miR-144-3p Targeting FLRT3 in Osteogenic Differentiation of Mandibular Bone Marrow Mesenchymal Stem Cells

miR-144-3p Targeting FLRT3 in Osteogenic Differentiation of Mandibular Bone Marrow Mesenchymal Stem Cells | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article miR-144-3p Targeting FLRT3 in Osteogenic Differentiation of Mandibular Bone Marrow Mesenchymal Stem Cells Jingjun Tian, Chen Lv, Tao Xie, Qi Sun, Changyu Liu, Wen Ma, Chaofeng Liu, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6619322/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Jul, 2025 Read the published version in Human Genomics → Version 1 posted 9 You are reading this latest preprint version Abstract Background Fibronectin Leucine-Rich Transmembrane Protein 3 (FLRT3) plays a crucial role in craniofacial development and osteogenic differentiation, yet the regulatory mechanisms of microRNAs (miRNAs) on FLRT3 remain largely unexplored. This study identifies miR-144-3p as a miRNA that targets FLRT3 and investigates its role in osteogenic differentiation. These findings provide a foundation for the development of miRNA-based therapeutic strategies for craniofacial diseases and contribute to a deeper understanding of FLRT3’s involvement in osteogenesis. Methods Mandibular bone marrow mesenchymal stem cells (MBMSCs) were isolated from SD rats using whole bone marrow and limiting dilution techniques. Flow cytometry and differentiation assays for osteogenesis and adipogenesis were conducted to characterize the cells. Bioinformatics analysis was employed to identify miRNAs that regulate FLRT3, with RT–qPCR used to select the most influential miRNA. A dual-luciferase reporter assay was performed to validate the interaction between the miRNAs and FLRT3. RT–qPCR measured miR-144-3p expression during osteogenic induction. Alkaline phosphatase (ALP) and Alizarin Red S staining were used to assess the role of miR-144-3p in osteogenic differentiation. The impact of miR-144-3p on FLRT3, BMP2, and RUNX2 expression during osteogenesis was further evaluated by RT–qPCR. Results MBMSCs exhibited spindle-shaped morphology, high purity, and robust proliferative capacity, with flow cytometry confirming positive expression of CD29 and CD90. Bioinformatics analysis identified four miRNAs associated with FLRT3: miR-27a-3p, miR-27b-3p, miR-199a-3p, and miR-144-3p, with miR-144-3p showing the strongest correlation. Dual-luciferase assays confirmed that FLRT3 is a target gene of miR-144-3p. Functional assays revealed that the miR-144- 3p mimic decreased FLRT3 expression, while the inhibitor increased it. During osteogenic differentiation, miR-144-3p mimic inhibited osteogenesis, while the inhibitor enhanced it, corresponding to alterations in the expression of FLRT3, BMP2, and RUNX2. Conclusion miR-144-3p regulates the osteogenic differentiation of MBMSCs by targeting and modulating FLRT3, with FLRT3 being a direct target of miR-144-3p. During osteogenic differentiation, miR-144-3p inhibits osteogenesis by downregulating FLRT3, BMP2, and RUNX2 expression. This study not only elucidates the miRNA-mediated regulatory mechanism in osteogenesis but also offers a novel strategy for mandibular bone defect repair. Fibronectin Leucine-Rich Transmembrane Protein 3 Mandibular bone marrow mesenchymal stem cells miR-144-3p osteogenic differentiation Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 13 Jul, 2025 Read the published version in Human Genomics → Version 1 posted Editorial decision: Revision requested 07 Jun, 2025 Reviews received at journal 06 Jun, 2025 Reviewers agreed at journal 30 May, 2025 Reviews received at journal 28 May, 2025 Reviewers agreed at journal 28 May, 2025 Reviewers invited by journal 09 May, 2025 Editor assigned by journal 09 May, 2025 Submission checks completed at journal 09 May, 2025 First submitted to journal 08 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6619322","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":455313621,"identity":"ba1eb093-96a0-4e33-9292-b4c9e9299024","order_by":0,"name":"Jingjun Tian","email":"","orcid":"","institution":"Department of Orthodontics, Affiliated Stomatology Hospital of Kunming Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jingjun","middleName":"","lastName":"Tian","suffix":""},{"id":455313622,"identity":"04fd08eb-88ae-4863-bb37-50deae20336b","order_by":1,"name":"Chen Lv","email":"","orcid":"","institution":"Yunnan Key Laboratory of Stomatology","correspondingAuthor":false,"prefix":"","firstName":"Chen","middleName":"","lastName":"Lv","suffix":""},{"id":455313623,"identity":"e9f4914b-5c10-4740-95a5-3d8835d88a46","order_by":2,"name":"Tao