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.
Cell Therapy
Mesenchymal stem Cells
Radiotherapy
Systematic Review
Xerostomia
Journal
Stem cell reviews and reports
ISSN: 2629-3277
Titre abrégé: Stem Cell Rev Rep
Pays: United States
ID NLM: 101752767
Informations de publication
Date de publication:
02 Mar 2024
02 Mar 2024
Historique:
accepted:
17
02
2024
medline:
2
3
2024
pubmed:
2
3
2024
entrez:
2
3
2024
Statut:
aheadofprint
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
CONCLUSIONS
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.
Identifiants
pubmed: 38430363
doi: 10.1007/s12015-024-10700-y
pii: 10.1007/s12015-024-10700-y
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
Références
Marur, S., & Forastiere, A. A. (2016). Head and Neck squamous cell carcinoma: Update on Epidemiology, diagnosis, and treatment. Mayo Clinic Proceedings, 91, 386–396. https://doi.org/10.1016/j.mayocp.2015.12.017 .
doi: 10.1016/j.mayocp.2015.12.017
pubmed: 26944243
Jensen, S. B., Vissink, A., Limesand, K. H., & Reyland, M. E. Salivary gland hypofunction and Xerostomia in Head and Neck Radiation patients. Journal of the National Cancer Institute. Monographs 2019;2019. https://doi.org/10.1093/jncimonographs/lgz016 .
Vissink, A., van Luijk, P., Langendijk, J. A., & Coppes, R. P. (2015). Current ideas to reduce or salvage radiation damage to salivary glands. Oral Diseases, 21, e1–10. https://doi.org/10.1111/odi.12222 .
doi: 10.1111/odi.12222
pubmed: 24581290
Nutting, C. M., Morden, J. P., Harrington, K. J., Urbano, T. G., Bhide, S. A., Clark, C., et al. (2011). Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): A phase 3 multicentre randomised controlled trial. The Lancet Oncology, 12, 127–136. https://doi.org/10.1016/S1470-2045(10)70290-4 .
doi: 10.1016/S1470-2045(10)70290-4
pubmed: 21236730
pmcid: 3033533
Kakoei, S., Haghdoost, A. A., Rad, M., Mohammadalizadeh, S., Pourdamghan, N., Nakhaei, M., et al. (2012). Xerostomia after radiotherapy and its effect on quality of life in head and neck cancer patients. Archives of Iranian Medicine, 15, 214–218.
pubmed: 22424038
Memtsa, P. T., Tolia, M., Tzitzikas, I., Bizakis, J., Pistevou-Gombaki, K., Charalambidou, M., et al. (2017). Assessment of xerostomia and its impact on quality of life in head and neck cancer patients undergoing radiation therapy. Mol Clin Oncol, 6, 789–793. https://doi.org/10.3892/mco.2017.1200 .
doi: 10.3892/mco.2017.1200
pubmed: 28529753
pmcid: 5431738
Liu, X. K., Zeng, Z. Y., Hong, M. H., Zhang, A. L., Cui, N. J., & Chen, F. J. (2004). [Clinical analysis of xerostomia in patients with nasopharyngeal carcinoma after radiation therapy]. Ai Zheng, 23, 593–596.
pubmed: 15142462
El Agha, E., Kramann, R., Schneider, R. K., Li, X., Seeger, W., Humphreys, B. D., et al. (2017). Mesenchymal stem cells in Fibrotic Disease. Cell Stem Cell, 21, 166–177. https://doi.org/10.1016/j.stem.2017.07.011 .
doi: 10.1016/j.stem.2017.07.011
pubmed: 28777943
Ozdemir, T., Fowler, E. W., Hao, Y., Ravikrishnan, A., Harrington, D. A., Witt, R. L., et al. (2016). Biomaterials-based strategies for salivary gland tissue regeneration. Biomater Sci, 4, 592–604. https://doi.org/10.1039/c5bm00358j .
doi: 10.1039/c5bm00358j
pubmed: 26878077
pmcid: 4803517
Galipeau, J., Krampera, M., Barrett, J., Dazzi, F., Deans, R. J., DeBruijn, J., et al. (2015). International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials. Cytotherapy, 18, 151–159. https://doi.org/10.1016/j.jcyt.2015.11.008 .
doi: 10.1016/j.jcyt.2015.11.008
pubmed: 26724220
pmcid: 4745114
Singer, N. G., & Caplan, A. I. (2011). Mesenchymal stem cells: Mechanisms of inflammation. Annu Rev Pathol Mech Dis, 6, 457–478. https://doi.org/10.1146/annurev-pathol-011110-130230 .
