Identification of MMP1 as a novel risk factor for intracranial aneurysms in ADPKD using iPSC models

Ameku, Tomonaga; Taura, Daisuke; Sone, Masakatsu; Numata, Tomohiro; Nakamura, Masahiro; Shiota, Fumihiko; Toyoda, Tarō; Matsui, Satoshi; Araoka, Toshikazu; Yasuno, Tetsuhiko; Mae, Shin Ichi; Kobayashi, Hatasu; Kondo, Naoya; Kitaoka, Fumiyo; Amano, Naoki; Arai, Sayaka; Ichisaka, Tomoko; Matsuura, Nobuki; Inoue, Sumiko; Yamamoto, Takuya; Takahashi, Kazutoshi; Asaka, Isao; Yamada, Yoshihiko; Ubara, Yoshifumi; Muso, Eri; Fukatsu, Atsushi; Watanabe, Akira; Sato, Yasunori; Nakahata, Tatsutoshi; Mori, Yasuo; Nakao, Kazuwa; Yamanaka, Shinya; Osafune, Kenji

doi:10.1038/srep30013

Cited by 33 publications

(25 citation statements)

References 60 publications

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“…They found that the expression level of a metalloenzyme gene, matric metaloproteinase (MMP)-1 was specifically elevated in hiPSC-derived endothelial cells from ADPKD patients with aneurysms. In addition, they confirmed a positive correlation between serum MMP1 levels and the development of intracranial aneurysms in 354 ADPKD patients, indicating that high serum MMP1 levels might constitute a novel risk factor for ADPKD [146]. …”

Section: Disease Modeling Using Kidney Organoidsmentioning

confidence: 94%

“…This phenomenon might help explain the cause for cystogenesis in ADPKD patients; yet, further studies are required to elucidate the mechanisms of cystogenesis due to reduced PKD2 expression in the cilium and furthermore, on how this relates to why it takes a number of decades to form cysts in ADPKD patients. Another recent study on ADPKD using patient-derived hiPSCs attempted to explore risk factors for intracranial aneurysms [146]. The authors established hiPSCs from three ADPKD patients without intracranial aneurysms and four patients with aneurysms, and compared gene expression profiles between those two groups after hiPSC differentiation into endothelial cells.…”

Section: Disease Modeling Using Kidney Organoidsmentioning

confidence: 99%

“…In both of these studies, clinical manifestations of ADPKD, such as kidney cysts and aneurysms were not reproduced in culture systems using hiPSCs derived from ADPKD patients [145, 146]. One reason might be that there were inadequate differentiation protocols to generate kidney organoids at that time.…”

Section: Disease Modeling Using Kidney Organoidsmentioning

confidence: 99%

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Kidney Organoids: A Translational Journey

Morizane

Bonventre

2017

Trends in Molecular Medicine

121

110

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Human pluripotent stem cells (hPSCs) are attractive sources for regenerative medicine and disease modeling in vitro. Directed hPSC differentiation approaches have derived from knowledge of cell development in vivo rather than from stochastic cell differentiation. Moreover, there has been great success in the generation of 3-dimensional organ-buds termed “organoids” from hPSCs; these consist of a variety of cell types in vitro to mimic organs in vivo. The organoid bears great potential in the study of human diseases in vitro especially when combined with CRISPR/Cas9-based genome editing approaches. We summarize the current literature describing organoid studies with a special focus on kidney organoids, and discuss goals and future opportunities for organoid-based studies.

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Section: Disease Modeling Using Kidney Organoidsmentioning

confidence: 94%

Section: Disease Modeling Using Kidney Organoidsmentioning

confidence: 99%

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Kidney Organoids: A Translational Journey

Morizane

Bonventre

2017

Trends in Molecular Medicine

121

110

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“…Previously, iPSCs cells have been established from ADPKD patients heterozygous for a PKD1 mutation . Since these iPSCs were derived from fibroblasts, somatic mutations that might have contributed to cystogenesis will be missed.…”

Section: Introductionmentioning

confidence: 99%

Cystic renal-epithelial derived induced pluripotent stem cells from polycystic kidney disease patients

Kenter¹,

Rentmeester

Riet³

et al. 2020

Stem Cells Translational Medicine

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Autosomal‐dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, leading to kidney failure in most patients. In approximately 85% of cases, the disease is caused by mutations in PKD1. How dysregulation of PKD1 leads to cyst formation on a molecular level is unknown. Induced pluripotent stem cells (iPSCs) are a powerful tool for in vitro modeling of genetic disorders. Here, we established ADPKD patient‐specific iPSCs to study the function of PKD1 in kidney development and cyst formation in vitro. Somatic mutations are proposed to be the initiating event of cyst formation, and therefore, iPSCs were derived from cystic renal epithelial cells rather than fibroblasts. Mutation analysis of the ADPKD iPSCs revealed germline mutations in PKD1 but no additional somatic mutations in PKD1/PKD2. Although several somatic mutations in other genes implicated in ADPKD were identified in cystic renal epithelial cells, only few of these mutations were present in iPSCs, indicating a heterogeneous mutational landscape, and possibly in vitro cell selection before and during the reprogramming process. Whole‐genome DNA methylation analysis indicated that iPSCs derived from renal epithelial cells maintain a kidney‐specific DNA methylation memory. In addition, comparison of PKD1+/− and control iPSCs revealed differences in DNA methylation associated with the disease history. In conclusion, we generated and characterized iPSCs derived from cystic and healthy control renal epithelial cells, which can be used for in vitro modeling of kidney development in general and cystogenesis in particular.

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“…In patients with polycystic kidney disease (PKD), serum MMP-1 concentrations were elevated compared to the controls [33]. Serum MMP-1 levels were found to be significantly increased in the induced pluripotent stem cell-derived endothelial cells from patients with ADPKD and intracranial aneurysms [34]. …”

Section: Collagenases (Mmp-1 Mmp-8 Mmp-13 and Mmp-18)mentioning

confidence: 99%

Matrix Metalloproteinases in Renal Diseases: A Critical Appraisal

Zakiyanov

Kalousová

Zima

et al. 2019

Kidney Blood Press Res

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Matrix metalloproteinases (MMPs) are endopeptidases within the metzincin protein family that not only cleave extracellular matrix (ECM) components, but also process the non-ECM molecules, including various growth factors and their binding proteins. MMPs participate in cell to ECM interactions, and MMPs are known to be involved in cell proliferation mechanisms and most probably apoptosis. These proteinases are grouped into six classes: collagenases, gelatinases, stromelysins, matrilysins, membrane type MMPs, and other MMPs. Various mechanisms regulate the activity of MMPs, inhibition by tissue inhibitors of metalloproteinases being the most important. In the kidney, intrinsic glomerular cells and tubular epithelial cells synthesize several MMPs. The measurement of circulating MMPs can provide valuable information in patients with kidney diseases. They play an important role in many renal diseases, both acute and chronic. This review attempts to summarize the current knowledge of MMPs in the kidney and discusses recent data from patient and animal studies with reference to specific diseases. A better understanding of the MMPs’ role in renal remodeling may open the way to new interventions favoring deleterious renal changes in a number of kidney diseases.

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Identification of MMP1 as a novel risk factor for intracranial aneurysms in ADPKD using iPSC models

Cited by 33 publications

References 60 publications

Kidney Organoids: A Translational Journey

Kidney Organoids: A Translational Journey

Cystic renal-epithelial derived induced pluripotent stem cells from polycystic kidney disease patients

Matrix Metalloproteinases in Renal Diseases: A Critical Appraisal

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