{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:06:59Z","timestamp":1760058419396,"version":"build-2065373602"},"reference-count":59,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T00:00:00Z","timestamp":1743379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NICHD intramural funding","award":["ZIA HD008830-16"],"award-info":[{"award-number":["ZIA HD008830-16"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Type VII osteogenesis imperfecta (OI), caused by recessive CRTAP mutations, is predominantly lethal in the first year of life. Due to its early lethality, little is known about bone dysplasia mechanism. RNA-seq analysis of differentiated osteoblasts of siblings with a non-lethal homozygous CRTAP-null variant showed an enrichment of gene ontology terms involved in DNA replication and cell cycle compared to control. BrdU incorporation confirmed a \u22482-fold increase in proliferation in non-lethal proband osteoblasts in comparison to control cells. In addition, the expression of cyclin dependent kinase inhibitor 2A (CDKN2A), encoding a protein involved in cell cycle inhibition, was significantly reduced (&gt;50%) in CRTAP-null osteoblasts, while cyclin B1 (CCNB1), encoding a promoter of the cell cycle, was enhanced. Ossification and bone and cartilage development gene ontology pathways were enriched among upregulated genes throughout osteoblast differentiation, as was protein secretion. Ingenuity pathway analysis indicated an upregulation of BMP2 signaling, supported by increase in both BMP2 and MSX2, an early BMP2-responsive gene, by qPCR. Throughout differentiation, CRTAP-null osteoblasts showed a decrease in transcripts related to cell adhesion and extracellular matrix organization pathways. We propose that increased proliferation and osteogenesis of type VII OI osteoblasts may be stimulated through upregulation of BMP2 signaling, altering bone homeostasis, and leading to weaker bones.<\/jats:p>","DOI":"10.3390\/cells14070518","type":"journal-article","created":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T04:21:01Z","timestamp":1743481261000},"page":"518","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CRTAP-Null Osteoblasts Have Increased Proliferation, Protein Secretion, and Skeletal Morphogenesis Gene Expression with Downregulation of Cellular Adhesion"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8021-4997","authenticated-orcid":false,"given":"Aileen M.","family":"Barnes","sequence":"first","affiliation":[{"name":"Section on Heritable Disorders of Bone and Extracellular Matrix, <i>Eunice Kennedy Shriver<\/i> National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Apratim","family":"Mitra","sequence":"additional","affiliation":[{"name":"Bioinformatics & Scientific Programming Core, <i>Eunice Kennedy Shriver<\/i> National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marianne M.","family":"Knue","sequence":"additional","affiliation":[{"name":"Office of the Clinical Director, Division of Intramural Research, <i>Eunice Kennedy Shriver<\/i> National Institute of Child Health and Human Development, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberta","family":"Derkyi","sequence":"additional","affiliation":[{"name":"Office of the Clinical Director, Division of Intramural Research, <i>Eunice Kennedy Shriver<\/i> National Institute of Child Health and Human Development, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4171-0493","authenticated-orcid":false,"given":"An","family":"Dang Do","sequence":"additional","affiliation":[{"name":"Office of the Clinical Director, Division of Intramural Research, <i>Eunice Kennedy Shriver<\/i> National Institute of Child Health and Human Development, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan K.","family":"Dale","sequence":"additional","affiliation":[{"name":"Bioinformatics & Scientific Programming Core, <i>Eunice Kennedy Shriver<\/i> National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joan C.","family":"Marini","sequence":"additional","affiliation":[{"name":"Section on Heritable Disorders of Bone and Extracellular Matrix, <i>Eunice Kennedy Shriver<\/i> National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1016\/S0140-6736(15)00728-X","article-title":"Osteogenesis imperfecta","volume":"387","author":"Forlino","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/S8756-3282(02)00790-1","article-title":"Osteogenesis imperfecta type VII: An autosomal recessive form of brittle bone disease","volume":"31","author":"Ward","year":"2002","journal-title":"Bone"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2757","DOI":"10.1056\/NEJMoa063804","article-title":"Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta","volume":"355","author":"Barnes","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.cell.2006.08.039","article-title":"CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive osteogenesis imperfecta","volume":"127","author":"Morello","year":"2006","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.4161\/cc.6.14.4474","article-title":"Components of the collagen prolyl 3-hydroxylation complex are crucial for normal bone development","volume":"6","author":"Marini","year":"2007","journal-title":"Cell Cycle"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/ng1968","article-title":"Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal\/severe osteogenesis imperfecta","volume":"39","author":"Cabral","year":"2007","journal-title":"Nat Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1056\/NEJMoa0907705","article-title":"Lack of cyclophilin B in osteogenesis imperfecta with normal collagen folding","volume":"362","author":"Barnes","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"17641","DOI":"10.1074\/jbc.M109.007070","article-title":"Biochemical characterization of the prolyl 3-hydroxylase 1.cartilage-associated protein.cyclophilin B complex","volume":"284","author":"Ishikawa","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1093\/hmg\/ddp481","article-title":"Prolyl 3-hydroxylase 1 and CRTAP are mutually stabilizing in the endoplasmic reticulum collagen prolyl 3-hydroxylation complex","volume":"19","author":"Chang","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Baldridge, D., Lennington, J., Weis, M., Homan, E.P., Jiang, M.M., Munivez, E., Keene, D.R., Hogue, W.R., Pyott, S., and Byers, P.H. (2010). Generalized connective tissue disease in Crtap-\/- mouse. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0010560"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e63488","DOI":"10.7554\/eLife.63488","article-title":"Tendon and motor phenotypes in the Crtap(-\/-) mouse model of recessive osteogenesis imperfecta","volume":"10","author":"Grol","year":"2021","journal-title":"eLife"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.ajhg.2010.02.022","article-title":"Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta","volume":"86","author":"Alanay","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2865","DOI":"10.1002\/ajmg.a.34269","article-title":"Severe osteogenesis imperfecta caused by a small in-frame deletion in CRTAP","volume":"155A","author":"Amor","year":"2011","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1002\/humu.20799","article-title":"CRTAP and LEPRE1 mutations in recessive osteogenesis imperfecta","volume":"29","author":"Baldridge","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"116683","DOI":"10.1016\/j.bone.2023.116683","article-title":"Genetic analysis of osteogenesis imperfecta in a large Brazilian cohort","volume":"169","author":"Holtz","year":"2023","journal-title":"Bone"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1111\/cge.14172","article-title":"Novel BMP1, CRTAP, and SERPINF1 variants causing autosomal recessive osteogenesis imperfecta","volume":"102","author":"Kuptanon","year":"2022","journal-title":"Clin. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/ahg.12403","article-title":"Osteogenesis imperfecta: Novel genetic variants and clinical observations from a clinical exome study of 54 Indian patients","volume":"85","author":"Madhuri","year":"2021","journal-title":"Ann. Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"116516","DOI":"10.1016\/j.bone.2022.116516","article-title":"Craniofacial and dental phenotype of two girls with osteogenesis imperfecta due to mutations in CRTAP","volume":"164","author":"Marulanda","year":"2022","journal-title":"Bone"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Tang, Y.A., Wang, L.Y., Chang, C.M., Lee, I.W., Tsai, W.H., and Sun, H.S. (2020). Novel Compound Heterozygous Mutations in CRTAP Cause Rare Autosomal Recessive Osteogenesis Imperfecta. Front. Genet., 11.","DOI":"10.3389\/fgene.2020.00897"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"116293","DOI":"10.1016\/j.bone.2021.116293","article-title":"Osteogenesis imperfecta in 140 Turkish families: Molecular spectrum and, comparison of long-term clinical outcome of those with COL1A1\/A2 and biallelic variants","volume":"155","author":"Tuysuz","year":"2022","journal-title":"Bone"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1038\/ejhg.2009.75","article-title":"CRTAP mutations in lethal and severe osteogenesis imperfecta: The importance of combining biochemical and molecular genetic analysis","volume":"17","author":"Nesbitt","year":"2009","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1210\/clinem\/dgae025","article-title":"Genetic analysis, phenotype spectrum and functional study of rare osteogenesis imperfecta caused by CRTAP