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Sufficiency for inducible Caspase-9 safety switch in human pluripotent stem cells and disease cells
Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have promising potential for opening new avenues in regenerative medicine. However, since the tumorigenic potential of undifferentiated pluripotent stem cells (PSCs) is a major safety concern for clinical transplantation, inducib...
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| Published in: | Gene therapy 2019-11, Vol.27 (10-11), p.525-534 |
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| cited_by | cdi_FETCH-LOGICAL-c570t-2656e853e15af24d701757b94181eb79745523ced3c3cfddbe3a34c3c23623f73 |
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| cites | cdi_FETCH-LOGICAL-c570t-2656e853e15af24d701757b94181eb79745523ced3c3cfddbe3a34c3c23623f73 |
| container_end_page | 534 |
| container_issue | 10-11 |
| container_start_page | 525 |
| container_title | Gene therapy |
| container_volume | 27 |
| creator | Nishimura, Toshinobu Xu, Haojun Iwasaki, Masayuki Karigane, Daiki Saavedra, Brandon Takahashi, Yusuke Suchy, Fabian P. Monobe, Shinichiro Martin, Renata M. Ohtaka, Manami Nakanishi, Mahito Burrows, Scott R. Cleary, Michael L. Majeti, Ravindra Shibuya, Akira Nakauchi, Hiromitsu |
| description | Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have promising potential for opening new avenues in regenerative medicine. However, since the tumorigenic potential of undifferentiated pluripotent stem cells (PSCs) is a major safety concern for clinical transplantation, inducible Caspase-9 (iC9) is under consideration for use as a fail-safe system. Here, we used targeted gene editing to introduce the iC9 system into human iPSCs, and then interrogated the efficiency of inducible apoptosis with normal iPSCs as well as diseased iPSCs derived from patients with acute myeloid leukemia (AML-iPSCs). The iC9 system induced quick and efficient apoptosis to iPSCs in vitro. More importantly, complete eradication of malignant cells without AML recurrence was shown in disease mouse models by using AML-iPSCs. In parallel, it shed light on several limitations of the iC9 system usage. Our results suggest that careful use of the iC9 system will serve as an important countermeasure against posttransplantation adverse events in stem cell transplantation therapies. |
| doi_str_mv | 10.1038/s41434-020-0179-z |
| format | article |
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Our results suggest that careful use of the iC9 system will serve as an important countermeasure against posttransplantation adverse events in stem cell transplantation therapies.</description><identifier>ISSN: 0969-7128</identifier><identifier>EISSN: 1476-5462</identifier><identifier>DOI: 10.1038/s41434-020-0179-z</identifier><identifier>PMID: 32704085</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/2 ; 42/100 ; 42/41 ; 59/5 ; 631/532/1542 ; 631/61/201/2110 ; Acute myeloid leukemia ; Adverse events ; Animal models ; Apoptosis ; Biomedical and Life Sciences ; Biomedicine ; Brief Communication ; Caspase-9 ; Cell Biology ; Embryo cells ; Embryonic stem cells ; Gene Expression ; Gene Therapy ; Genetic aspects ; Genome editing ; Health aspects ; Human Genetics ; Myeloid leukemia ; Nanotechnology ; Pluripotency ; Proteases ; Regenerative medicine ; Stem cell transplantation ; Stem cells ; Transplantation</subject><ispartof>Gene therapy, 2019-11, Vol.27 (10-11), p.525-534</ispartof><rights>Springer Nature Limited 2020</rights><rights>COPYRIGHT 2019 Nature Publishing Group</rights><rights>Springer Nature Limited 2020.