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      Maintenance of human haematopoietic stem and progenitor cells in vitro using a chemical cocktail

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Identification of effective culture conditions to maintain and possibly expand human HSPCs in vitro is an important goal. Recent advances highlight the efficacy of chemicals in maintaining and converting cell fates. We screened 186 chemicals and found that a combination of CHIR-99021, Forskolin and OAC1 (CFO) maintained human CD34-positive cells in vitro. Efficiency of the culture system was characterized using flow cytometry for CD34-positive cells, a colony-forming assay and xeno-transplants. We found that human CD34-positive cells treated with this combination had enhanced expression of human HSPC markers and increased haematopoietic re-populating ability in immune-deficient mice. Single-cell RNA-seq analyses showed that the in vitro cultured human CD34-positive cells were heterogeneous. We found that CFO supports maintenance of human CD34-positive cells by activating HOXA9, GATA2 and AKT-cAMP signaling pathway. These data have implications in therapies requiring maintenance and/or expansion of human HSPCs.

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          Most cited references18

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          Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells.

          Anthony Boitano, Jian Wang, Russell D. Romeo … (2010)
          Although practiced clinically for more than 40 years, the use of hematopoietic stem cell (HSC) transplants remains limited by the ability to expand these cells ex vivo. An unbiased screen with primary human HSCs identified a purine derivative, StemRegenin 1 (SR1), that promotes the ex vivo expansion of CD34+ cells. Culture of HSCs with SR1 led to a 50-fold increase in cells expressing CD34 and a 17-fold increase in cells that retain the ability to engraft immunodeficient mice. Mechanistic studies show that SR1 acts by antagonizing the aryl hydrocarbon receptor (AHR). The identification of SR1 and AHR modulation as a means to induce ex vivo HSC expansion should facilitate the clinical use of HSC therapy.
          Article 0 comments Cited 351 times – based on 0 reviews     Review now
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            Distinct routes of lineage development reshape the human blood hierarchy across ontogeny.

            F Notta, S. Zandi, N Takayama … (2016)
            In a classical view of hematopoiesis, the various blood cell lineages arise via a hierarchical scheme starting with multipotent stem cells that become increasingly restricted in their differentiation potential through oligopotent and then unipotent progenitors. We developed a cell-sorting scheme to resolve myeloid (My), erythroid (Er), and megakaryocytic (Mk) fates from single CD34(+) cells and then mapped the progenitor hierarchy across human development. Fetal liver contained large numbers of distinct oligopotent progenitors with intermingled My, Er, and Mk fates. However, few oligopotent progenitor intermediates were present in the adult bone marrow. Instead, only two progenitor classes predominate, multipotent and unipotent, with Er-Mk lineages emerging from multipotent cells. The developmental shift to an adult "two-tier" hierarchy challenges current dogma and provides a revised framework to understand normal and disease states of human hematopoiesis.
            Article 0 comments Cited 298 times – based on 0 reviews     Review now
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              Expression profiling. Combinatorial labeling of single cells for gene expression cytometry.

              H Christina Fan, Glenn K Fu, Stephen Fodor (2015)
              We present a technically simple approach for gene expression cytometry combining next-generation sequencing with stochastic barcoding of single cells. A combinatorial library of beads bearing cell- and molecular-barcoding capture probes is used to uniquely label transcripts and reconstruct the digital gene expression profile of thousands of individual cells in a single experiment without the need for robotics or automation. We applied the technology to dissect the human hematopoietic system and to characterize heterogeneous response to in vitro stimulation. High sensitivity is demonstrated by detection of low-abundance transcripts and rare cells. Under current implementation, the technique can analyze a few thousand cells simultaneously and can readily scale to 10,000s or 100,000s of cells.
              Article 0 comments Cited 164 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Xiaoping Han: xhan@zju.edu.cn
                He Huang: hehuangyu@126.com
                Guoji Guo: +89-13750802684 , ggj@zju.edu.cn
                Journal
                Journal ID (nlm-ta): Cell Discov
                Journal ID (iso-abbrev): Cell Discov
                Title: Cell Discovery
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2056-5968
                Publication date (Electronic): 30 October 2018
                Publication date PMC-release: 30 October 2018
                Publication date Collection: 2018
                Volume: 4
                Electronic Location Identifier: 59
                Affiliations
                [1 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Center for Stem Cell and Regenerative Medicine, , Zhejiang University School of Medicine, ; Zhejiang, Hangzhou, 310058 China
                [2 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Stem Cell Institute, , Zhejiang University, ; Zhejiang, Hangzhou, 310058 China
                [3 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Institute of Hematology, First Affiliated Hospital, , Zhejiang University School of Medicine, ; Zhejiang, Hangzhou, 310003 China
                [4 ]ISNI 0000 0001 2315 1184, GRID grid.411461.7, UT-ORNL Graduate School of Genome Science and Technology, , The University of Tennessee, ; Knoxville, TN 37996 USA
                [5 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Core Facilities, , Zhejiang University School of Medicine, ; Zhejiang, Hangzhou, 310058 China
                [6 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Institute of Mechatronic Control Engineering, , Zhejiang University, ; Zhejiang, Hangzhou, 310027 China
                [7 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Department of Chemistry, Institute of Microanalytical Systems, , Zhejiang University, ; Zhejiang, Hangzhou, 310058 China
                [8 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Department of Medicine, Haematology Research Centre, Division of Experimental Medicine, , Imperial College London, ; London, UK
                [9 ]Alliance for Atlas of Blood Cells, Hangzhou, China
                [10 ]Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang, Hangzhou, 310058 China
                Article
                Publisher ID: 59
                DOI: 10.1038/s41421-018-0059-5
                PMC ID: 6206058
                SO-VID: 80832ff2-287d-4f60-9f7c-a05e3b0169fe
                Copyright © © The Author(s) 2018
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 14 March 2018
                Date revision received : 10 July 2018
                Date accepted : 20 August 2018
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 81770188
                Award Recipient :
                Funded by: Fundamental Research Funds for the Central Universities (2016XZZX002-04), Zhejiang Provincial Natural Science Foundation of China (R17H080001), National Key Program on Stem Cell and Translational Research (2017YFA0103401) and 973 Program (2015CB964900).
                Categories
                Subject: Article
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                issue-copyright-statement © The Author(s) 2018

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