Variants","volume":"109","author":"Zhou","year":"2024","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/BF02557826","article-title":"Human bone cells in vitro","volume":"37","author":"Robey","year":"1985","journal-title":"Calcif. Tissue Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/316363a0","article-title":"Subtle structural alterations in the chains of type I procollagen produce osteogenesis imperfecta type II","volume":"316","author":"Bonadio","year":"1985","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/978-1-60327-198-1_8","article-title":"Biological tissue and cell culture specimen preparation for TEM nanoparticle characterization","volume":"Volume 697","author":"Nagashima","year":"2011","journal-title":"Methods in Molecular Biology"},{"key":"ref_26","first-page":"644","article-title":"Bone microdamage, remodeling and bone fragility: How much damage is too much damage?","volume":"4","author":"Kennedy","year":"2015","journal-title":"Bonekey Rep."},{"key":"ref_27","unstructured":"Andrews, S. (2025, January 30). FastQC: A Quality Control Tool for High Throughput Sequence Data. Available online: http:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc\/."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3","DOI":"10.14806\/ej.17.1.200","article-title":"Cutadapt removes adapter sequences from high-throughput sequencing reads","volume":"17","author":"Martin","year":"2011","journal-title":"EMBnet. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: An efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Love, M.I., Huber, W., and Anders, S. (2014). Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol., 15.","DOI":"10.1186\/s13059-014-0550-8"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS A J. Integr. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1136\/jmedgenet-2012-101142","article-title":"Study of autosomal recessive osteogenesis imperfecta in Arabia reveals a novel locus defined by TMEM38B mutation","volume":"49","author":"Shaheen","year":"2012","journal-title":"J. Med. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1136\/jmg-2022-109009","article-title":"Pulmonary function and structure abnormalities in children and young adults with osteogenesis imperfecta point to intrinsic and extrinsic lung abnormalities","volume":"60","author":"Gochuico","year":"2023","journal-title":"J. Med. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1111\/j.1399-0004.2011.01794.x","article-title":"Deficiency of CRTAP in non-lethal recessive osteogenesis imperfecta reduces collagen deposition into matrix","volume":"82","author":"Valli","year":"2012","journal-title":"Clin. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/BF03401664","article-title":"The CDKN2A (p16) gene and human cancer","volume":"3","author":"Foulkes","year":"1997","journal-title":"Mol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1016\/0092-8674(89)90936-7","article-title":"Isolation of a human cyclin cDNA: Evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34cdc2","volume":"58","author":"Pines","year":"1989","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"29513","DOI":"10.1074\/jbc.M803681200","article-title":"MSX2 stimulates chondrocyte maturation by controlling Ihh expression","volume":"283","author":"Amano","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Muttigi, M.S., Han, I., Park, H.K., Park, H., and Lee, S.H. (2016). Matrilin-3 Role in Cartilage Development and Osteoarthritis. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17040590"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"34768","DOI":"10.1074\/jbc.M114.583104","article-title":"Matrilin-3 inhibits chondrocyte hypertrophy as a bone morphogenetic protein-2 antagonist","volume":"289","author":"Yang","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1016\/S0002-9440(10)62497-2","article-title":"Integrin alpha(v)beta8-mediated activation of transforming growth factor-beta by perivascular astrocytes: An angiogenic control switch","volume":"166","author":"Cambier","year":"2005","journal-title":"Am. J. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.bone.2009.10.037","article-title":"CRTAP deficiency leads to abnormally high bone matrix mineralization in a murine model and in children with osteogenesis imperfecta type VII","volume":"46","author":"Morello","year":"2010","journal-title":"Bone"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1096\/fj.11-186197","article-title":"Misfolded proteins inhibit proliferation and promote stress-induced death in SV40-transformed mammalian cells","volume":"26","author":"Arslan","year":"2012","journal-title":"FASEB J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.matbio.2023.06.004","article-title":"Absence of TRIC-B from type XIV Osteogenesis Imperfecta osteoblasts alters cell adhesion and mitochondrial function\u2014A multi-omics study","volume":"121","author":"Jovanovic","year":"2023","journal-title":"Matrix Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e21620","DOI":"10.1096\/fj.202100067R","article-title":"Mitochondrial fusion and fission: The fine-tune balance for cellular homeostasis","volume":"35","author":"Adebayo","year":"2021","journal-title":"FASEB J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1002\/jbmr.3732","article-title":"Compromised Exercise Capacity and Mitochondrial Dysfunction in the Osteogenesis Imperfecta Murine (oim) Mouse Model","volume":"34","author":"Gremminger","year":"2019","journal-title":"J. Bone Miner. Res."