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c570t-2656e853e15af24d701757b94181eb79745523ced3c3cfddbe3a34c3c23623f73</citedby><cites>FETCH-LOGICAL-c570t-2656e853e15af24d701757b94181eb79745523ced3c3cfddbe3a34c3c23623f73</cites><orcidid>0000-0002-5425-1708 ; 0000-0002-5814-0984 ; 0000-0001-9600-1945 ; 0000-0003-2996-4260 ; 0000-0003-4211-9993 ; 0000-0001-7127-3223 ; 0000-0002-3003-3853 ; 0000-0001-6507-9088 ; 0000-0002-4017-5193 ; 0000-0002-1430-0472 ; 0000-0002-7187-5360 ; 0000-0002-9841-6973</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32704085$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nishimura, Toshinobu</creatorcontrib><creatorcontrib>Xu, Haojun</creatorcontrib><creatorcontrib>Iwasaki, Masayuki</creatorcontrib><creatorcontrib>Karigane, Daiki</creatorcontrib><creatorcontrib>Saavedra, Brandon</creatorcontrib><creatorcontrib>Takahashi, Yusuke</creatorcontrib><creatorcontrib>Suchy, Fabian P.</creatorcontrib><creatorcontrib>Monobe, Shinichiro</creatorcontrib><creatorcontrib>Martin, Renata M.</creatorcontrib><creatorcontrib>Ohtaka, Manami</creatorcontrib><creatorcontrib>Nakanishi, Mahito</creatorcontrib><creatorcontrib>Burrows, Scott R.</creatorcontrib><creatorcontrib>Cleary, Michael L.</creatorcontrib><creatorcontrib>Majeti, Ravindra</creatorcontrib><creatorcontrib>Shibuya, Akira</creatorcontrib><creatorcontrib>Nakauchi, Hiromitsu</creatorcontrib><title>Sufficiency for inducible Caspase-9 safety switch in human pluripotent stem cells and disease cells</title><title>Gene therapy</title><addtitle>Gene Ther</addtitle><addtitle>Gene Ther</addtitle><description>Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have promising potential for opening new avenues in regenerative medicine. However, since the tumorigenic potential of undifferentiated pluripotent stem cells (PSCs) is a major safety concern for clinical transplantation, inducible Caspase-9 (iC9) is under consideration for use as a fail-safe system. Here, we used targeted gene editing to introduce the iC9 system into human iPSCs, and then interrogated the efficiency of inducible apoptosis with normal iPSCs as well as diseased iPSCs derived from patients with acute myeloid leukemia (AML-iPSCs). The iC9 system induced quick and efficient apoptosis to iPSCs in vitro. More importantly, complete eradication of malignant cells without AML recurrence was shown in disease mouse models by using AML-iPSCs. In parallel, it shed light on several limitations of the iC9 system usage. Our results suggest that careful use of the iC9 system will serve as an important countermeasure against posttransplantation adverse events in stem cell transplantation therapies.</description><subject>13/2</subject><subject>42/100</subject><subject>42/41</subject><subject>59/5</subject><subject>631/532/1542</subject><subject>631/61/201/2110</subject><subject>Acute myeloid leukemia</subject><subject>Adverse events</subject><subject>Animal models</subject><subject>Apoptosis</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Brief Communication</subject><subject>Caspase-9</subject><subject>Cell Biology</subject><subject>Embryo cells</subject><subject>Embryonic stem cells</subject><subject>Gene Expression</subject><subject>Gene Therapy</subject><subject>Genetic aspects</subject><subject>Genome editing</subject><subject>Health aspects</subject><subject>Human Genetics</subject><subject>Myeloid 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| subjects | 13/2 42/100 42/41 59/5 631/532/1542 631/61/201/2110 Acute myeloid leukemia Adverse events Animal models Apoptosis Biomedical and Life Sciences Biomedicine Brief Communication Caspase-9 Cell Biology Embryo cells Embryonic stem cells Gene Expression Gene Therapy Genetic aspects Genome editing Health aspects Human Genetics Myeloid leukemia Nanotechnology Pluripotency Proteases Regenerative medicine Stem cell transplantation Stem cells Transplantation |
| title | Sufficiency for inducible Caspase-9 safety switch in human pluripotent stem cells and disease cells |
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