doi: 10.1146/annurev-pathol-011110-130230
Caplan, A. I., & Dennis, J. E. (2006). Mesenchymal stem cells as trophic mediators. Journal of Cellular Biochemistry, 98, 1076–1084. https://doi.org/10.1002/jcb.20886 .
doi: 10.1002/jcb.20886
pubmed: 16619257
Caplan, A. I., & Correa, D. (2011). The MSC: An injury drugstore. Cell Stem Cell, 9, 11–15. https://doi.org/10.1016/j.stem.2011.06.008 .
doi: 10.1016/j.stem.2011.06.008
pubmed: 21726829
pmcid: 3144500
Coppes, R. P., & Stokman, M. A. (2011). Stem cells and the repair of radiation-induced salivary gland damage. Oral Diseases, 17, 143–153. https://doi.org/10.1111/j.1601-0825.2010.01723.x .
doi: 10.1111/j.1601-0825.2010.01723.x
pubmed: 20796229
Jensen, D. H., Oliveri, R. S., Trojahn Kølle, S. F., Fischer-Nielsen, A., Specht, L., Bardow, A., et al. (2014). Mesenchymal stem cell therapy for salivary gland dysfunction and xerostomia: A systematic review of preclinical studies. Oral Surg Oral Med Oral Pathol Oral Radiol, 117, 335–342e1. https://doi.org/10.1016/j.oooo.2013.11.496 .
doi: 10.1016/j.oooo.2013.11.496
pubmed: 24528792
Lynggaard, C. D., Grønhøj, C., Christensen, R., Fischer-Nielsen, A., Melchiors, J., Specht, L., et al. (2022). Intraglandular off-the-Shelf allogeneic mesenchymal stem cell treatment in patients with Radiation-Induced Xerostomia: A Safety Study (MESRIX-II). Stem Cells Transl Med, 11, 478–489. https://doi.org/10.1093/stcltm/szac011 .
doi: 10.1093/stcltm/szac011
pubmed: 35435231
pmcid: 9154319
Blitzer, G. C., Glazer, T., Burr, A., Gustafson, S., Ganz, O., Meyers, R., et al. (2023). Marrow-derived autologous stromal cells for the restoration of salivary hypofunction (MARSH): A pilot, first-in-human study of interferon gamma-stimulated marrow mesenchymal stromal cells for treatment of radiation-induced xerostomia. Cytotherapy, 25, 1139–1144. https://doi.org/10.1016/j.jcyt.2023.07.009 .
doi: 10.1016/j.jcyt.2023.07.009
pubmed: 37589639
Lynggaard, C. D., Grønhøj, C., Jensen, S. B., Christensen, R., Specht, L., Andersen, E., et al. (2022). Long-term safety of treatment with autologous mesenchymal stem cells in patients with Radiation-Induced Xerostomia: Primary results of the MESRIX Phase I/II Randomized Trial. Clinical Cancer Research, 28, 2890–2897. https://doi.org/10.1158/1078-0432.CCR-21-4520 .
doi: 10.1158/1078-0432.CCR-21-4520
pubmed: 35486613
pmcid: 9365378
Grønhøj, C., Jensen, D. H., Vester-Glowinski, P., Jensen, S. B., Bardow, A., Oliveri, R. S., et al. (2018). Safety and efficacy of mesenchymal stem cells for Radiation-Induced Xerostomia: A randomized, placebo-controlled phase 1/2 trial (MESRIX). International Journal of Radiation Oncology Biology Physics, 101, 581–592. https://doi.org/10.1016/j.ijrobp.2018.02.034 .
doi: 10.1016/j.ijrobp.2018.02.034
pubmed: 29678523
Jansson, P. M., Lynggaard, C. D., Carlander, A. F., Jensen, S. B., Follin, B., Hoeeg, C., et al. (2022). Mesenchymal stromal/stem cell therapy for radiation-induced salivary gland hypofunction in animal models: A protocol for a systematic review and meta-analysis. Syst Rev, 11, 72. https://doi.org/10.1186/s13643-022-01943-2 .
doi: 10.1186/s13643-022-01943-2
pubmed: 35436971
pmcid: 9016929
Percie du Sert, N., Hurst, V., Ahluwalia, A., Alam, S., Avey, M. T., Baker, M., et al. (2020). The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. Plos Biology, 18, e3000410. https://doi.org/10.1371/journal.pbio.3000410 .
