Modena and Reggio Emilia, Modena, Italy
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Cho JM, Yoon YJ, Lee S, Kim D, Choi D, Kim J, Lim JY. Retroductal Delivery of Epidermal Growth Factor Protects Salivary Progenitors after Irradiation. J Dent Res 2021; 100:883-890. [PMID: 33754871 DOI: 10.1177/0022034521999298] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Salivary gland hypofunction after irradiation is associated with a deficit of epithelial stem/progenitors in salivary glands. Although epidermal growth factor (EGF) is known to stimulate the proliferation of epithelial cells, the therapeutic effect of EGF on salivary epithelial stem/progenitors remains undetermined. In this study, we administered EGF to submandibular glands (SMGs) via a retrograde route through the SMG excretory duct before fractionated irradiation and examined whether EGF could protect salivary epithelial progenitor cells from radiation and alleviate radiation-induced salivary hypofunction. EGF-treated mice exhibited greater body and gland weights at 12 wk after irradiation than untreated mice. The retroductal delivery of EGF improved salivary secretory function and increased salivary amylase activity in a dose-dependent manner. Histological examinations highlighted the amelioration of the loss of keratine-14+ (KRT14+) basal ductal and/or MIST1+ acinar cells, as well as induction of fibrosis, following irradiation in EGF-treated mice. An additional in vitro experiment using a salivary gland organoid irradiation model indicated that the radioprotective effects of EGF promoted the growth and inhibited the apoptotic cell death of salivary epithelial cells. Our results suggest that retroductal delivery of EGF may be a promising therapeutic option for preventing radiation-induced salivary gland hypofunction.
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Affiliation(s)
- J M Cho
- Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Y J Yoon
- Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - S Lee
- Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - D Kim
- Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - D Choi
- Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - J Kim
- Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - J Y Lim
- Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea
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35
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I T, Ueda Y, Wörsdörfer P, Sumita Y, Asahina I, Ergün S. Resident CD34-positive cells contribute to peri-endothelial cells and vascular morphogenesis in salivary gland after irradiation. J Neural Transm (Vienna) 2020; 127:1467-1479. [PMID: 33025085 PMCID: PMC7578140 DOI: 10.1007/s00702-020-02256-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 09/22/2020] [Indexed: 02/08/2023]
Abstract
Salivary gland (SG) hypofunction is a common post-radiotherapy complication. Besides the parenchymal damage after irradiation (IR), there are also effects on mesenchymal stem cells (MSCs) which were shown to contribute to regeneration and repair of damaged tissues by differentiating into stromal cell types or releasing vesicles and soluble factors supporting the healing processes. However, there are no adequate reports about their roles during SG damage and regeneration so far. Using an irradiated SG mouse model, we performed certain immunostainings on tissue sections of submandibular glands at different time points after IR. Immunostaining for CD31 revealed that already one day after IR, vascular impairment was induced at the level of capillaries. In addition, the expression of CD44—a marker of acinar cells—diminished gradually after IR and, by 20 weeks, almost disappeared. In contrast, the number of CD34-positive cells significantly increased 4 weeks after IR and some of the CD34-positive cells were found to reside within the adventitia of arteries and veins. Laser confocal microscopic analyses revealed an accumulation of CD34-positive cells within the area of damaged capillaries where they were in close contact to the CD31-positive endothelial cells. At 4 weeks after IR, a fraction of the CD34-positive cells underwent differentiation into α-SMA-positive cells, which suggests that they may contribute to regeneration of smooth muscle cells and/or pericytes covering the small vessels from the outside. In conclusion, SG-resident CD34-positive cells represent a population of progenitors that could contribute to new vessel formation and/or remodeling of the pre-existing vessels after IR and thus, might be an important player during SG tissue healing.