Xie","email":"","orcid":"","institution":"Department of Orthodontics, Affiliated Stomatology Hospital of Kunming Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tao","middleName":"","lastName":"Xie","suffix":""},{"id":455313624,"identity":"e207bda6-cdd8-4230-858f-6d8f5d07a4c8","order_by":3,"name":"Qi Sun","email":"","orcid":"","institution":"Yunnan Key Laboratory of Stomatology","correspondingAuthor":false,"prefix":"","firstName":"Qi","middleName":"","lastName":"Sun","suffix":""},{"id":455313625,"identity":"ca8b2a7e-a099-427d-a056-384b4b450472","order_by":4,"name":"Changyu Liu","email":"","orcid":"","institution":"Department of Orthodontics, Affiliated Stomatology Hospital of Kunming Medical University","correspondingAuthor":false,"prefix":"","firstName":"Changyu","middleName":"","lastName":"Liu","suffix":""},{"id":455313628,"identity":"5647c38e-683f-4dc8-87a9-4a6af24fec4d","order_by":5,"name":"Wen Ma","email":"","orcid":"","institution":"Yunnan Key Laboratory of Stomatology","correspondingAuthor":false,"prefix":"","firstName":"Wen","middleName":"","lastName":"Ma","suffix":""},{"id":455313630,"identity":"2b10f4a4-a50b-46bb-aa88-30f2ff910b72","order_by":6,"name":"Chaofeng Liu","email":"","orcid":"","institution":"Yunnan Key Laboratory of Stomatology","correspondingAuthor":false,"prefix":"","firstName":"Chaofeng","middleName":"","lastName":"Liu","suffix":""},{"id":455313631,"identity":"bcd6961e-7a9c-4174-a753-64c741242605","order_by":7,"name":"Renyi Cheng","email":"","orcid":"","institution":"Department of Orthodontics, Affiliated Stomatology Hospital of Kunming Medical University","correspondingAuthor":false,"prefix":"","firstName":"Renyi","middleName":"","lastName":"Cheng","suffix":""},{"id":455313636,"identity":"08137126-6ed1-43b2-bef4-cb715f0f05b3","order_by":8,"name":"Yanhua Xu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA10lEQVRIiWNgGAWjYLACxgYGBjb25gMHPvwgRQsfz7HEgzN7SNEiJ5FjfJiDjQjVBjdyDD8X7jgsz8Zz5sNhBh4GeX6xA/i1SM7IMZaeeeawYRt774bDBRYMhjNnJ+DXwi+RYyDN23aYsY3n7IbDM3gYEgxuE9DCBvTCb6AW+zaJnAeHediI0AK0xQxkSyJQCwNxWiR7npVZ87alJ7fxHDMABrIEYb8YHE/efJu3zdp2fnvz4w8fftjI80sT0MLAwGGAzJMgpBwE2B8Qo2oUjIJRMApGMgAAvxRFNHQJMzgAAAAASUVORK5CYII=","orcid":"","institution":"Department of Orthodontics, Affiliated Stomatology Hospital of Kunming Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yanhua","middleName":"","lastName":"Xu","suffix":""},{"id":455313643,"identity":"ccf5bbfe-a4fd-4c06-9307-51bbcec6eff5","order_by":9,"name":"Kang Yin","email":"","orcid":"","institution":"Department of Orthodontics, Affiliated Stomatology Hospital of Kunming Medical University","correspondingAuthor":false,"prefix":"","firstName":"Kang","middleName":"","lastName":"Yin","suffix":""}],"badges":[],"createdAt":"2025-05-08 09:53:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6619322/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6619322/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40246-025-00788-9","type":"published","date":"2025-07-13T15:57:04+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82611026,"identity":"f99d73fc-6f86-47a4-858a-44ab759af1c9","added_by":"auto","created_at":"2025-05-13 10:47:16","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":275183,"visible":true,"origin":"","legend":"\u003cp\u003eA psiCHECK-2 Vector Map\u003c/p\u003e\n\u003cp\u003eB Double Digestion Analysis of psiCHECK-2 Plasmid: (a) Plasmid; (b) Plasmid Digested\u003c/p\u003e\n\u003cp\u003ewith XhoI-EcoRI; (c) DNA Marker\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6619322/v1/39aa94d87caf23f54c011b1b.jpg"},{"id":82611028,"identity":"4733fe07-d28a-4008-be9d-2e09de587b8a","added_by":"auto","created_at":"2025-05-13 10:47:16","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":720332,"visible":true,"origin":"","legend":"\u003cp\u003eIsolation, culture, and identification of MBMSCs from SD rats: A. Morphological observation of MBMSCs from SD rats: Primary cells (10×) (A), P2 generation cells (20×) (B). B. Identification of typical surface markers of MBMSCs: Flow cytometry analysis results (C). C. Results of multi-lineage differentiation capability of MBMSCs: Alizarin Red staining for osteogenic induction (10×) (D), Oil Red O staining for adipogenic induction (20×) (E), Oil Red O staining for adipogenic induction (40×) (F). D. Colony formation assay with crystal violet staining: Visible colony formation, with one colony representing one clone (G), A clone observed under a microscope (10×) (H).