2. Academic Validation
  3. Chemically defined cytokine-free expansion of human haematopoietic stem cells

Chemically defined cytokine-free expansion of human haematopoietic stem cells

  • Nature. 2023 Feb 22. doi: 10.1038/s41586-023-05739-9.
Masatoshi Sakurai # 1 2,  Kantaro Ishitsuka # 3,  Ryoji Ito 4,  Adam C Wilkinson 1 5 6,  Takaharu Kimura 3,  Eiji Mizutani 3 7,  Hidekazu Nishikii 8,  Kazuhiro Sudo 9,  Hans Jiro Becker 1 3,  Hiroshi Takemoto 10,  Tsubasa Sano 11,  Keisuke Kataoka 2 12,  Satoshi Takahashi 13,  Yukio Nakamura 9,  David G Kent 14 15,  Atsushi Iwama 16,  Shigeru Chiba 8,  Shinichiro Okamoto 2,  Hiromitsu Nakauchi 17 18,  Satoshi Yamazaki 19 20
Affiliations

Affiliations

  • 1 Division of Stem Cell Biology, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 2 Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
  • 3 Laboratory of Stem Cell Therapy, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
  • 4 Human Disease Model Laboratory, Central Institute for Experimental Animals, Kawasaki, Japan.
  • 5 MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • 6 Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
  • 7 Division of Stem Cell Therapy, Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 8 Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
  • 9 Cell Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan.
  • 10 Department of Neuroscience, Drug Discovery and Disease Research Laboratory, Shionogi; Business-Academia Collaborative Laboratory (Shionogi), Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
  • 11 Pharma Solutions, Nutrition and Health, BASF Japan, Tokyo, Japan.
  • 12 Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, Japan.
  • 13 Division of Clinical Precision Research Platform, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 14 Department of Biology, York Biomedical Research Institute, University of York, York, UK.
  • 15 Wellcome MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
  • 16 Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 17 Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. nakauchi@stanford.edu.
  • 18 Division of Stem Cell Therapy, Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. nakauchi@stanford.edu.
  • 19 Division of Stem Cell Biology, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. y-sato4@md.tsukuba.ac.jp.
  • 20 Laboratory of Stem Cell Therapy, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. y-sato4@md.tsukuba.ac.jp.
  • # Contributed equally.
PMID: 36813966 DOI: 10.1038/s41586-023-05739-9
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.

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