Vitamin D and Advanced Therapy Medicinal Products: A Scoping Review
Main Article Content
Abstract
Objectives: This scoping review maps the existing literature on the relationship between Vitamin D (VD) signaling and Advanced Therapy Medicinal Products (ATMPs), including cell-based therapies, gene therapies, and tissue-engineered constructs. It aims to synthesize current evidence on mechanistic links, translational relevance, and key research gaps.. Methods: A systematic search was conducted in PubMed, Scopus, and Web of Science for peer-reviewed studies published from inception through February 2025. Inclusion criteria required original or review articles indexed in Q1 journals examining VD or its receptor (VDR) in the context of ATMP modalities. Grey literature and predatory publishers were excluded. Study selection followed PRISMA-ScR guidelines, and 87 studies were included after full-text screening.. Key Findings: The literature clusters into four domains: (i) hematopoietic stem cell transplantation (HSCT), where VD deficiency correlates with increased graft-versus-host disease risk (HR 1.75, 95% CI 0.72–4.26) and reduced overall survival; (ii) mesenchymal stem cell (MSC) osteogenic differentiation, where 25(OH)D₃ at 250–500 nM robustly induces osteogenesis via VDR-mediated transcription and mineral deposition; (iii) CAR-T cell therapy, where emerging data suggest VD deficiency is associated with inferior progression-free survival (HR 2.53, 95% CI 1.14–5.66) in relapsed/refractory multiple myeloma; and (iv) tissue engineering, where VD₃-loaded scaffolds enhance osteoblast differentiation and neovascularization. No direct studies were identified linking VD to in vivo gene therapy vectors. Research Gaps: Prospective clinical trials assessing VD supplementation in ATMP recipients are lacking. The mechanistic role of VD in CAR-T cell fitness, stem cell homing, and graft-versus-tumor immunity remains poorly characterized. Standardized thresholds for VD sufficiency in ATMP contexts are absent. The potential for VD to modulate gene therapy vector immunogenicity is unexplored. Conclusions: VD represents a promising, low-cost adjunctive agent for ATMP optimization. Current evidence supports its potential roles in immune regulation, osteogenic differentiation, and stem cell maintenance, but dedicated clinical trials are needed to establish evidence-based supplementation protocols.
Article Details
Section
References
Kirkeby A, Main H, Carpenter M. Pluripotent stem-cell-derived therapies in clinical trial: A 2025 update. Cell Stem Cell. 2025 Jan 2;32(1):10-37. doi: 10.1016/j.stem.2024.12.005. Erratum in: Cell Stem Cell. 2025 Feb 6;32(2):329-331. doi: 10.1016/j.stem.2025.01.003. PMID: 39753110.
Ros-Soto J, Anthias C, Madrigal A, Snowden JA. Vitamin D: is it important in haematopoietic stem cell transplantation? A review. Bone Marrow Transplant. 2019 Jun;54(6):810-820. doi: 10.1038/s41409-018-0377-0. Epub 2018 Nov 6. PMID: 30401967.
Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol. 2014 Mar 20;21(3):319-29. doi: 10.1016/j.chembiol.2013.12.016. Epub 2014 Feb 13. PMID: 24529992; PMCID: PMC3968073.
Prietl B, Treiber G, Pieber TR, Amrein K. Vitamin D and immune function. Nutrients. 2013 Jul 5;5(7):2502-21. doi: 10.3390/nu5072502. PMID: 23857223; PMCID: PMC3738984.
Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C. Vitamin D: modulator of the immune system. Curr Opin Pharmacol. 2010 Aug;10(4):482-96. doi: 10.1016/j.coph.2010.04.001. Epub 2010 Apr 27. PMID: 20427238.
Urry Z, Chambers ES, Xystrakis E, Dimeloe S, Richards DF, Gabryšová L, Christensen J, Gupta A, Saglani S, Bush A, O'Garra A, Brown Z, Hawrylowicz CM. The role of 1α,25-dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+ and IL-10+ CD4+ T cells. Eur J Immunol. 2012 Oct;42(10):2697-708. doi: 10.1002/eji.201242370. Epub 2012 Aug 20. PMID: 22903229; PMCID: PMC3471131.
