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Review Article

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Blood Res 2015; 50(4):

Published online December 31, 2015

https://doi.org/10.5045/br.2015.50.4.194

© The Korean Society of Hematology

Hematopoietic stem cell expansion and generation: the ways to make a breakthrough

Bokyung Park1, Keon Hee Yoo2,3*, and Changsung Kim1*

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1Department of Bioscience and Biotechnology, Sejong University, Korea.

2Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Korea.

3Department of Medical Device Management and Research, SAIHST, Sungkyunkwan University, Seoul, Korea.

Correspondence to : Correspondence to Changsung Kim, Ph.D. Department of Bioscience and Biotechnology, Sejong University, 209 Neungdong-ro, Gwangjin-gu, Seoul 05006, Korea. Tel: +82-2-3408-4485, changkim@sejong.ac.kr

Received: November 30, 2015; Revised: December 11, 2015; Accepted: December 16, 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Hematopoietic stem cell transplantation (HSCT) is the first field where human stem cell therapy was successful. Flooding interest on human stem cell therapy to cure previously incurable diseases is largely indebted to HSCT success. Allogeneic HSCT has been an important modality to cure various diseases including hematologic malignancies, various non-malignant hematologic diseases, primary immunodeficiency diseases, and inborn errors of metabolism, while autologous HSCT is generally performed to rescue bone marrow aplasia following high-dose chemotherapy for solid tumors or multiple myeloma. Recently, HSCs are also spotlighted in the field of regenerative medicine for the amelioration of symptoms caused by neurodegenerative diseases, heart diseases, and others. Although the demand for HSCs has been growing, their supply often fails to meet the demand of the patients needing transplant due to a lack of histocompatible donors or a limited cell number. This review focuses on the generation and large-scale expansion of HSCs, which might overcome current limitations in the application of HSCs for clinical use. Furthermore, current proof of concept to replenish hematological homeostasis from non-hematological origin will be covered.

Keywords HSCT, Stem cell, HLA, Blood generation, HSC expansion

Article

Review Article

Blood Res 2015; 50(4): 194-203

Published online December 31, 2015 https://doi.org/10.5045/br.2015.50.4.194

Copyright © The Korean Society of Hematology.

Hematopoietic stem cell expansion and generation: the ways to make a breakthrough

Bokyung Park1, Keon Hee Yoo2,3*, and Changsung Kim1*

1Department of Bioscience and Biotechnology, Sejong University, Korea.

2Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Korea.

3Department of Medical Device Management and Research, SAIHST, Sungkyunkwan University, Seoul, Korea.

Correspondence to: Correspondence to Changsung Kim, Ph.D. Department of Bioscience and Biotechnology, Sejong University, 209 Neungdong-ro, Gwangjin-gu, Seoul 05006, Korea. Tel: +82-2-3408-4485, changkim@sejong.ac.kr

Received: November 30, 2015; Revised: December 11, 2015; Accepted: December 16, 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Hematopoietic stem cell transplantation (HSCT) is the first field where human stem cell therapy was successful. Flooding interest on human stem cell therapy to cure previously incurable diseases is largely indebted to HSCT success. Allogeneic HSCT has been an important modality to cure various diseases including hematologic malignancies, various non-malignant hematologic diseases, primary immunodeficiency diseases, and inborn errors of metabolism, while autologous HSCT is generally performed to rescue bone marrow aplasia following high-dose chemotherapy for solid tumors or multiple myeloma. Recently, HSCs are also spotlighted in the field of regenerative medicine for the amelioration of symptoms caused by neurodegenerative diseases, heart diseases, and others. Although the demand for HSCs has been growing, their supply often fails to meet the demand of the patients needing transplant due to a lack of histocompatible donors or a limited cell number. This review focuses on the generation and large-scale expansion of HSCs, which might overcome current limitations in the application of HSCs for clinical use. Furthermore, current proof of concept to replenish hematological homeostasis from non-hematological origin will be covered.

Keywords: HSCT, Stem cell, HLA, Blood generation, HSC expansion

Fig 1.

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Figure 1.

HSC proliferation and engraftment ability enhanced by stem cell niche replacing components. Current usage of SR1 and Notch ligand supplemented HSC ex vivo expansion could benefit the HSC engraftment ability and epigenetic regulation.

Blood Research 2015; 50: 194-203https://doi.org/10.5045/br.2015.50.4.194

Fig 2.

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Figure 2.

Schematic view of HSC expansion, non-hematological origin HSC generation, and application. Considering the current shortage of HLA-matched HSCs for patients who need allogeneic HSCT, ex vivo expanded and HLA-matched iPSC-derived HSCs could be the next generation solution. Humanized large animals could be used for the blood product generation applicable to human and for the long-term engraftment studies, because they mimic human immune complexity and might replace the artificial large scale HSC expansion.

Blood Research 2015; 50: 194-203https://doi.org/10.5045/br.2015.50.4.194
Representative clinical trials with <italic>ex vivo</italic> expanded CB-HSCs.

Abbreviations: TEPA, tertraethylenepentamine; TNC, Total nucleated cells; ALL, Acute lymphoblastic leukemia; AML, acute myeloid leukemia; SCF, stem cell factor; Flt-3L, Fms-related tyrosine kinase 3 ligand; TPO, thrombopoietin; MSC, mesenchymal stromal cell; G-CSF, granulocyte-colony stimulating factor; SR1, stemregenin-1; NA, Not applicable..
HSC and blood generation from non-hematological cells.

Abbreviations: hESC, human embryonic stem cell; iPSC, induced pluripotent stem cell; hiPSC, human iPSC; BMP-4, bone morphogenetic protein 4; PGE2, prostaglandin E2; bFGF, Basic fibroblast growth factor; VEGF, Vascular endothelial growth factor; SCF, stem cell factor; Flt3L, Fms-related tyrosine kinase 3 ligand; TPO, thrombopoietin; IGF-1, insulin-like growth factor; EC, endothelial cell; EB, Embryoid body; HOXA9, Homeobox protein-A9; ERG, erythroblast transformation-specific (ETS)-related gene; RORA, retinoic acid receptor (RAR)-related orphan receptor A; SOX4, sex-determining region Y (SRY)-related high mobility group box 4; MYB, myeloblastosis proto-oncogene protein; RUNX1, Runt-related transcription factor 1; FOSB, Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog B; GFI1, Growth factor independent 1 transcription repressor; HLF, Hepatic leukemia factor; PBX1, Pre-B-cell leukemia homeobox 1; LMO2, LIM domain only 2; PRDM5, PR Domain Containing zinc finger protein 5; ZFP37, Zinc Finger Protein 37; GATA2, GATA binding protein 2; SCL, stem cell leukemia gene product; MK, megakaryocyte; BMI1, B lymphoma Mo-MLV insertion region 1 homolog; EPO, erythropoietin; hHFMSC, human hair follicle mesenchymal stem cell; Oct-4, octamer-binding transcription factor 4..
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