Genetic reprogramming with stem cells regenerates glomerular epithelial podocytes in Alport syndrome

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dc.citation.issueNumber6
dc.citation.journalTitleLife Science Alliance
dc.citation.volumeNumber7
dc.contributor.authorLeBleu, Valerie S.
dc.contributor.authorKanasaki, Keizo
dc.contributor.authorLovisa, Sara
dc.contributor.authorAlge, Joseph L.
dc.contributor.authorKim, Jiha
dc.contributor.authorChen, Yang
dc.contributor.authorTeng, Yingqi
dc.contributor.authorGerami-Naini, Behzad
dc.contributor.authorSugimoto, Hikaru
dc.contributor.authorKato, Noritoshi
dc.contributor.authorRevuelta, Ignacio
dc.contributor.authorGrau, Nicole
dc.contributor.authorSleeman, Jonathan P.
dc.contributor.authorTaduri, Gangadhar
dc.contributor.authorKizu, Akane
dc.contributor.authorRafii, Shahin
dc.contributor.authorHochedlinger, Konrad
dc.contributor.authorQuaggin, Susan E.
dc.contributor.authorKalluri, Raghu
dc.date.accessioned2024-07-25T20:55:16Z
dc.date.available2024-07-25T20:55:16Z
dc.date.issued2024
dc.description.abstractGlomerular filtration relies on the type IV collagen (ColIV) network of the glomerular basement membrane, namely, in the triple helical molecules containing the α3, α4, and α5 chains of ColIV. Loss of function mutations in the genes encoding these chains (Col4a3, Col4a4, and Col4a5) is associated with the loss of renal function observed in Alport syndrome (AS). Precise understanding of the cellular basis for the patho-mechanism remains unknown and a specific therapy for this disease does not currently exist. Here, we generated a novel allele for the conditional deletion of Col4a3 in different glomerular cell types in mice. We found that podocytes specifically generate α3 chains in the developing glomerular basement membrane, and that its absence is sufficient to impair glomerular filtration as seen in AS. Next, we show that horizontal gene transfer, enhanced by TGFβ1 and using allogenic bone marrow–derived mesenchymal stem cells and induced pluripotent stem cells, rescues Col4a3 expression and revive kidney function in Col4a3-deficient AS mice. Our proof-of-concept study supports that horizontal gene transfer such as cell fusion enables cell-based therapy in Alport syndrome.
dc.identifier.citationLeBleu, V. S., Kanasaki, K., Lovisa, S., Alge, J. L., Kim, J., Chen, Y., Teng, Y., Gerami-Naini, B., Sugimoto, H., Kato, N., Revuelta, I., Grau, N., Sleeman, J. P., Taduri, G., Kizu, A., Rafii, S., Hochedlinger, K., Quaggin, S. E., & Kalluri, R. (2024). Genetic reprogramming with stem cells regenerates glomerular epithelial podocytes in Alport syndrome. Life Science Alliance, 7(6). https://doi.org/10.26508/lsa.202402664
dc.identifier.digitale202402664-full
dc.identifier.doihttps://doi.org/10.26508/lsa.202402664
dc.identifier.urihttps://hdl.handle.net/1911/117511
dc.language.isoeng
dc.publisherEmbo Press
dc.rightsExcept where otherwise noted, this work is licensed under a Creative Commons Attribution (CC BY) license.  Permission to reuse, publish, or reproduce the work beyond the terms of the license or beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleGenetic reprogramming with stem cells regenerates glomerular epithelial podocytes in Alport syndrome
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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