doi: 10.1371/journal.pbio.3000410
pubmed: 32663219
pmcid: 7360023
Hooijmans, C. R., Rovers, M. M., de Vries, R. B. M., Leenaars, M., Ritskes-Hoitinga, M., & Langendam, M. W. (2014). SYRCLE’s risk of bias tool for animal studies. Bmc Medical Research Methodology, 14, 43. https://doi.org/10.1186/1471-2288-14-43 .
doi: 10.1186/1471-2288-14-43
pubmed: 24667063
pmcid: 4230647
https://handbook-5-1.cochrane.org/chapter_9/9_2_3_2_the_standardized_mean_difference.htm . (n.d).
Lin, C. Y., Chang, F. H., Chen, C. Y., Huang, C. Y., Hu, F. C., Huang, W. K., et al. (2011). Cell therapy for salivary gland regeneration. Journal of Dental Research, 90, 341–346. https://doi.org/10.1177/0022034510386374 .
doi: 10.1177/0022034510386374
pubmed: 21297017
Kojima, T., Kanemaru, S. I., Hirano, S., Tateya, I., Ohno, S., Nakamura, T., et al. (2011). Regeneration of radiation damaged salivary glands with adipose-derived stromal cells. The Laryngoscope, 121, 1864–1869. https://doi.org/10.1002/lary.22080 .
doi: 10.1002/lary.22080
pubmed: 21748735
Jeong, J., Baek, H., Kim, Y. J., Choi, Y., Lee, H., Lee, E., et al. (2013). Human salivary gland stem cells ameliorate hyposalivation of radiation-damaged rat salivary glands. Experimental & Molecular Medicine, 45, e58. https://doi.org/10.1038/emm.2013.121 .
doi: 10.1038/emm.2013.121
Lim, J. Y., Yi, T., Choi, J. S., Jang, Y. H., Lee, S., Kim, H. J., et al. (2013). Intraglandular transplantation of bone marrow-derived clonal mesenchymal stem cells for amelioration of post-irradiation salivary gland damage. Oral Oncology, 49, 136–143. https://doi.org/10.1016/j.oraloncology.2012.08.010 .
doi: 10.1016/j.oraloncology.2012.08.010
pubmed: 22981389
Lim, J. Y., Ra, J. C., Shin, I. S., Jang, Y. H., An, H. Y., Choi, J. S., et al. (2013). Systemic transplantation of human adipose tissue-derived mesenchymal stem cells for the regeneration of irradiation-induced salivary gland damage. PLoS One, 8, e71167. https://doi.org/10.1371/journal.pone.0071167 .
doi: 10.1371/journal.pone.0071167
pubmed: 23951100
pmcid: 3739795
Xiong, X., Shi, X., & Chen, F. (2014). Human adipose tissuederived stem cells alleviate radiationinduced xerostomia. International Journal of Molecular Medicine, 34, 749–755. https://doi.org/10.3892/ijmm.2014.1837 .
doi: 10.3892/ijmm.2014.1837
pubmed: 25017690
pmcid: 4121343
Chen, Y., Niu, Z., Xue, Y., Yuan, F., Fu, Y., & Bai, N. (2014). Improvement in the repair of defects in maxillofacial soft tissue in irradiated minipigs by a mixture of adipose-derived stem cells and platelet-rich fibrin. British Journal of Oral and Maxillofacial Surgery, 52, 740–745. https://doi.org/10.1016/j.bjoms.2014.06.006 .
doi: 10.1016/j.bjoms.2014.06.006
pubmed: 24993354
Li, Z., Wang, Y., Xing, H., Wang, Z., Hu, H., An, R., et al. (2015). Protective efficacy of intravenous transplantation of adipose-derived stem cells for the prevention of radiation-induced salivary gland damage. Archives of Oral Biology, 60, 1488–1496. https://doi.org/10.1016/j.archoralbio.2015.07.016 .
doi: 10.1016/j.archoralbio.2015.07.016
pubmed: 26263537
Wang, Z., Ju, Z., He, L., Li, Z., Liu, Y., & Liu, B. (2017). Intraglandular transplantation of adipose-derived stem cells for the Alleviation of Irradiation-Induced parotid gland damage in Miniature pigs. Journal of Oral and Maxillofacial Surgery, 75, 1784–1790. https://doi.org/10.1016/j.joms.2016.08.001 .
