Hypoxic Preconditioned Bone Marrow-Derived Mesenchymal Stromal/Stem Cells Enhance Myoblast Fusion and Skeletal Muscle Regeneration

Hypoxic Preconditioned Bone Marrow-Derived Mesenchymal Stromal/Stem Cells Enhance Myoblast Fusion and Skeletal Muscle Regeneration | 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 Hypoxic Preconditioned Bone Marrow-Derived Mesenchymal Stromal/Stem Cells Enhance Myoblast Fusion and Skeletal Muscle Regeneration Karolina Archacka, Iwona Grabowska, Bartosz Mierzejewski, Joanna Graffstain, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-474083/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Aug, 2021 Read the published version in Stem Cell Research & Therapy → Version 1 posted 12 You are reading this latest preprint version Abstract Background : The skeletal muscle reconstruction occurs thanks to unipotent stem cells, i.e., satellite cells. The satellite cells remain quiescent and localized between myofiber sarcolemma and basal lamina. They are activated in response to muscle injury, proliferate, differentiate into myoblasts, and recreate myofibers. Many stem and progenitor cells support skeletal muscle regeneration, which could be disturbed by extensive damage, sarcopenia, cachexia, or genetic diseases like dystrophy. Many lines of evidence showed that the level of oxygen regulates the course of cell proliferation and differentiation. Methods : In the present study, we analyzed hypoxic’s impact on human and pig bone marrow-derived mesenchymal stromal cell (MSC) and mouse myoblast proliferation, differentiation, and fusion. Moreover, the influence of the transplantation of human bone marrow-derived MSCs cultured under hypoxic conditions on skeletal muscle regeneration was studied. Results : We showed that bone marrow-derived MSCs increased VEGF expression and improved myogenesis under hypoxic conditions in vitro. Transplantation of hypoxic preconditioned bone marrow-derived MSCs into injured muscles resulted in the improved cell engraftment and formation of new vessels. Conclusions : We suggested that SDF-1 and VEGF secreted by hypoxic preconditioned bone marrow-derived MSCs played an essential role in cell engraftment and angiogenesis. Importantly, hypoxic preconditioned bone marrow-derived MSCs more efficiently engrafted injured muscles, however, they did not undergo myogenic differentiation. General Biochemistry Molecular Biology BM-MSC fusion hypoxic normoxic migration myogenic differentiation Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Full Text Cite Share Download PDF Status: Published Journal Publication published 09 Aug, 2021 Read the published version in Stem Cell Research & Therapy → Version 1 posted Editorial decision: Major Revision 07 May, 2021 Review # 1 received at journal 05 May, 2021 Review # 2 received at journal 04 May, 2021 Reviewer # 3 agreed at journal 28 Apr, 2021 Reviewer # 2 agreed at journal 27 Apr, 2021 Reviewers invited by journal 27 Apr, 2021 Reviews received at journal 27 Apr, 2021 Reviewer # 1 agreed at journal 27 Apr, 2021 Editor assigned by journal 26 Apr, 2021 Submission checks completed at journal 26 Apr, 2021 Editor invited by journal 26 Apr, 2021 First submitted to journal 26 Apr, 2021 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. 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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-474083","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":23926321,"identity":"df199e5a-6e97-4678-b24e-2cc3f7fea172","order_by":0,"name":"Karolina Archacka","email":"","orcid":"","institution":"University of Warsaw: Uniwersytet Warszawski","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Karolina","middleName":"","lastName":"Archacka","suffix":""},{"id":23926322,"identity":"259f4b0b-bd1a-474f-a989-add98623dccd","order_by":1,"name":"Iwona Grabowska","email":"","orcid":"","institution":"University of 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Brzoska","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA90lEQVRIiWNgGAWjYFCCHDBpwMDew3CAoQAiJgHEMoS18JwBajFAaOEhrEUiB0wR1sLPnnvs44+KOmP+mW8PHvhgwJC44QDzwds8DHdwapHseZc8Q+LMYTOJ23kJB2eAtbAlW/MwPMOpxeBGjjGDYdsBG4bbOQaHeYBath3gMZPmYTiMU4s9SEtiW52N/M0zMC383/BqMZAAajnYxmxmcIMHbgsbXi0SZ94lMzacOWxseAbsFwnj/YfZjC3nGOD2C3977mFGYIgZzjt+9vCHDxU2sjPbmx/eeFNxRw6XFgxbGRiYwQ4+QKwOBCBDyygYBaNgFAxXAABqxFYLWveJAgAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-7886-0436","institution":"Uniwersytet Warszawski","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Edyta","middleName":"","lastName":"Brzoska","suffix":""}],"badges":[],"createdAt":"2021-04-28 