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Affiliation(s)
- Takashi I
- Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany. .,Unit of Translational Medicine, Department of Regenerative Oral Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
| | - Yuichiro Ueda
- Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany
| | - Philipp Wörsdörfer
- Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany
| | - Yoshinori Sumita
- Basic and Translational Research Center for Hard Tissue Disease, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Izumi Asahina
- Unit of Translational Medicine, Department of Regenerative Oral Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Süleyman Ergün
- Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany
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Pignatti M, Spinella A, Cocchiara E, Boscaini G, Lusetti IL, Citriniti G, Lumetti F, Setti G, Dominici M, Salvarani C, De Santis G, Giuggioli D. Autologous Fat Grafting for the Oral and Digital Complications of Systemic Sclerosis: Results of a Prospective Study. Aesthetic Plast Surg 2020; 44:1820-1832. [PMID: 32632623 DOI: 10.1007/s00266-020-01848-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 06/14/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Systemic sclerosis is a connective tissue disease. Skin involvement of the mouth and hand may compromise function and quality of life. Autologous fat grafting has been described as a specific treatment of these clinical features. We report the results of our prospective study designed to treat and prevent skin complications in systemic sclerosis. MATERIALS AND METHODS We treated 25 patients with mouth and/or hand involvement (microstomia, xerostomia, skin sclerosis, Raynaud's phenomenon and long-lasting digital ulcers) with autologous fat grafting, according to the Coleman's technique, around the mouth and/or at the base of each finger. The surgical procedures were repeated in each patient every 6 months for a total of two or three times. Clinical data were collected before the first surgery and again 6 months after each surgical procedure. Pain, skin thickness, saliva production and disability were assessed with validated tests. RESULTS Overall we performed 63 autologous fat grafting sessions (either on the mouth, on the hands or on both anatomical areas). Results at 6 moths after the last session included improvement of xerostomia evaluated with a sialogram, reduction of the skin tension around the mouth and, in the hands, reduction of the Raynaud phenomenon as well as skin thickness. Pain was reduced while the perception of disability improved. Digital ulcers healed completely in 8/9 patients. CONCLUSIONS Our results confirm the efficacy and safety of autologous fat grafting for the treatment of skin complications and digital ulcers due to systemic sclerosis. In addition, the patients' subjective well-being improved. Level of evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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Prevention of irradiation-induced damage to salivary glands by local delivery of adipose-derived stem cells via hyaluronic acid-based hydrogels. J IND ENG CHEM 2020. [DOI: 10.1016/j.jiec.2020.06.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Qian L, Cen J. Hematopoietic Stem Cells and Mesenchymal Stromal Cells in Acute Radiation Syndrome. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:8340756. [PMID: 32855768 PMCID: PMC7443042 DOI: 10.1155/2020/8340756] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 07/02/2020] [Accepted: 07/24/2020] [Indexed: 02/08/2023]
Abstract
With the extensive utilization of radioactive materials for medical, industrial, agricultural, military, and research purposes, medical researchers are trying to identify new methods to treat acute radiation syndrome (ARS). Radiation may cause injury to different tissues and organs, but no single drug has been proven to be effective in all circumstances. Radioprotective agents are always effective if given before irradiation, but many nuclear accidents are unpredictable. Medical countermeasures that can be beneficial to different organ and tissue injuries caused by radiation are urgently needed. Cellular therapy, especially stem cell therapy, has been a promising approach in ARS. Hematopoietic stem cells (HSCs) and mesenchymal stromal cells (MSCs) are the two main kinds of stem cells which show good efficacy in ARS and have attracted great attention from researchers. There are also some limitations that need to be investigated in future studies. In recent years, there are also some novel methods of stem cells that could possibly be applied on ARS, like "drug" stem cell banks obtained from clinical grade human induced pluripotent stem cells (hiPSCs), MSC-derived products, and infusion of HSCs without preconditioning treatment, which make us confident in the future treatment of ARS. This review focuses on major scientific and clinical advances of hematopoietic stem cells and mesenchymal stromal cells on ARS.
