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Acute myeloid leukemia

Phorbol ester induced ex vivo expansion of rigorously-defined phenotypic but not functional human cord blood hematopoietic stem cells: a cautionary tale demonstrating that phenotype does not always recapitulate stem cell function

Leukemia volume 33, pages 2962–2966 (2019)Cite this article

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Hematopoietic stem cells (HSCs) are a rare population residing at the apex of the hematopoietic hierarchy [1]. HSCs have the capacity to self-renew and differentiate into all blood cell types, thus they play a key role in hematopoietic cell transplantation (HCT) [2]. HCT is widely used as a curative therapy for numerous malignant and non-malignant hematological and even non-hematological diseases [3]. The fast developing field of gene editing techniques, including ZFNs, TALENs and CRISPR-Cas9, broaden usage of HCT in clinical therapy of diseases caused by genetic mutations [4]. i.e. β-thalassaemia or Sickle Cell Disease (SCD) may possibly be interrogated by CRISPR based gene editing of β-globin in HSCs from patients [5]. However, efficient gene editing and infusion of the gene edited HSC into patients requires sufficient numbers of donor HSC. In addition, when cord blood (CB) is used as the source of HSC for HCT, rare HSC numbers in single CB units may lead to delayed hematopoietic recovery in recipients [6]. It is thus important in some cases to develop efficient means that can overcome limited HSC numbers to enhance the efficacy of HCT.

Efforts are underway by many scientific groups to develop potential ways to improve engraftment of HSC. This includes mitigating EPHOSS [7], enhancing HSC homing efficiency [8, 9], promoting ex vivo expansion [10,11,12], and by reprogramming iPS or endothelial cells to human HSC [13, 14]. However, most of these methods have not yet been adapted for clinical use, and there is still an urgent need to dissect the mechanisms behind these encouraging processes. Rigorous phenotypic analysis of HSC is an easily accessible and important method to evaluate the function of a heterogeneous cell population from bone marrow or blood samples. The rigorous phenotyping identity of human HSC identity was confirmed at a single cell level [15]. In general, freshly isolated human HSC are defined as CD34+CD38−CD45RA−CD90+CD49f+. However, we still don’t know if all cells in different circumstances, especially under stress conditions such as ex-vivo expansion, that are identified by CD34+CD38−CD45RA−CD90+CD49f+ are functional HSC with long-term repopulating capacity.

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Acknowledgements

These studies were supported by the following Public Health Service grants from the US National Institute of Health to HEB: R35 HL139599, R01 DK109188, R01 HL056416, and U54 DK106846, and by start-up grants to BG from Shanghai Jiao Tong University School of Medicine, and by Shanghai Eastern Scholar Program (TP2018047). The bioinformatics analysis was performed by the Collaborative Core for Cancer Bioinformatics (C3B) shared by Indiana University Simon Cancer Center (P30CA082709) and Purdue University Center for Cancer Research (P30CA023168) with support from the Walther Cancer Foundation.

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  1. These authors contributed equally: Yandan Chen, Chunxu Yao

Authors and Affiliations

  1. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Yandan Chen, Chunxu Yao & Bin Guo

  2. Obstetric Intensive Care Center, The Institute of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Affiliated Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, 200233, China

    Yincheng Teng & Rongzhen Jiang

  3. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Xinxin Huang & Hal E. Broxmeyer

  4. Department of Medical and Molecular Genetics, Center for Computational Biology and Bioinformatics (CCBB), Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Sheng Liu & Jun Wan

  5. Department of BioHealth Informatics, School of Informatics and Computing, Indiana University Purdue University Indianapolis (IUPUI), Indianapolis, IN, 46202, USA

    Jun Wan

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Contributions

YC, CY, BG and XH performed the experiments and data analysis. YT and RJ collected blood samples and performed data analysis. SL and JW performed RNA-seq data analysis and functional enrichment analysis. BG and HEB designed and supervised this study. All authors had access to the final draft manuscript and approved the submission of the article.

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Correspondence to Hal E. Broxmeyer or Bin Guo.

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Chen, Y., Yao, C., Teng, Y. et al. Phorbol ester induced ex vivo expansion of rigorously-defined phenotypic but not functional human cord blood hematopoietic stem cells: a cautionary tale demonstrating that phenotype does not always recapitulate stem cell function. Leukemia 33, 2962–2966 (2019). https://doi.org/10.1038/s41375-019-0528-3

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