Pluripotent stem cell model of Shwachman–Diamond syndrome reveals apoptotic predisposition of hemoangiogenic progenitors

Takayuki Hamabata, Katsutsugu Umeda, Kagehiro Kouzuki, Takayuki Tanaka, Tomoo Daifu, Seishiro Nodomi, Satoshi Saida, Itaru Kato, Shiro Baba, Hidefumi Hiramatsu, Mitsujiro Osawa, Akira Niwa, Megumu K. Saito, Yasuhiko Kamikubo, Souichi Adachi, Yoshiko Hashii, Akira Shimada, Hiroyoshi Watanabe, Kenji Osafune, Keisuke OkitaTatsutoshi Nakahata, Kenichiro Watanabe, Junko Takita, Toshio Heike

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5 Citations (Scopus)


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.

Original languageEnglish
Article number14859
JournalScientific reports
Issue number1
Publication statusPublished - Dec 1 2020

ASJC Scopus subject areas

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