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Affiliation(s)
- Liren Qian
- Department of Hematology, The Sixth Medical Center, Chinese PLA General Hospital, Fucheng Road #6, Beijing 100048, China
| | - Jian Cen
- Department of Hematology, The Sixth Medical Center, Chinese PLA General Hospital, Fucheng Road #6, Beijing 100048, China
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Rocchi C, Emmerson E. Mouth-Watering Results: Clinical Need, Current Approaches, and Future Directions for Salivary Gland Regeneration. Trends Mol Med 2020; 26:649-669. [PMID: 32371171 DOI: 10.1016/j.molmed.2020.03.009] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 03/03/2020] [Accepted: 03/27/2020] [Indexed: 12/31/2022]
Abstract
Permanent damage to the salivary glands and resulting hyposalivation and xerostomia have a substantial impact on patient health, quality of life, and healthcare costs. Currently, patients rely on lifelong treatments that alleviate the symptoms, but no long-term restorative solutions exist. Recent advances in adult stem cell enrichment and transplantation, bioengineering, and gene transfer have proved successful in rescuing salivary gland function in a number of animal models that reflect human diseases and that result in hyposalivation and xerostomia. By overcoming the limitations of stem cell transplants and better understanding the mechanisms of cellular plasticity in the adult salivary gland, such studies provide encouraging evidence that a regenerative strategy for patients will be available in the near future.
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Affiliation(s)
- Cecilia Rocchi
- The MRC Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Elaine Emmerson
- The MRC Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, Edinburgh, EH16 4UU, UK.
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Abstract
Head and neck structures govern the vital functions of breathing and swallowing. Additionally, these structures facilitate our sense of self through vocal communication, hearing, facial animation, and physical appearance. Loss of these functions can lead to loss of life or greatly affect quality of life. Regenerative medicine is a rapidly developing field that aims to repair or replace damaged cells, tissues, and organs. Although the field is largely in its nascence, regenerative medicine holds promise for improving on conventional treatments for head and neck disorders or providing therapies where no current standard exists. This review presents milestones in the research of regenerative medicine in head and neck surgery.
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Affiliation(s)
- Michael J McPhail
- Head and Neck Regenerative Medicine Laboratory, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Jeffrey R Janus
- Department of Otolaryngology - Head and Neck Surgery, Mayo Clinic Florida, Jacksonville, FL, USA
| | - David G Lott
- Head and Neck Regenerative Medicine Laboratory, Mayo Clinic Arizona, Scottsdale, AZ, USA
- Department of Otolaryngology - Head and Neck Surgery, Mayo Clinic Arizona, Phoenix, AZ, USA
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41
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Khan E, Farooq I, Khabeer A, Ali S, Zafar MS, Khurshid Z. Salivary gland tissue engineering to attain clinical benefits: a special report. Regen Med 2020; 15:1455-1461. [PMID: 32253995 DOI: 10.2217/rme-2019-0079] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The salivary glands produce saliva, which helps in mediating the oral colonization of microbes, the repair of mucosa, the remineralization of teeth, lubrication and gustation. However, certain medications, therapeutic radiation and certain autoimmune diseases can cause a reduction in the salivary flow. The aim of this report was to review and highlight the indications and techniques of salivary gland engineering to counter hyposalivation. This report concludes that in the literature, numerous strategies have been suggested and discussed pertaining to the engineering of salivary gland, however, challenges remain in terms of its production and accurate function. Dedicated efforts are required from researchers all over the world to obtain the maximum benefits from salivary gland engineering techniques.