22:56:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-474083/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-474083/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13287-021-02530-3","type":"published","date":"2021-08-09T15:00:44+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":8738091,"identity":"5b3f45dd-3ccb-42d8-a6c9-151ffa82bbd6","added_by":"auto","created_at":"2021-05-03 22:27:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2112894,"visible":true,"origin":"","legend":"Cell proliferation and migration under normoxic and hypoxic conditions. A - The number of mouse primary myoblasts (mPM), human bone marrow-derived mesenchymal stromal cells (hMSC), pig bone marrow-derived mesenchymal stromal cells (pMSC), cells in co-cultures of hMSC and mPM, and cells in co-cultures of pMSC and mPM, cultured in two types of medium: MSCmed and PMmed, under normoxic (NORM) or hypoxic (HYPO) conditions. B – the invaded area measured in scratch wound healing assay of hMSC and pMSC cultured in MSCmed under normoxic and hypoxic conditions. C – the scratch wound healing assay of hMSC and pMSC cultured in MSCmed under normoxic and hypoxic conditions. P-value: * \u003c 0.05; ** \u003c 0.01; ***\u003c0.001; ****\u003c0.0001.","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-474083/v1/a49f2e76fa6bacacdc8e8f5c.png"},{"id":8738157,"identity":"2d0a1f21-67cd-4377-8ce7-3156c19d9075","added_by":"auto","created_at":"2021-05-03 22:30:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2239338,"visible":true,"origin":"","legend":"The fusion index and hybrid myotubes presence in either human bone marrow-derived mesenchymal stromal cells (hMSC) or pig bone marrow-derived mesenchymal stem cells (pMSC) co-culture with myoblasts: mouse primary myoblasts (mPM) or C2C12 myoblasts. A – the fusion index of mPM and hMSC or pMSC co-cultured in MSCmed or PMmed under normoxic (NORM) or hypoxic (HYPO) conditions. B – the fusion index of C2C12 myoblasts and hMSC or pMSC co-cultured in 3:2.5; 3:5; 3:7.5 ratio, in C2C12med, under normoxic (NORM) or hypoxic (HYPO) conditions. C – the percentage of hybrid myotubes in mPM and hMSC or pMSC co-cultures in MSCmed or PMmed under normoxic (NORM) or hypoxic (HYPO) conditions. D – the immunolocalization of hybrid myotubes in mPM and hMSC co-cultures, red – skeletal myosin, blue – cell nuclei, green human cell nuclei. E – the percentage of hybrid myotubes in C2C12 and hMSC or pMSC co-cultures in C2C12med under normoxic (NORM) or hypoxic (HYPO) conditions. F – the immunolocalization of hybrid myotubes in C2C12 and hMSC co-cultures, red – skeletal myosin, blue – cell nuclei, green human cell nuclei. P-value: * \u003c 0.05; ** \u003c 0.01; ***\u003c0.001; ****\u003c0.0001.","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-474083/v1/95fe09d8bcd9d7524a236ee5.png"},{"id":8738096,"identity":"9beccc2f-21ad-4e62-9641-3eeab7cb30d4","added_by":"auto","created_at":"2021-05-03 22:27:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1593394,"visible":true,"origin":"","legend":"The expression of selected markers in cell cultures. A - the level of transcripts encoding PAX7, MYF5, MYOD1, myogenin (MYOG), VCAM1, NCAM1, CD9, ADAM9, m-cadherin (CDH15) in mouse primary myoblasts (mPM) cultured in PMmed or MSCsmed under normoxic (NORM) or hypoxic (HYPO) conditions. B – the level of transcripts encoding MYF5, MYOD1, myogenin (MYOG), VCAM1, CD9, ADAM9, m-cadherin (CDH15), nestin (NES) in human bone marrow-derived mesenchymal stromal cells (hMSC) cultured in PMmed or MSCsmed under normoxic (NORM) or hypoxic (HYPO) conditions. C - the level of transcripts encoding myogenin (MYOG), α-sarcoglycan (SGCA), desmin (DES), and actin α1 (ACTA1) in pig bone marrow-derived mesenchymal stem cells (pMSC) cultured in PMmed or MSCsmed under normoxic (NORM) or hypoxic (HYPO) conditions. P-value: * \u003c 0.05; ** \u003c 0.01; ***\u003c0.001; ****\u003c0.0001.","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-474083/v1/0e8b6e788e434e25fc3d4a1e.png"},{"id":8738159,"identity":"7aefebed-0aab-4d5d-9228-ae6631575c49","added_by":"auto","created_at":"2021-05-03 22:30:58","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1225553,"visible":true,"origin":"","legend":"The expression of selected markers in cell co-cultures. A - the level of human transcripts encoding MYF5, MYOD1, myogenin (MYOG), VCAM1, CD9, ADAM9, m-cadherin (CDH15), nestin (NES) in co-cultures of mouse primary myoblasts (mPM) and human bone marrow-derived mesenchymal