Browsing by Author "Alge, Joseph L."

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    Genetic reprogramming with stem cells regenerates glomerular epithelial podocytes in Alport syndrome
    (Embo Press, 2024) LeBleu, Valerie S.; Kanasaki, Keizo; Lovisa, Sara; Alge, Joseph L.; Kim, Jiha; Chen, Yang; Teng, Yingqi; Gerami-Naini, Behzad; Sugimoto, Hikaru; Kato, Noritoshi; Revuelta, Ignacio; Grau, Nicole; Sleeman, Jonathan P.; Taduri, Gangadhar; Kizu, Akane; Rafii, Shahin; Hochedlinger, Konrad; Quaggin, Susan E.; Kalluri, Raghu
    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.
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    Identification of unique α4 chain structure and conserved antiangiogenic activity of α3NC1 type IV collagen in zebrafish
    (Wiley, 2023) LeBleu, Valerie S.; Dai, Jianli; Tsutakawa, Susan; MacDonald, Brian A.; Alge, Joseph L.; Sund, Malin; Xie, Liang; Sugimoto, Hikaru; Tainer, John; Zon, Leonard I.; Kalluri, Raghu
    Background Type IV collagen is an abundant component of basement membranes in all multicellular species and is essential for the extracellular scaffold supporting tissue architecture and function. Lower organisms typically have two type IV collagen genes, encoding α1 and α2 chains, in contrast with the six genes in humans, encoding α1–α6 chains. The α chains assemble into trimeric protomers, the building blocks of the type IV collagen network. The detailed evolutionary conservation of type IV collagen network remains to be studied. Results We report on the molecular evolution of type IV collagen genes. The zebrafish α4 non-collagenous (NC1) domain, in contrast with its human ortholog, contains an additional cysteine residue and lacks the M93 and K211 residues involved in sulfilimine bond formation between adjacent protomers. This may alter α4 chain interactions with other α chains, as supported by temporal and anatomic expression patterns of collagen IV chains during the zebrafish development. Despite the divergence between zebrafish and human α3 NC1 domain (endogenous angiogenesis inhibitor, Tumstatin), the zebrafish α3 NC1 domain exhibits conserved antiangiogenic activity in human endothelial cells. Conclusions Our work supports type IV collagen is largely conserved between zebrafish and humans, with a possible difference involving the α4 chain.