Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic mosaicism and drug discovery
Chronic infantile neurologic cutaneous and articular (CINCA) syndrome is an IL-1–driven autoinflammatory disorder caused mainly by NLRP3 mutations. The pathogenesis of CINCA syndrome patients who carry NLRP3 mutations as somatic mosaicism has not been precisely described because of the difficulty in...
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| Veröffentlicht in: | Blood 2012-08, Vol.120 (6), p.1299-1308 |
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| creator | Tanaka, Takayuki Takahashi, Kazutoshi Yamane, Mayu Tomida, Shota Nakamura, Saori Oshima, Koichi Niwa, Akira Nishikomori, Ryuta Kambe, Naotomo Hara, Hideki Mitsuyama, Masao Morone, Nobuhiro Heuser, John E. Yamamoto, Takuya Watanabe, Akira Sato-Otsubo, Aiko Ogawa, Seishi Asaka, Isao Heike, Toshio Yamanaka, Shinya Nakahata, Tatsutoshi Saito, Megumu K. |
| description | Chronic infantile neurologic cutaneous and articular (CINCA) syndrome is an IL-1–driven autoinflammatory disorder caused mainly by NLRP3 mutations. The pathogenesis of CINCA syndrome patients who carry NLRP3 mutations as somatic mosaicism has not been precisely described because of the difficulty in separating individual cells based on the presence or absence of the mutation. Here we report the generation of NLRP3-mutant and nonmutant-induced pluripotent stem cell (iPSC) lines from 2 CINCA syndrome patients with somatic mosaicism, and describe their differentiation into macrophages (iPS-MPs). We found that mutant cells are predominantly responsible for the pathogenesis in these mosaic patients because only mutant iPS-MPs showed the disease relevant phenotype of abnormal IL-1β secretion. We also confirmed that the existing anti-inflammatory compounds inhibited the abnormal IL-1β secretion, indicating that mutant iPS-MPs are applicable for drug screening for CINCA syndrome and other NLRP3-related inflammatory conditions. Our results illustrate that patient-derived iPSCs are useful for dissecting somatic mosaicism and that NLRP3-mutant iPSCs can provide a valuable platform for drug discovery for multiple NLRP3-related disorders. |
| doi_str_mv | 10.1182/blood-2012-03-417881 |
| format | Article |
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The pathogenesis of CINCA syndrome patients who carry NLRP3 mutations as somatic mosaicism has not been precisely described because of the difficulty in separating individual cells based on the presence or absence of the mutation. Here we report the generation of NLRP3-mutant and nonmutant-induced pluripotent stem cell (iPSC) lines from 2 CINCA syndrome patients with somatic mosaicism, and describe their differentiation into macrophages (iPS-MPs). We found that mutant cells are predominantly responsible for the pathogenesis in these mosaic patients because only mutant iPS-MPs showed the disease relevant phenotype of abnormal IL-1β secretion. We also confirmed that the existing anti-inflammatory compounds inhibited the abnormal IL-1β secretion, indicating that mutant iPS-MPs are applicable for drug screening for CINCA syndrome and other NLRP3-related inflammatory conditions. Our results illustrate that patient-derived iPSCs are useful for dissecting somatic mosaicism and that NLRP3-mutant iPSCs can provide a valuable platform for drug discovery for multiple NLRP3-related disorders.</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2012-03-417881</identifier><identifier>PMID: 22723549</identifier><language>eng</language><publisher>Washington, DC: Elsevier Inc</publisher><subject>Animals ; Biological and medical sciences ; Carrier Proteins - genetics ; Carrier Proteins - physiology ; Cells, Cultured ; Cryopyrin-Associated Periodic Syndromes - drug therapy ; Cryopyrin-Associated Periodic Syndromes - genetics ; Cryopyrin-Associated Periodic Syndromes - pathology ; Drug Discovery - methods ; Hematologic and hematopoietic diseases ; Humans ; Induced Pluripotent Stem Cells - pathology ; Induced Pluripotent Stem Cells - physiology ; Infant ; Medical sciences ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Mice, Transgenic ; Models, Theoretical ; Mosaicism ; Mutant Proteins - genetics ; Mutant Proteins - physiology ; NLR Family, Pyrin Domain-Containing 3 Protein</subject><ispartof>Blood, 2012-08, Vol.120 (6), p.1299-1308</ispartof><rights>2012 American Society of