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Dobson, P.F., Dennis, E.P., Hipps, D., Reeve, A., Laude, A., Bradshaw, C., Stamp, C., Smith, A., Deehan, D.J., and Turnbull, D.M. (2020). Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-68566-2"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1186\/s13287-020-01789-2","article-title":"A glance on the role of actin in osteogenic and adipogenic differentiation of mesenchymal stem cells","volume":"11","author":"Khan","year":"2020","journal-title":"Stem Cell Res. Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"6118","DOI":"10.1093\/hmg\/ddv328","article-title":"Altered cytoskeletal organization characterized lethal but not surviving Brtl+\/\u2212 mice: Insight on phenotypic variability in osteogenesis imperfecta","volume":"24","author":"Bianchi","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_50","first-page":"e10171","article-title":"The Osteocyte Transcriptome Is Extensively Dysregulated in Mouse Models of Osteogenesis Imperfecta","volume":"3","author":"Zimmerman","year":"2019","journal-title":"J. Bone Miner. Res. Plus"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"100734","DOI":"10.1016\/j.bonr.2020.100734","article-title":"Histopathology of osteogenesis imperfecta bone. Supramolecular assessment of cells and matrices in the context of woven and lamellar bone formation using light polarization and ultrastructural microscopy","volume":"14","author":"Shapiro","year":"2021","journal-title":"Bone Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"272","DOI":"10.7150\/ijbs.2929","article-title":"TGF-beta and BMP signaling in osteoblast differentiation and bone formation","volume":"8","author":"Chen","year":"2012","journal-title":"Int. J. Biol. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"32","DOI":"10.4236\/jbise.2013.68A1004","article-title":"BMP signaling in mesenchymal stem cell differentiation and bone formation","volume":"6","author":"Beederman","year":"2013","journal-title":"J. Biomed. Sci. Eng."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3428","DOI":"10.1242\/jcs.083659","article-title":"BMP2, but not BMP4, is crucial for chondrocyte proliferation and maturation during endochondral bone development","volume":"124","author":"Shu","year":"2011","journal-title":"J. Cell Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1038\/nm.3544","article-title":"Excessive transforming growth factor-beta signaling is a common mechanism in osteogenesis imperfecta","volume":"20","author":"Grafe","year":"2014","journal-title":"Nat. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/S0945-053X(00)00097-4","article-title":"Influence of decorin expression on transforming growth factor-beta-mediated collagen gel retraction and biglycan induction","volume":"19","author":"Markmann","year":"2000","journal-title":"Matrix Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1242\/jcs.110.12.1351","article-title":"Cartilage associated protein (CASP) is a novel developmentally regulated chick embryo protein","volume":"110","author":"Castagnola","year":"1997","journal-title":"J. Cell Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3516","DOI":"10.1210\/jc.2016-1334","article-title":"Non-Lethal Type VIII Osteogenesis Imperfecta Has Elevated Bone Matrix Mineralization","volume":"101","author":"Barnes","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_59","unstructured":"Hall, J.G., Gripp, K.W., and Slavotinek, A.M. (2006). Hall\u2019s Handbook of Physical Measurements, Oxford University Press."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/7\/518\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:06:50Z","timestamp":1760029610000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/7\/518"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,31]]},"references-count":59,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["cells14070518"],"URL":"https:\/\/doi.org\/10.3390\/cells14070518","relation":{},"ISSN":["2073-4409"],"issn-type":[{"type":"electronic","value":"2073-4409"}],"subject":[],"published":{"date-parts":[[2025,3,31]]}}}