\u003c/p\u003e","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6619322/v1/ed529de47532c4f41b71ca5a.jpg"},{"id":82611914,"identity":"36b936fa-ee33-43dc-b974-e3cc38f6d653","added_by":"auto","created_at":"2025-05-13 10:55:16","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":279865,"visible":true,"origin":"","legend":"\u003cp\u003ePrediction of miRNAs that can target and regulate FLRT3 in different species: A. Human FLRT3 (A), B. Mouse FLRT3 (B), C. Rat FLRT3 (C), D. Venn analysis of the prediction results for the three species (D).\u003c/p\u003e","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6619322/v1/6714464c71a86ba8ba39d389.jpg"},{"id":82611915,"identity":"80233ef2-64de-4e92-b0a4-315772cdfc3b","added_by":"auto","created_at":"2025-05-13 10:55:16","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":463264,"visible":true,"origin":"","legend":"\u003cp\u003eFluorescent marker overlay images: A. Cell image under an inverted microscope (A), B. Visible fluorescent markers under a fluorescence microscope (B), C. Overlay of cells with fluorescence (C). D. Transfection efficiency assessment (** indicates P\u0026lt;0.01; *** indicates P\u0026lt;0.001; # indicates P\u0026lt;0.0001) (D). E. Screening results for miRNAs with the closest regulatory relationship (* indicates P\u0026lt;0.05) (E). F. Dual-luciferase assay results: Schematic diagram of the binding site between miR-144-3p and FLRT3 and expression changes of the reporter gene in the FLRT3-WT and FLRT3-MUT groups (F).\u003c/p\u003e","description":"","filename":"Fig4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6619322/v1/434d08927eb6d6c15be50b18.jpg"},{"id":82612160,"identity":"b60236fe-0137-45b6-9b69-d11f694e7252","added_by":"auto","created_at":"2025-05-13 11:03:16","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":922787,"visible":true,"origin":"","legend":"\u003cp\u003eRegulatory impact of miR-144-3p on FLRT3 expression during osteogenic differentiation. A. The regulation of FLRT3 expression by miR-144-3p (* indicates P\u0026lt;0.05; # indicates P\u0026lt;0.0001) (A). B. Changes in the expression of miR-144-3p during osteogenic induction at 0, 3, 5, and 7 days (** indicates P\u0026lt;0.01, indicating significant differences between two groups; # indicates P\u0026lt;0.0001, indicating extremely significant differences between two groups) (B). C. Alizarin Red staining at 14 days of osteogenic induction: (a) miR-144-3p mimic group; (b) control group; (c) miR-144-3p inhibitor group; scale bar = 200 μm.(C) D. ALP staining at 7 days of osteogenic induction: (a) Control group; (b) mimic NC group; (c) inhibitor NC group; (d) mimic group; (e) inhibitor group; scale bar = 100 μm.(D) E. FLRT3 expression at 7 days of osteogenic induction (** indicates P\u0026lt;0.01) (E). F. BMP2 expression at 7 days of osteogenic induction (** indicates P\u0026lt;0.01; *** indicates P\u0026lt;0.001) (F). G. RUNX2 expression at 7 days of osteogenic induction (* indicates P\u0026lt;0.05; ** indicates P\u0026lt;0.01) (G).\u003c/p\u003e","description":"","filename":"Fig5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6619322/v1/e7389ca5d497cf5400a03062.jpg"},{"id":86699554,"identity":"3d1198cd-441b-4dae-818c-a4f30d43f756","added_by":"auto","created_at":"2025-07-14 16:10:57","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3098443,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6619322/v1_covered_bf8458d2-21d9-4a9b-a72e-819f7553e25f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"miR-144-3p Targeting FLRT3 in Osteogenic Differentiation of Mandibular Bone Marrow Mesenchymal Stem Cells","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"human-genomics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"hugm","sideBox":"Learn more about [Human Genomics](http://humgenomics.biomedcentral.com/)","snPcode":"40246","submissionUrl":"https://submission.nature.com/new-submission/40246/3","title":"Human Genomics","twitterHandle":"@OAgenetics","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Fibronectin Leucine-Rich Transmembrane Protein 3, Mandibular bone marrow mesenchymal stem cells, miR-144-3p, osteogenic differentiation","lastPublishedDoi":"10.21203/rs.3.rs-6619322/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6619322/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003eFibronectin Leucine-Rich Transmembrane Protein 3 (FLRT3) plays a crucial role in craniofacial development and osteogenic differentiation, yet the regulatory mechanisms of microRNAs (miRNAs) on FLRT3 remain largely unexplored. This