stromal cells (hMSC) in PMmed or MSCsmed under normoxic (NORM) or hypoxic (HYPO) conditions. B – the level of pig transcripts encoding myogenin (MYOG) SGCA, desmin (DES), and actin α1 (ACTA1) in mPM and pig bone marrow-derived mesenchymal stem cells (pMSC) co-cultured in PMmed or MSCsmed under normoxic (NORM) or hypoxic (HYPO) conditions. P-value: * \u003c 0.05; ** \u003c 0.01; ***\u003c0.001; ****\u003c0.0001.","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-474083/v1/bed6e7096cc81225c807ddf7.png"},{"id":8738160,"identity":"2dea3ae2-f8a3-4e11-931f-9547120ff080","added_by":"auto","created_at":"2021-05-03 22:30:58","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":367933,"visible":true,"origin":"","legend":"The level of selected markers expression in human bone marrow-derived mesenchymal stromal cells (hMSC) cultured in MSCsmed under normoxic (NORM) or hypoxic (HYPO) conditions. P value: * \u003c 0.05; ** \u003c 0.01; ***\u003c0.001; ****\u003c0.0001.","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-474083/v1/a7f070f2d71a42092d8e6203.png"},{"id":8738170,"identity":"41af174d-e7b6-4552-ac79-84bd16a3fd02","added_by":"auto","created_at":"2021-05-03 22:33:58","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":2320854,"visible":true,"origin":"","legend":"The skeletal muscle regeneration after human bone marrow mesenchymal stromal cells (hMSC) transplantation. The hMSCs were cultured under normoxic (NORM) or hypoxic (HYPO) conditions and injected into cardiotoxin (CTX) injured muscles. A – the skeletal muscle weight, the area of connective tissue, blood vessels, nerves, and frequency of new myofibers in intact muscles or muscles injured (CTX) and transplanted with hMSC cultured either under normoxic (NORM) or hypoxic (HYPO) conditions. B – histology of intact muscles or in muscles injured (CTX) and transplanted with hMSC cultured under normoxic (NORM) or hypoxic (HYPO) conditions. C - localization of transplanted cells (blue – nuclei, red – laminin, green – human nuclei) in intact muscles or muscles injured (CTX) and transplanted with hMSC cultured under normoxic (NORM) or hypoxic (HYPO) conditions. D – the expression of selected mouse transcripts in intact muscles or muscles injured (CTX) and transplanted with hMSC cultured under normoxic (NORM) or hypoxic (HYPO) conditions. E – the expression of selected human transcripts in intact muscles or muscles injured (CTX) and transplanted with hMSC cultured under normoxic (NORM) or hypoxic (HYPO) conditions. P-value: * \u003c 0.05; ** \u003c 0.01; ***\u003c0.001; ****\u003c0.0001.","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-474083/v1/49070e94449b0612160589b1.png"},{"id":13690443,"identity":"5ee9534a-0e36-4a87-b3a9-a7259ead8d30","added_by":"auto","created_at":"2021-09-17 12:33:40","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2431353,"visible":true,"origin":"","legend":"","description":"","filename":"ArchackaGrabowskaetalSCRT.pdf","url":"https://assets-eu.researchsquare.com/files/rs-474083/v1_covered.pdf"},{"id":13627690,"identity":"20a2bb8d-4080-4d80-bc55-4b6761ca77b0","added_by":"auto","created_at":"2021-09-17 07:56:37","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1848530,"visible":true,"origin":"","legend":"","description":"","filename":"ArchackaGrabowskaetalSCRT.pdf","url":"https://assets-eu.researchsquare.com/files/rs-474083/v1_covered.pdf"},{"id":8738242,"identity":"c82c8ef2-9a4e-4938-8aa1-567dea03d1d8","added_by":"auto","created_at":"2021-05-03 22:37:05","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2133760,"visible":true,"origin":"","legend":"","description":"","filename":"ArchackaGrabowskaetalSCRT.pdf","url":"https://assets-eu.researchsquare.com/files/rs-474083/v1_stamped.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eHypoxic Preconditioned Bone Marrow-Derived Mesenchymal Stromal/Stem Cells Enhance Myoblast Fusion and Skeletal Muscle Regeneration\u003c/p\u003e","fulltext":[{"header":"Full Text","content":"This preprint is available for \u003ca href='/article/rs-474083/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e."}],"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":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"stem-cell-research-and-therapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scrt","sideBox":"Learn more about [Stem Cell Research \u0026 Therapy](http://stemcellres.