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Affiliation(s)
- Erum Khan
- CODE-M Center of Dental Education & Medicine, Karachi, Pakistan.,Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Imran Farooq
- Department of Biomedical Dental Sciences, College of Dentistry, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Abdul Khabeer
- Department of Restorative Dental Sciences, College of Dentistry, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Saqib Ali
- Department of Biomedical Dental Sciences, College of Dentistry, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Muhammad Sohail Zafar
- Department of Restorative Dentistry, College of Dentistry, Taibah University, Al Madina Al Munawwarra, Saudi Arabia.,Department of Dental Materials, Islamic International Dental College, Riphah International University, Islamabad, Pakistan
| | - Zohaib Khurshid
- Department of Prosthodontics and Dental Implantology, College of Dentistry, King Faisal University, Al-Ahsa, Saudi Arabia
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42
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Doppalapudi R, Vundavalli S, Prabhat MP. Effect of probiotic bacteria on oral Candida in head- and neck-radiotherapy patients: A randomized clinical trial. J Cancer Res Ther 2020; 16:470-477. [PMID: 32719253 DOI: 10.4103/jcrt.jcrt_334_18] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
OBJECTIVE The aim of the study is to assess the effect of probiotic bacteria on oral Candida counts in cancer patients who are undergoing head- and neck-radiotherapy in a tertiary care center. STUDY DESIGN The study was a randomized clinical trial including 90 patients who just completed head- and neck-radiotherapy. MATERIALS AND METHODS Participants were randomly allocated into three equal sized groups, i.e., probiotics group, candid group, and combination groups. Oral rinse samples of the patients were collected before and after the intervention for the identification of Candida. The samples were incubated on Sabouraud's Dextrose Agar with Chloramphenicol at 37°C for 48 h, to assess the counts of colony-forming units/milliliter (CFU/ml) of Candida in saliva, and further on chrome agar plates to identify the Candida spp. Data were analyzed using mixed ANOVA to compare mean CFU/ml of Candida among three groups before and after the intervention. RESULTS A total of 86 patients were included in the final analysis and there was a statistically significant reduction in mean Candida spp. Counts (CFU/ml) after intervention in all the three groups (P = 0.000) and significant reductions identified in both probiotic and combination therapy groups. Apart from reduction in Candida albicans, significant decrease in Candida glabrata and Candida tropicalis was observed after probiotics usage compared to other groups. CONCLUSIONS The present study suggests that probiotic bacteria were effective in reducing oral Candida spp which can be recommended alone or in combination with traditional antifungal agents for effective reduction in oral Candida in head- and neck-radiotherapy patients.
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Affiliation(s)
- Radhika Doppalapudi
- Department of Oral Radiology, College of Dentistry, Aljouf University, Sakaka, Kingdom of Saudi Arabia
| | - Sudhakar Vundavalli
- Department of Preventive Dentistry, College of Dentistry, Aljouf University, Sakaka, Kingdom of Saudi Arabia
| | - M P Prabhat
- Department of Oral Medicine and Radiology, Drs. S and NR Siddhartha Institute of Dental Sciences, Gannavaram, Andhra Pradesh, India
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43
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Su X, Liu Y, Bakkar M, ElKashty O, El-Hakim M, Seuntjens J, Tran SD. Labial Stem Cell Extract Mitigates Injury to Irradiated Salivary Glands. J Dent Res 2020; 99:293-301. [PMID: 31937182 DOI: 10.1177/0022034519898138] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Stem cell-based therapies could provide a permanent treatment for salivary gland (SG) hypofunction caused by ionizing radiation (IR) injury. However, current challenges for SG stem cells to reach the clinic include surgical invasiveness, amount of tissue needed, cell delivery, and storage methods. The objective of this study was to develop a clinically less invasive method to isolate and expand human SG stem cells and then to obtain a cell-free extract to be used as a therapy for IR-injured SGs. Human labial glands were biopsied, and labial stem cells (LSCs) were expanded by explant culture. The LSC extract (LSCE) was obtained by releasing the cellular components after 3 freeze-thaw cycles and 17,000g force centrifugation. LSCE was injected intravenously into mice that had their SGs injured with 13-Gy IR. Positive (non-IR) and negative (IR) control mice received injections of saline (vehicle control). Three pieces of labial glands (0.1 g weight) could expand 1 to 2 million cells. LSCs had a doubling time of 18.8 h; could differentiate into osteocytes, adipocytes, and chondrocytes; and were positive for mesenchymal stem cell markers. Both angiogenic (FGF-1, FGF-2, KGF, angiopoietin, uPA, VEGF) and antiangiogenic factors (PAI-1, TIMP-1, TSP-1, CD26) were detected in LSCE. In addition, some angiogenic factors (PEDF, PTX3, VEGF) possessed neurotrophic functions. Mice treated with LSCE had 50% to 60% higher salivary flow rate than saline-treated mice at 8 and 12 wk post-IR. Saliva lag time measurements also confirmed that LSCE restored SG function. Histologic analyses of parotids and submandibular glands reported comparable numbers of acinar cells, blood vessels, and parasympathetic nerves and cell proliferation rates in sham IR and LSCE-treated mice, though significantly lower in saline-treated mice. An explant culture method can harvest a large number of LSCs from small pieces of labial glands. LSCE showed clinical potential to mitigate IR-injured SGs.