doi: 10.1016/j.joms.2016.08.001
pubmed: 27621149
Choi, J. S., An, H. Y., Shin, H. S., Kim, Y. M., & Lim, J. Y. (2018). Enhanced tissue remodelling efficacy of adipose-derived mesenchymal stem cells using injectable matrices in radiation-damaged salivary gland model. Journal of Tissue Engineering and Regenerative Medicine, 12, e695–706. https://doi.org/10.1002/term.2352 .
doi: 10.1002/term.2352
pubmed: 27860388
Shin, H. S., Lee, S., Hong, H. J., Lim, Y. C., Koh, W. G., & Lim, J. Y. (2018). Stem cell properties of human clonal salivary gland stem cells are enhanced by three-dimensional priming culture in nanofibrous microwells. Stem Cell Research & Therapy, 9, 74. https://doi.org/10.1186/s13287-018-0829-x .
doi: 10.1186/s13287-018-0829-x
Shin, H. S., Lee, S., Kim, Y. M., & Lim, J. Y. (2018). Hypoxia-activated adipose mesenchymal stem cells prevents Irradiation-Induced Salivary Hypofunction by enhanced paracrine effect through fibroblast growth factor 10. Stem Cells, 36, 1020–1032. https://doi.org/10.1002/stem.2818 .
doi: 10.1002/stem.2818
pubmed: 29569790
Elsaadany, B., Zakaria, M., & Mousa, M. R. (2019). 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, 7, 1588–1592. https://doi.org/10.3889/oamjms.2019.350 .
doi: 10.3889/oamjms.2019.350
pubmed: 31210805
pmcid: 6560309
Mulyani, S. W. M., Astuti, E. R., Wahyuni, O. R., Ernawati, D. S., & Ramadhani, N. F. (2019). Xerostomia Therapy due to Ionized Radiation using preconditioned bone marrow-derived mesenchymal stem cells. Eur J Dent, 13, 238–242. https://doi.org/10.1055/s-0039-1694697 .
doi: 10.1055/s-0039-1694697
pubmed: 31509876
pmcid: 6777157
Wang, Z., Xing, H., Hu, H., Dai, T., Wang, Y., Li, Z., et al. (2016). Intraglandular transplantation of adipose-derived stem cells combined with platelet-rich fibrin extract for the treatment of irradiation-induced salivary gland damage. Exp Ther Med, 15, 795–805. https://doi.org/10.3892/etm.2017.5497 .
doi: 10.3892/etm.2017.5497
A, H. Y., C, H. S. S. J. S., & K, H. J. (2015). Adipose mesenchymal stem cell secretome modulated in hypoxia for remodeling of radiation-induced salivary gland damage. PLoS One, 10, e0141862. https://doi.org/10.1371/journal.pone.0141862 .
doi: 10.1371/journal.pone.0141862
Eisbruch, A., Ten Haken, R. K., Kim, H. M., Marsh, L. H., & Ship, J. A. (1999). Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer. International Journal of Radiation Oncology Biology Physics, 45, 577–587. https://doi.org/10.1016/s0360-3016(99)00247-3 .
doi: 10.1016/s0360-3016(99)00247-3
pubmed: 10524409
Dohan, D. M., Choukroun, J., Diss, A., Dohan, S. L., Dohan, A. J. J., Mouhyi, J., et al. (2006). Platelet-rich fibrin (PRF): A second-generation platelet concentrate. Part I: Technological concepts and evolution. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontics, 101, e37–44. https://doi.org/10.1016/j.tripleo.2005.07.008 .
doi: 10.1016/j.tripleo.2005.07.008
pubmed: 16504849
Kronberg Jakobsen, K., Duch Lynggard, C., Paaske, N., Fenger Carlander, A. L., Kastrup, J., Hauge Werner, A., et al. (2023). Long-term outcome following treatment with allogeneic mesenchymal stem/Stromal cells for Radiation-Induced Hyposalivation and Xerostomia. Stem Cells Transl Med.
Lynggaard, C. D., Jersie-Christensen, R., Juhl, M., Jensen, S. B., Grønhøj, C., Melchiors, J., et al. (2022). Intraglandular mesenchymal stem cell treatment induces changes in the salivary proteome of irradiated patients. Communications Medicine, 2, 160. https://doi.org/10.1038/s43856-022-00223-3 .
doi: 10.1038/s43856-022-00223-3
pubmed: 36496530
pmcid: 9735277