Browsing by Author "Lovisa, Sara"

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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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    Type-I collagen produced by distinct fibroblast lineages reveals specific function during embryogenesis and Osteogenesis Imperfecta
    (Springer Nature, 2021) Chen, Yang; Yang, Sujuan; Lovisa, Sara; Ambrose, Catherine G.; McAndrews, Kathleen M.; Sugimoto, Hikaru; Kalluri, Raghu
    Type I collagen (Col1) is the most abundant protein in mammals. Col1 contributes to 90% of the total organic component of bone matrix. However, the precise cellular origin and functional contribution of Col1 in embryogenesis and bone formation remain unknown. Single-cell RNA-sequencing analysis identifies Fap+ cells and Fsp1+ cells as the major contributors of Col1 in the bone. We generate transgenic mouse models to genetically delete Col1 in various cell lineages. Complete, whole-body Col1 deletion leads to failed gastrulation and early embryonic lethality. Specific Col1 deletion in Fap+ cells causes severe skeletal defects, with hemorrhage, edema, and prenatal lethality. Specific Col1 deletion in Fsp1+ cells results in Osteogenesis Imperfecta-like phenotypes in adult mice, with spontaneous fractures and compromised bone healing. This study demonstrates specific contributions of mesenchymal cell lineages to Col1 production in organogenesis, skeletal development, and bone formation/repair, with potential insights into cell-based therapy for patients with Osteogenesis Imperfecta.