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Affiliation(s)
- X Su
- McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, Montreal, QC, Canada
| | - Y Liu
- McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, Montreal, QC, Canada
| | - M Bakkar
- McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, Montreal, QC, Canada
| | - O ElKashty
- McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, Montreal, QC, Canada
| | - M El-Hakim
- Department of Oral and Maxillofacial Surgery, McGill University, Montreal, QC, Canada
| | - J Seuntjens
- Gerald Bronfman Department of Oncology, Medical Physics Unit, McGill University, Montreal, Canada
| | - S D Tran
- McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, Montreal, QC, Canada
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Xu H, Wang Z, Liu L, Zhang B, Li B. Exosomes derived from adipose tissue, bone marrow, and umbilical cord blood for cardioprotection after myocardial infarction. J Cell Biochem 2019; 121:2089-2102. [PMID: 31736169 DOI: 10.1002/jcb.27399] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Accepted: 07/11/2018] [Indexed: 02/06/2023]
Abstract
Human mesenchymal stem cells (MSCs) have the potential for improving cardiac function following myocardial infarction (MI). This study was performed to explore the cardioprotection of bone marrow mesenchymal stem cells (BMMSCs), adipose tissue-derived mesenchymal stem cells (ADMSCs), and umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) for myocardium in rats after MI. MI models were established in rats, which were injected with PBS, BMMSCs, ADMSCs, and UCMSCs. Cardiac function was detected by ultrasonic cardiogram. TTC staining, TUNEL staining, and immunohistochemistry were adopted to determine infarction area, cardiomyocyte apoptosis, and microvascular density (MVD), respectively. Exosomes were derived from BMMSCs, ADMSCs, and UCBMSCs, and identified by morphological observation and CD63 expression detection. Neonatal rat cardiomyocytes (NRCMs) were isolated and cultured with hypoxia, subjected to PBS and exosomes derived from BMMSCs, ADMSCs, and UCMSCs. Flow cytometry and enzyme-linked immunosorbent assay were used to determine NRCM apoptosis and the levels of angiogenesis-related markers (VEGF, bFGF, and HGF). According to ultrasonic cardiogram, BMMSCs, ADMSCs, and UCMSCs facilitated the cardiac function of MI rats. Furthermore, three kinds of MSCs inhibited cardiomyocyte apoptosis, infarction area, and increased MVD. NRCMs treated with exosomes derived from BMMSCs, ADMSCs, and UCMSCs reduced the NRCM apoptosis and promoted angiogenesis by increasing levels of VEGF, bFGF, and HGF. Notably, exosomes from ADMSCs had the most significant effect. On the basis of the results obtained from this study, exosomes derived from BMMSCs, ADMSCs, and UCBMSCs inhibited the cardiomyocyte apoptosis and promoted angiogenesis, thereby improving cardiac function and protecting myocardium. Notably, exosomes from ADMSCs stimulated most of the cardioprotection factors.