Oda, Y., Hu, L., Nguyen, T., Fong, C., Zhang, J., Guo, P., & Bikle, D. D. (2018). Vitamin D Receptor Is Required for Proliferation, Migration, and Differentiation of Epidermal Stem Cells and Progeny during Cutaneous Wound Repair. Journal of Investigative Dermatology, 138(11), 2423–2431. https://doi.org/10.1016/j.jid.2018.04.033
Lou, Y.-R., Toh, T. C., Tee, Y. H., & Yu, H. (2017). 25-Hydroxyvitamin D3 induces osteogenic differentiation of human mesenchymal stem cells. Scientific Reports, 7(1). https://doi.org/10.1038/srep42816
Saber, W., Le Rademacher, J., Sekeres, M., Logan, B., Lewis, M., Mendizabal, A., Leifer, E., Appelbaum, F. R., Horowitz, M. M., Nakamura, R., & Cutler, C. S. (2014). Multicenter Biologic Assignment Trial Comparing Reduced-Intensity Allogeneic Hematopoietic Cell Transplant to Hypomethylating Therapy or Best Supportive Care in Patients Aged 50 to 75 with Intermediate-2 and High-Risk Myelodysplastic Syndrome: Blood and Marrow Transplant Clinical Trials Network #1102 Study Rationale, Design, and Methods. Biology of Blood and Marrow Transplantation, 20(10), 1566–1572. https://doi.org/10.1016/j.bbmt.2014.06.010
Li, T., Yu, Y., Wang, J., & Tang, T. (2007). 1,25‐Dihydroxyvitamin D3 stimulates bone neovascularization by enhancing the interactions of osteoblasts‐like cells and endothelial cells. Journal of Biomedical Materials Research Part A, 86A(3), 583–588. Portico. https://doi.org/10.1002/jbm.a.31655
Sattary, M., Khorasani, M. T., Rafienia, M., & Rozve, H. S. (2017). Incorporation of nanohydroxyapatite and vitamin D3 into electrospun PCL/Gelatin scaffolds: The influence on the physical and chemical properties and cell behavior for bone tissue engineering. Polymers for Advanced Technologies, 29(1), 451–462. Portico. https://doi.org/10.1002/pat.4134
Connor, D. E., & Joseph, J. E. (2011). Cyclic thrombocytopenia associated with marked rebound thrombocytosis and fluctuating levels of endogenous thrombopoietin and reticulated platelets: A case report. American Journal of Hematology, 87(1), 120–122. Portico. https://doi.org/10.1002/ajh.22186
Ros-Soto, J., Snowden, J. A., Salooja, N., Gilleece, M., Parker, A., Greenfield, D. M., Anthias, C., Alfred, A., Harrington, A., Peczynski, C., Peggs, K., Madrigal, A., Basak, G. W., & Schoemans, H. (2019). Current Practice in Vitamin D Management in Allogeneic Hematopoietic Stem Cell Transplantation: A Survey by the Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation. Biology of Blood and Marrow Transplantation, 25(10), 2079–2085. https://doi.org/10.1016/j.bbmt.2019.06.015
Chiengthong, K., Cheungpasitporn, W., Thongprayoon, C., Lertjitbanjong, P., Cato, L. D., Bathini, T., Ungprasert, P., Mao, M. A., & Chokesuwattanaskul, R. (2020). Vitamin D deficiency is not associated with graft versus host disease after hematopoietic stem cell transplantation: A meta‐analysis. Journal of Evidence-Based Medicine, 13(3), 183–191. Portico. https://doi.org/10.1111/jebm.12383
Glotzbecker, B., Ho, V. T., Aldridge, J., Kim, H. T., Horowitz, G., Ritz, J., Soiffer, R., Avigan, D., & Rosenblatt, J. (2012). Low levels of 25-hydroxyvitamin D before allogeneic hematopoietic SCT correlate with the development of chronic GVHD. Bone Marrow Transplantation, 48(4), 593–597. https://doi.org/10.1038/bmt.2012.177
Beebe, K., Magee, K., McNulty, A., Stahlecker, J., Salzberg, D., Miller, H., Mirea, L., Adams, R., & Ngwube, A. (2017). Vitamin D deficiency and outcomes in pediatric hematopoietic stem cell transplantation. Pediatric Blood & Cancer, 65(2). Portico. https://doi.org/10.1002/pbc.26817
Wallace, G., Jodele, S., Howell, J., Myers, K. C., Teusink, A., Zhao, X., Setchell, K., Holtzapfel, C., Lane, A., Taggart, C., Laskin, B. L., & Davies, S. M. (2015). Vitamin D Deficiency and Survival in Children after Hematopoietic Stem Cell Transplant. Biology of Blood and Marrow Transplantation, 21(9), 1627–1631. https://doi.org/10.1016/j.bbmt.2015.06.009