Hematology</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c504t-9d89803b7a94b87b5722422041e3cffb90b19177460bd5db69f56408a5027e403</citedby><cites>FETCH-LOGICAL-c504t-9d89803b7a94b87b5722422041e3cffb90b19177460bd5db69f56408a5027e403</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26220477$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22723549$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tanaka, Takayuki</creatorcontrib><creatorcontrib>Takahashi, Kazutoshi</creatorcontrib><creatorcontrib>Yamane, Mayu</creatorcontrib><creatorcontrib>Tomida, Shota</creatorcontrib><creatorcontrib>Nakamura, Saori</creatorcontrib><creatorcontrib>Oshima, Koichi</creatorcontrib><creatorcontrib>Niwa, Akira</creatorcontrib><creatorcontrib>Nishikomori, Ryuta</creatorcontrib><creatorcontrib>Kambe, Naotomo</creatorcontrib><creatorcontrib>Hara, Hideki</creatorcontrib><creatorcontrib>Mitsuyama, Masao</creatorcontrib><creatorcontrib>Morone, Nobuhiro</creatorcontrib><creatorcontrib>Heuser, John E.</creatorcontrib><creatorcontrib>Yamamoto, Takuya</creatorcontrib><creatorcontrib>Watanabe, Akira</creatorcontrib><creatorcontrib>Sato-Otsubo, Aiko</creatorcontrib><creatorcontrib>Ogawa, Seishi</creatorcontrib><creatorcontrib>Asaka, Isao</creatorcontrib><creatorcontrib>Heike, Toshio</creatorcontrib><creatorcontrib>Yamanaka, Shinya</creatorcontrib><creatorcontrib>Nakahata, Tatsutoshi</creatorcontrib><creatorcontrib>Saito, Megumu K.</creatorcontrib><title>Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic mosaicism and drug discovery</title><title>Blood</title><addtitle>Blood</addtitle><description>Chronic infantile neurologic cutaneous and articular (CINCA) syndrome is an IL-1–driven autoinflammatory disorder caused mainly by NLRP3 mutations. The pathogenesis of CINCA syndrome patients who carry NLRP3 mutations as somatic mosaicism has not been precisely described because of the difficulty in separating individual cells based on the presence or absence of the mutation. Here we report the generation of NLRP3-mutant and nonmutant-induced pluripotent stem cell (iPSC) lines from 2 CINCA syndrome patients with somatic mosaicism, and describe their differentiation into macrophages (iPS-MPs). We found that mutant cells are predominantly responsible for the pathogenesis in these mosaic patients because only mutant iPS-MPs showed the disease relevant phenotype of abnormal IL-1β secretion. We also confirmed that the existing anti-inflammatory compounds inhibited the abnormal IL-1β secretion, indicating that mutant iPS-MPs are applicable for drug screening for CINCA syndrome and other NLRP3-related inflammatory conditions. 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The pathogenesis of CINCA syndrome patients who carry NLRP3 mutations as somatic mosaicism has not been precisely described because of the difficulty in separating individual cells based on the presence or absence of the mutation. Here we report the generation of NLRP3-mutant and nonmutant-induced pluripotent stem cell (iPSC) lines from 2 CINCA syndrome patients with somatic mosaicism, and describe their differentiation into macrophages (iPS-MPs). We found that mutant cells are predominantly responsible for the pathogenesis in these mosaic patients because only mutant iPS-MPs showed the disease relevant phenotype of abnormal IL-1β secretion. We also confirmed that the existing anti-inflammatory compounds inhibited the abnormal IL-1β secretion, indicating that mutant iPS-MPs are applicable for drug screening for CINCA syndrome and other NLRP3-related inflammatory conditions. Our results illustrate that patient-derived iPSCs are useful for dissecting somatic mosaicism and that NLRP3-mutant iPSCs can provide a valuable platform for drug discovery for multiple NLRP3-related disorders.</abstract><cop>Washington, DC</cop><pub>Elsevier Inc</pub><pmid>22723549</pmid><doi>10.1182/blood-2012-03-417881</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biological and medical sciences Carrier Proteins - genetics Carrier Proteins - physiology Cells, Cultured Cryopyrin-Associated Periodic Syndromes - drug therapy Cryopyrin-Associated Periodic Syndromes - genetics Cryopyrin-Associated Periodic Syndromes - pathology Drug Discovery - methods Hematologic and hematopoietic diseases Humans Induced Pluripotent Stem Cells - pathology Induced Pluripotent Stem Cells - physiology Infant Medical sciences Mice Mice, Inbred NOD Mice, SCID Mice, Transgenic Models, Theoretical Mosaicism Mutant Proteins - genetics Mutant Proteins - physiology NLR Family, Pyrin Domain-Containing 3 Protein |
| title | Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic mosaicism and drug discovery |
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