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Affiliation(s)
- Huiyu Xu
- Shanxi Medical University, Taiyuan, Shanxi, China.,Department of Cardiology, Shanxi Cardiovascular Hospital, Taiyuan, Shanxi, China
| | - Zhongchao Wang
- Department of Cardiology, Shanxi Cardiovascular Hospital, Taiyuan, Shanxi, China
| | - Longmei Liu
- Department of Cardiovascular laboratory, Shanxi Cardiovascular Hospital, Taiyuan, Shanxi, China
| | - Baoxia Zhang
- Department of Cardiology, Shanxi Cardiovascular Hospital, Taiyuan, Shanxi, China
| | - Bao Li
- Shanxi Medical University, Taiyuan, Shanxi, China.,Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
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Kim JW, Kim JM, Choi ME, Kim SK, Kim YM, Choi JS. Adipose-derived mesenchymal stem cells regenerate radioiodine-induced salivary gland damage in a murine model. Sci Rep 2019; 9:15752. [PMID: 31673085 PMCID: PMC6823479 DOI: 10.1038/s41598-019-51775-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Accepted: 10/08/2019] [Indexed: 02/08/2023] Open
Abstract
After radioiodine (RI) therapy, patients with thyroid cancer frequently suffer from painful salivary gland (SG) swelling, xerostomia, taste alterations, and oral infections. This study was aimed to determine whether adipose-derived mesenchymal stem cells (AdMSCs) might restore RI-induced SG dysfunction in a murine model. Forty -five mice were divided into three groups; a PBS sham group, a RI+ PBS sham group (0.01 mCi/g mouse, orally), and an RI+AdMSCs (1 × 105 cells/150 uL, intraglandular injection on experimental day 28) treated group. At 16 weeks after RI treatment, body weights, SG weight, salivary flow rates (SFRs), and salivary lag times were measured. Morphologic and histologic examinations and immunohistochemistry (IHC) were performed and the activities of amylase and EGF in saliva were also measured. Changes in salivary 99mTc pertechnetate excretion were followed by SPECT and TUNEL assays were performed. The body and SG weights were similar in the AdMSCs and sham groups. Hematoxylin and eosin staining revealed the AdMSCs group had more mucin-containing acini than the RI group. Furthermore, AdMSCs treatment resulted in tissue remodeling and elevated expressions of epithelial (AQP5) and endothelial (CD31) markers, and increased SFRs. The activities of amylase and EGF were higher in the AdMSCs group than in the RI treated group. 99mTc pertechnetate excretions were similar in the AdMSCs and sham group. Also, TUNEL positive apoptotic cell numbers were less in the AdMSCs group than in the RI group. Local delivery of AdMSCs might regenerate SG damage induced by RI.
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Affiliation(s)
- Ji Won Kim
- Department of Otolaryngology, Inha University, College of Medicine, Incheon, Republic of Korea
| | - Jeong Mi Kim
- Department of Otolaryngology, Inha University, College of Medicine, Incheon, Republic of Korea
| | - Mi Eun Choi
- Department of Otolaryngology, Inha University, College of Medicine, Incheon, Republic of Korea
| | - Seok-Ki Kim
- Department of Nuclear Medicine, National Cancer Center, Goyang, Republic of Korea
| | - Young-Mo Kim
- Department of Otolaryngology, Inha University, College of Medicine, Incheon, Republic of Korea
| | - Jeong-Seok Choi
- Department of Otolaryngology, Inha University, College of Medicine, Incheon, Republic of Korea.
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Mesenchymal Stem Cell Therapy in Submandibular Salivary Gland Allotransplantation: Experimental Study. Transplantation 2019; 103:1111-1120. [DOI: 10.1097/tp.0000000000002612] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Du ZH, Ding C, Zhang Q, Zhang Y, Ge XY, Li SL, Yu GY. Stem cells from exfoliated deciduous teeth alleviate hyposalivation caused by Sjögren syndrome. Oral Dis 2019; 25:1530-1544. [PMID: 31046162 DOI: 10.1111/odi.13113] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 04/08/2019] [Accepted: 04/22/2019] [Indexed: 12/16/2022]
Abstract
OBJECTIVES To evaluate the effect of stem cells from exfoliated deciduous teeth on the hyposalivation caused by Sjögren syndrome (SS) and investigate the mechanism. METHODS Stem cells were injected into the tail veins of non-obese diabetic mice, the animal model of SS. The saliva flow was measured after pilocarpine intraperitoneal injection. Apoptosis and autophagy were evaluated by TUNEL and Western blot. Lymphocyte proportions were detected by flow cytometer. RESULTS Fluid secretion was decreased in 21-week-old mice. Stem cell treatment increased fluid secretion, alleviated inflammation in the submandibular glands and reduced inflammatory cytokine levels in the serum, submandibular glands and saliva. Stem cells decreased the apoptotic cell number and the expressions of ATG5 and Beclin-1 in the submandibular glands. Stem cells have no effect on other organs. Furthermore, the infused stem cells migrated to the spleen and liver, not the submandibular gland. Stem cells directed T cells towards Treg cells and suppressed Th1 and Tfh cells in spleen lymphocytes. CONCLUSION Stem cells from exfoliated deciduous teeth alleviate the hyposalivation caused by SS via decreasing the inflammatory cytokines, regulating the inflammatory microenvironment and decreasing the apoptosis and autophagy. The stem cells regulated in T-cell differentiation are involved in the immunomodulatory effects.