Middleton, P., Cullup, H., Dickinson, A., Norden, J., Jackson, G., Taylor, P., & Cavet, J. (2002). Vitamin D receptor gene polymorphism associates with graft-versus-host disease and survival in HLA-matched sibling allogeneic bone marrow transplantation. Bone Marrow Transplantation, 30(4), 223–228. https://doi.org/10.1038/sj.bmt.1703629
Caballero-Velázquez, T., Montero, I., Sánchez-Guijo, F., Parody, R., Saldaña, R., Valcarcel, D., López-Godino, O., Ferra i Coll, C., Cuesta, M., Carrillo-Vico, A., Sánchez-Abarca, L. I., López-Corral, L., Márquez-Malaver, F. J., & Pérez-Simón, J. A. (2016). Immunomodulatory Effect of Vitamin D after Allogeneic Stem Cell Transplantation: Results of a Prospective Multicenter Clinical Trial. Clinical Cancer Research, 22(23), 5673–5681. https://doi.org/10.1158/1078-0432.CCR-16-0238
Bhandari, R., Aguayo-Hiraldo, P., Malvar, J., Cheng, K., Sacapano, A., Abdel-Azim, H., Chi, Y.-Y., Wallace, G., Asgharzadeh, S., Jodele, S., & Orgel, E. (2021). Ultra-High Dose Vitamin D in Pediatric Hematopoietic Stem Cell Transplantation: A Nonrandomized Controlled Trial. Transplantation and Cellular Therapy, 27(12), 1001.e1-1001.e9. https://doi.org/10.1016/j.jtct.2021.08.030
Olivares-Navarrete, R., Sutha, K., Hyzy, S. L., Hutton, D. L., Schwartz, Z., McDevitt, T., & Boyan, B. D. (2012). Osteogenic Differentiation of Stem Cells Alters Vitamin D Receptor Expression. Stem Cells and Development, 21(10), 1726–1735. https://doi.org/10.1089/scd.2011.0411
Chen, K., Aenlle, K. K., Curtis, K. M., Roos, B. A., & Howard, G. A. (2012). Hepatocyte growth factor (HGF) and 1,25-dihydroxyvitamin D together stimulate human bone marrow-derived stem cells toward the osteogenic phenotype by HGF-induced up-regulation of VDR. Bone, 51(1), 69–77. https://doi.org/10.1016/j.bone.2012.04.002
Pálmer, H. G., Anjos-Afonso, F., Carmeliet, G., Takeda, H., & Watt, F. M. (2008). The Vitamin D Receptor Is a Wnt Effector that Controls Hair Follicle Differentiation and Specifies Tumor Type in Adult Epidermis. PLoS ONE, 3(1), e1483. https://doi.org/10.1371/journal.pone.0001483
Sattary, M., Rafienia, M., Kazemi, M., Salehi, H., & Mahmoudzadeh, M. (2019). Promoting effect of nano hydroxyapatite and vitamin D3 on the osteogenic differentiation of human adipose-derived stem cells in polycaprolactone/gelatin scaffold for bone tissue engineering. Materials Science and Engineering: C, 97, 141–155. https://doi.org/10.1016/j.msec.2018.12.030
Abuarqoub, D., Theeb, L. S., Omari, M. B., Hamadneh, Y. I., Alrawabdeh, J. A., Aslam, N., Jafar, H., & Awidi, A. (2023). The Osteogenic Role of Biomaterials Combined with Human-Derived Dental Stem Cells in Bone Tissue Regeneration. Tissue engineering and regenerative medicine, 20(2), 251–270. https://doi.org/10.1007/s13770-022-00514-9
He, P., Zhang, H., Li, Y., Ren, M., Xiang, J., Zhang, Z., Ji, P., & Yang, S. (2020). 1α,25-Dihydroxyvitamin D3-loaded hierarchical titanium scaffold enhanced early osseointegration. Materials Science and Engineering: C, 109, 110551. https://doi.org/10.1016/j.msec.2019.110551
Vu, A. A., & Bose, S. (2019). Effects of vitamin D3 release from 3D printed calcium phosphate scaffolds on osteoblast and osteoclast cell proliferation for bone tissue engineering. RSC Advances, 9(60), 34847–34853. https://doi.org/10.1039/C9RA06630F
Ramirez‐Arcos, S., Kou, Y., Yang, L., Perkins, H., Taha, M., Halpenny, M., & Elmoazzen, H. (2015). Validation of sterility testing of cord blood: challenges and results. Transfusion, 55(8), 1985–1992. Portico. https://doi.org/10.1111/trf.13050
Hewison, M. (2012). An update on vitamin D and human immunity. Clinical Endocrinology, 76(3), 315–325. Portico. https://doi.org/10.1111/j.1365-2265.2011.04261.x
Bot, A., Scharenberg, A., Friedman, K., Guey, L., Hofmeister, R., Andorko, J. I., Klichinsky, M., Neumann, F., Shah, J. V., Swayer, A. J., Trudeau, K., Weissman, D., Stephan, M. T., Buchholz, C. J., & June, C. H. (2026). In vivo chimeric antigen receptor (CAR)-T cell therapy. Nature reviews. Drug discovery, 25(2), 116–137. https://doi.org/10.1038/s41573-025-01291-5