study identifies miR-144-3p as a miRNA that targets FLRT3 and investigates its role in osteogenic differentiation. These findings provide a foundation for the development of miRNA-based therapeutic strategies for craniofacial diseases and contribute to a deeper understanding of FLRT3’s involvement in osteogenesis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eMandibular bone marrow mesenchymal stem cells (MBMSCs) were isolated from SD rats using whole bone marrow and limiting dilution techniques. Flow cytometry and differentiation assays for osteogenesis and adipogenesis were conducted to characterize the cells. Bioinformatics analysis was employed to identify miRNAs that regulate FLRT3, with RT–qPCR used to select the most influential miRNA. A dual-luciferase reporter assay was performed to validate the interaction between the miRNAs and FLRT3. RT–qPCR measured miR-144-3p expression during osteogenic induction. Alkaline phosphatase (ALP) and Alizarin Red S staining were used to assess the role of miR-144-3p in osteogenic differentiation. The impact of miR-144-3p on FLRT3, BMP2, and RUNX2 expression during osteogenesis was further evaluated by RT–qPCR.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003eMBMSCs exhibited spindle-shaped morphology, high purity, and robust proliferative capacity, with flow cytometry confirming positive expression of CD29 and CD90. Bioinformatics analysis identified four miRNAs associated with FLRT3: miR-27a-3p, miR-27b-3p, miR-199a-3p, and miR-144-3p, with miR-144-3p showing the strongest correlation. Dual-luciferase assays confirmed that FLRT3 is a target gene of miR-144-3p. Functional assays revealed that the miR-144- 3p mimic decreased FLRT3 expression, while the inhibitor increased it. During osteogenic differentiation, miR-144-3p mimic inhibited osteogenesis, while the inhibitor enhanced it, corresponding to alterations in the expression of FLRT3, BMP2, and RUNX2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion \u003c/strong\u003emiR-144-3p regulates the osteogenic differentiation of MBMSCs by targeting and modulating FLRT3, with FLRT3 being a direct target of miR-144-3p. During osteogenic differentiation, miR-144-3p inhibits osteogenesis by downregulating FLRT3, BMP2, and RUNX2 expression. This study not only elucidates the miRNA-mediated regulatory mechanism in osteogenesis but also offers a novel strategy for mandibular bone defect repair.\u003c/p\u003e","manuscriptTitle":"miR-144-3p Targeting FLRT3 in Osteogenic Differentiation of Mandibular Bone Marrow Mesenchymal Stem Cells","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-13 10:47:11","doi":"10.21203/rs.3.rs-6619322/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-07T18:20:14+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-07T03:17:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"83029376929264367858291962655272994390","date":"2025-05-30T23:46:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-28T13:23:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"69200291794825583110626903109967456132","date":"2025-05-28T13:18:12+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-09T11:09:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-09T08:35:30+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-09T08:30:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"Human Genomics","date":"2025-05-08T09:49:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"human-genomics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"hugm","sideBox":"Learn more about [Human Genomics](http://humgenomics.biomedcentral.com/)","snPcode":"40246","submissionUrl":"https://submission.nature.com/new-submission/40246/3","title":"Human Genomics","twitterHandle":"@OAgenetics","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a8af1f10-9fcc-4664-bd85-2deea2c1b684","owner":[],"postedDate":"May 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-14T16:07:29+00:00","versionOfRecord":{"articleIdentity":"rs-6619322","link":"https://doi.org/10.1186/s40246-025-00788-9","journal":{"identity":"human-genomics","isVorOnly":false,"title":"Human Genomics"},"publishedOn":"2025-07-13 15:57:04","publishedOnDateReadable":"July 13th, 2025"},"versionCreatedAt":"2025-05-13 10:47:11","video":"","vorDoi":"10.1186/s40246-025-00788-9","vorDoiUrl":"https://doi.org/10.1186/s40246-025-00788-9","workflowStages":[]},"version":"v1","identity":"rs-6619322","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6619322","identity":"rs-6619322","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}