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Affiliation(s)
- Zhi-Hao Du
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China
| | - Chong Ding
- Center Laboratory, Peking University School and Hospital of Stomatology, Beijing, China
| | - Qian Zhang
- Center Laboratory, Peking University School and Hospital of Stomatology, Beijing, China
| | - Yan Zhang
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Beijing, China
| | - Xi-Yuan Ge
- Center Laboratory, Peking University School and Hospital of Stomatology, Beijing, China
| | - Sheng-Lin Li
- Center Laboratory, Peking University School and Hospital of Stomatology, Beijing, China
| | - Guang-Yan Yu
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China
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Elsaadany B, Zakaria M, Mousa MR. Transplantation of Bone Marrow-Derived Mesenchymal Stem Cells Preserve the Salivary Glands Structure after Head and Neck Radiation in Rats. Open Access Maced J Med Sci 2019; 7:1588-1592. [PMID: 31210805 PMCID: PMC6560309 DOI: 10.3889/oamjms.2019.350] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 05/18/2019] [Accepted: 05/19/2019] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND The salivary glands are one of the radiation sensitive tissues during radiotherapy in the treatment of head and neck cancer. Within the first weeks of radiotherapy, the radiation causes progressive loss of gland function, then continue throughout the later of the patient's life. AIM The present work was designed to discover the potential effect of bone marrow-derived mesenchymal stem cells (MSCs) injected locally and in decreasing the unwanted effects of radiation on rats salivary gland. MATERIAL AND METHODS 6 rats used as the control group (N) and 12 rats had a single radiation dose of 13Gy in the head and neck then, they were equally allocated into two groups: Irradiated only as a group (C), Irradiated then treated with MSCs as a group (S). The animals were euthanised 7 days post radiation. Then, submandibular salivary glands were cut up; the histological examination was done. RESULTS Histological examination of the treated group(S) shown an apparent improvement in the SG structure and function compared to the irradiated group (C), this improvement represented mainly as preserving acini diameter (mean diameter in µm group (C) 183.1 ± 4.5, in group (S) 356.3 ± 33.5 while, in (N) group 408.9 ± 5.9) and decrease in fibrotic areas in the gland (mean fibrosis parentage in group (C) 26.5 ± 5.9 in (C) group , in group (S) 11.7 ± 4.13 while in (N) group 0.2 ± 0.31). CONCLUSION BM-MSCs has revealed to be promising in mitigating the side effects of radiotherapy on salivary glands structure.
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Affiliation(s)
- Basma Elsaadany
- Oral Medicine and Periodontology Department, Faculty of Dentistry, Cairo University, Cairo, Egypt
| | - Mai Zakaria
- Oral Medicine and Periodontology Department, Faculty of Dentistry, Cairo University, Cairo, Egypt
| | - Mohamed Refat Mousa
- Pathology Department, Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt
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Dai TQ, Zhang LL, An Y, Xu FF, An R, Xu HY, Liu YP, Liu B. In vitro transdifferentiation of adipose tissue-derived stem cells into salivary gland acinar-like cells. Am J Transl Res 2019; 11:2908-2924. [PMID: 31217863 PMCID: PMC6556663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 03/26/2019] [Indexed: 06/09/2023]
Abstract
Current clinical approaches to treat irradiation-induced salivary gland hypofunction are ineffective. We previously reported that adipose-derived stem cell (ADSC)-based therapy ameliorates damaged salivary gland function in mice and that the effects were enhanced when the therapy was co-administrated with platelet-rich fibrin (PRF). We examined the feasibility of ADSC transdifferentiation into salivary gland acinar-like cells (SGALCs) and analyzed the potential of PRF to promote the transdifferentiation process in vitro. Salivary gland cells (SGCs) and ADSCs were indirectly co-cultured using Transwell inserts, and increasing concentrations of PRF-conditioned medium were applied to the co-culture system. The expression of α-amylase and AQP-5 were used to evaluate ADSC transdifferentiation. Notably, on day 7, 14, and 21, expression of both α-amylase and AQP-5 were detected in the co-cultured ADSCs. Additionally, PRF increased α-amylase and AQP-5 levels in ADSCs that were co-cultured for 7 days. These data demonstrate that ADSCs have the potential to transdifferentiate into SGALCs and that PRF can promote the transdifferentiation process. Therefore, these data reveal a possible mechanism to treat irradiation-induced salivary gland hypofunction and have translational medicine implications.
