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

Glomerular 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 wi...

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Main Authors: LeBleu, Valerie S. (Author) , Kanasaki, Keizo (Author) , Lovisa, Sara (Author) , Alge, Joseph L. (Author) , Kim, Jiha (Author) , Chen, Yang (Author) , Teng, Yingqi (Author) , Gerami-Naini, Behzad (Author) , Sugimoto, Hikaru (Author) , Kato, Noritoshi (Author) , Revuelta, Ignacio (Author) , Grau, Nicole (Author) , Sleeman, Jonathan P. (Author) , Taduri, Gangadhar (Author) , Kizu, Akane (Author) , Rafii, Shahin (Author) , Hochedlinger, Konrad (Author) , Quaggin, Susan E. (Author) , Kalluri, Raghu (Author)
Format: Article (Journal)
Language:English
Published: June 2024
In: Life science alliance
Year: 2024, Volume: 7, Issue: 6, Pages: 1-14
ISSN:2575-1077
DOI:10.26508/lsa.202402664
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.26508/lsa.202402664
Verlag, lizenzpflichtig, Volltext: https://www.life-science-alliance.org/content/7/6/e202402664
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Author Notes:Valerie S. LeBleu, Keizo Kanasaki, Sara Lovisa, Joseph L. Alge, Jiha Kim, Yang Chen, Yingqi Teng, Behzad Gerami-Naini, Hikaru Sugimoto, Noritoshi Kato, Ignacio Revuelta, Nicole Grau, Jonathan P. Sleeman, Gangadhar Taduri, Akane Kizu, Shahin Rafii, Konrad Hochedlinger, Susan E. Quaggin, Raghu Kalluri
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Summary:Glomerular 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.
Item Description:Veröffentlicht: 1 April 2024
Gesehen am 08.10.2024
Physical Description:Online Resource
ISSN:2575-1077
DOI:10.26508/lsa.202402664

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