Pluripotent stem cell model of Shwachman–Diamond syndrome reveals apoptotic predisposition of hemoangiogenic progenitors
| Autor: | Akira Niwa, Junko Takita, Akira Shimada, Yasuhiko Kamikubo, Itaru Kato, Kenichiro Watanabe, Yoshiko Hashii, Tomoo Daifu, Shiro Baba, Tatsutoshi Nakahata, Takayuki Hamabata, Takayuki Tanaka, Satoshi Saida, Mitsujiro Osawa, Seishiro Nodomi, Hiroyoshi Watanabe, Toshio Heike, Keisuke Okita, Kenji Osafune, Megumu K. Saito, Kagehiro Kouzuki, Katsutsugu Umeda, Hidefumi Hiramatsu, Souichi Adachi |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine CD34 lcsh:Medicine Apoptosis Biology Article 03 medical and health sciences 0302 clinical medicine Japan medicine Humans Progenitor cell Author Correction lcsh:Science Induced pluripotent stem cell Exocrine pancreatic insufficiency Cells Cultured Shwachman–Diamond syndrome Multidisciplinary lcsh:R Bone marrow failure Endothelial Cells Proteins Cell Differentiation SBDS Hematopoietic Stem Cells medicine.disease Shwachman-Diamond Syndrome Hematopoiesis Induced pluripotent stem cells Haematopoiesis 030104 developmental biology Differentiation Mutation Cancer research lcsh:Q 030215 immunology |
| Zdroj: | Scientific Reports Scientific Reports, Vol 10, Iss 1, Pp 1-12 (2020) |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-020-71844-8 |
| Popis: | Shwachman–Diamond syndrome (SDS), an autosomal recessive disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities, is caused by mutations in the Shwachman–Bodian–Diamond syndrome (SBDS) gene, which plays a role in ribosome biogenesis. Although the causative genes of congenital disorders frequently involve regulation of embryogenesis, the role of the SBDS gene in early hematopoiesis remains unclear, primarily due to the lack of a suitable experimental model for this syndrome. In this study, we established induced pluripotent stem cells (iPSCs) from patients with SDS (SDS-iPSCs) and analyzed their in vitro hematopoietic and endothelial differentiation potentials. SDS-iPSCs generated hematopoietic and endothelial cells less efficiently than iPSCs derived from healthy donors, principally due to the apoptotic predisposition of KDR+CD34+ common hemoangiogenic progenitors. By contrast, forced expression of SBDS gene in SDS-iPSCs or treatment with a caspase inhibitor reversed the deficiency in hematopoietic and endothelial development, and decreased apoptosis of their progenitors, mainly via p53-independent mechanisms. Patient-derived iPSCs exhibited the hematological abnormalities associated with SDS even at the earliest hematopoietic stages. These findings will enable us to dissect the pathogenesis of multiple disorders associated with ribosomal dysfunction. |
| Databáze: | OpenAIRE |
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