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Affiliation(s)
- Tai-Qiang Dai
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical UniversityXi’an 710032, PR China
| | - Lin-Lin Zhang
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical UniversityXi’an 710032, PR China
| | - Ying An
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Periodontology, School of Stomatology, The Fourth Military Medical UniversityXi’an 710032, PR China
| | - Fang-Fang Xu
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical UniversityXi’an 710032, PR China
| | - Ran An
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases, Laboratory Animal Center, School of Stomatology, The Fourth Military Medical UniversityXi’an 710032, PR China
| | - Hai-Yan Xu
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases, Laboratory Animal Center, School of Stomatology, The Fourth Military Medical UniversityXi’an 710032, PR China
| | - Yan-Pu Liu
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical UniversityXi’an 710032, PR China
| | - Bin Liu
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases, Laboratory Animal Center, School of Stomatology, The Fourth Military Medical UniversityXi’an 710032, PR China
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Mulyani SWM, Astuti ER, Wahyuni OR, Ernawati DS, Ramadhani NF. Xerostomia Therapy Due to Ionized Radiation Using Preconditioned Bone Marrow-Derived Mesenchymal Stem Cells. Eur J Dent 2019; 13:238-242. [PMID: 31509876 PMCID: PMC6777157 DOI: 10.1055/s-0039-1694697] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
OBJECTIVES The aim of this study was to describe the process of regeneration of damaged salivary glands due to ionizing radiations by bone marrow mesenchymal stem cells (BM-MSCs) transplantation that have been given hypoxic preconditioning with 1% O2 concentration. MATERIALS AND METHODS Stem cell culture was performed under normoxic (O2: 21%) and hypoxic conditions by incubating the cells for 48 hours in a low oxygen tension chamber consisting of 95% N2, 5% CO2, and 1% O2. Thirty male Wistar rats were divided into four groups: two groups of control and two groups of treatment. A single dose of 15 Gy radiation was provided to the ventral region of the neck in all treatment groups, damaging the salivary glands. BM-MSCs transplantation was performed in the treatment groups for normoxia and hypoxia 24-hour postradiation. STATISTICAL ANALYSIS Statistical analysis was done using normality test, followed by MANOVA test (p < 0.05). RESULTS There was a significant difference in the expression of binding SDF1-CXCR4, Bcl-2 (p < 0.05) and also the activity of the enzyme α-amylase in all groups of hypoxia. CONCLUSION BM-MSCs transplantation with hypoxic precondition increases the expression of binding SDF1-CXCR4, Bcl-2 that contributes to cell migration, cell survival, and cell differentiation.
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Affiliation(s)
- Sri Wigati Mardi Mulyani
- Department of Dentomaxillofacial Radiology, Faculty of Dental Medicine, Airlangga University, Surabaya, Indonesia
| | - Eha Renwi Astuti
- Department of Dentomaxillofacial Radiology, Faculty of Dental Medicine, Airlangga University, Surabaya, Indonesia
| | - Otty Ratna Wahyuni
- Department of Dentomaxillofacial Radiology, Faculty of Dental Medicine, Airlangga University, Surabaya, Indonesia
| | - Diah Savitri Ernawati
- Department of Oral Medicine, Faculty of Dental Medicine, Airlangga University, Surabaya, Indonesia
| | - Nastiti Faradilla Ramadhani
- Department of Dentomaxillofacial Radiology, Faculty of Dental Medicine, Airlangga University, Surabaya, Indonesia
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