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/scrt/default.aspx","title":"Stem Cell Research \u0026 Therapy","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"BM-MSC, fusion, hypoxic, normoxic, migration, myogenic differentiation","lastPublishedDoi":"10.21203/rs.3.rs-474083/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-474083/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: The skeletal muscle reconstruction occurs thanks to unipotent stem cells, i.e., satellite cells. The satellite cells remain quiescent and localized between myofiber sarcolemma and basal lamina. They are activated in response to muscle injury, proliferate, differentiate into myoblasts, and recreate myofibers. Many stem and progenitor cells support skeletal muscle regeneration, which could be disturbed by extensive damage, sarcopenia, cachexia, or genetic diseases like dystrophy. Many lines of evidence showed that the level of oxygen regulates the course of cell proliferation and differentiation. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: In the present study, we analyzed hypoxic’s impact on human and pig bone marrow-derived mesenchymal stromal cell (MSC) and mouse myoblast proliferation, differentiation, and fusion. Moreover, the influence of the transplantation of human bone marrow-derived MSCs cultured under hypoxic conditions on skeletal muscle regeneration was studied. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: We showed that bone marrow-derived MSCs increased VEGF expression and improved myogenesis under hypoxic conditions in vitro. Transplantation of hypoxic preconditioned bone marrow-derived MSCs into injured muscles resulted in the improved cell engraftment and formation of new vessels. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: We suggested that SDF-1 and VEGF secreted by hypoxic preconditioned bone marrow-derived MSCs played an essential role in cell engraftment and angiogenesis. Importantly, hypoxic preconditioned bone marrow-derived MSCs more efficiently engrafted injured muscles, however, they did not undergo myogenic differentiation.\u003c/p\u003e","manuscriptTitle":"Hypoxic Preconditioned Bone Marrow-Derived Mesenchymal Stromal/Stem Cells Enhance Myoblast Fusion and Skeletal Muscle Regeneration","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-05-03 22:27:56","doi":"10.21203/rs.3.rs-474083/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revision","date":"2021-05-08T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-05-06T00:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"editorInvitedReview","content":"","date":"2021-05-05T00:00:00+00:00","index":2,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewerAgreed","content":"","date":"2021-04-29T00:00:00+00:00","index":3,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-04-28T01:00:00+00:00","index":2,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-04-28T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-04-28T00:00:00+00:00","index":0,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-04-28T00:00:00+00:00","index":1,"fulltext":""},{"type":"editorAssigned","content":"","date":"2021-04-27T00:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2021-04-26T23:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2021-04-26T23:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"Stem Cell Research \u0026 Therapy","date":"2021-04-26T09:17:44+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"stem-cell-research-and-therapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scrt","sideBox":"Learn more about [Stem Cell Research \u0026 Therapy](http://stemcellres.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/scrt/default.aspx","title":"Stem Cell Research \u0026 Therapy","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bbae6789-916d-4d3a-8247-a7a883f9670e","owner":[],"postedDate":"May 3rd, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":4002182,"name":"General Biochemistry"},{"id":4002183,"name":"Molecular Biology"}],"tags":[],"updatedAt":"2021-08-22T15:06:41+00:00","versionOfRecord":{"articleIdentity":"rs-474083","link":"https://doi.org/10.1186/s13287-021-02530-3","journal":{"identity":"stem-cell-research-and-therapy","isVorOnly":false,"title":"Stem Cell Research \u0026 Therapy"},"publishedOn":"2021-08-09 15:00:44","publishedOnDateReadable":"August 9th, 2021"},"versionCreatedAt":"2021-05-03 22:27:56","video":"","vorDoi":"10.1186/s13287-021-02530-3","vorDoiUrl":"https://doi.org/10.1186/s13287-021-02530-3","workflowStages":[]},"version":"v1","identity":"rs-474083","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-474083","identity":"rs-474083","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}