Chemically defined cytokine-free expansion of human haematopoietic stem cells

Masatoshi Sakurai, Kantaro Ishitsuka, Ryoji Ito, Adam C. Wilkinson, Takaharu Kimura, Eiji Mizutani, Hidekazu Nishikii, Kazuhiro Sudo, Hans Jiro Becker, Hiroshi Takemoto, Tsubasa Sano, Keisuke Kataoka, Satoshi Takahashi, Yukio Nakamura, David G. Kent, Atsushi Iwama, Shigeru Chiba, Shinichiro Okamoto, Hiromitsu Nakauchi () and Satoshi Yamazaki ()
Additional contact information
Masatoshi Sakurai: The University of Tokyo
Kantaro Ishitsuka: University of Tsukuba
Ryoji Ito: Central Institute for Experimental Animals
Adam C. Wilkinson: The University of Tokyo
Takaharu Kimura: University of Tsukuba
Eiji Mizutani: University of Tsukuba
Hidekazu Nishikii: University of Tsukuba
Kazuhiro Sudo: RIKEN BioResource Research Center
Hans Jiro Becker: The University of Tokyo
Hiroshi Takemoto: The University of Tokyo
Tsubasa Sano: BASF Japan
Keisuke Kataoka: Keio University School of Medicine
Satoshi Takahashi: The University of Tokyo
Yukio Nakamura: RIKEN BioResource Research Center
David G. Kent: University of York
Atsushi Iwama: The University of Tokyo
Shigeru Chiba: University of Tsukuba
Shinichiro Okamoto: Keio University School of Medicine
Hiromitsu Nakauchi: Stanford University School of Medicine
Satoshi Yamazaki: The University of Tokyo

Nature, 2023, vol. 615, issue 7950, 127-133

Abstract: Abstract Haematopoietic stem cells (HSCs) are a rare cell type that reconstitute the entire blood and immune systems after transplantation and can be used as a curative cell therapy for a variety of haematological diseases1,2. However, the low number of HSCs in the body makes both biological analyses and clinical application difficult, and the limited extent to which human HSCs can be expanded ex vivo remains a substantial barrier to the wider and safer therapeutic use of HSC transplantation3. Although various reagents have been tested in attempts to stimulate the expansion of human HSCs, cytokines have long been thought to be essential for supporting HSCs ex vivo4. Here we report the establishment of a culture system that allows the long-term ex vivo expansion of human HSCs, achieved through the complete replacement of exogenous cytokines and albumin with chemical agonists and a caprolactam-based polymer. A phosphoinositide 3-kinase activator, in combination with a thrombopoietin-receptor agonist and the pyrimidoindole derivative UM171, were sufficient to stimulate the expansion of umbilical cord blood HSCs that are capable of serial engraftment in xenotransplantation assays. Ex vivo HSC expansion was further supported by split-clone transplantation assays and single-cell RNA-sequencing analysis. Our chemically defined expansion culture system will help to advance clinical HSC therapies.

Date: 2023
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DOI: 10.1038/s41586-023-05739-9

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