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A novel small molecule CXCR4 antagonist potently mobilizes hematopoietic stem cells in mice and monkeys
BACKGROUND: Hematopoietic stem cell (HSC) transplantation is an effective treatment strategy for many types of diseases. Peripheral blood (PB) is the most commonly used source of bone marrow (BM)-derived stem cells for current HSC transplantation. However, PB usually contains very few HSCs under nor...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791974/ https://www.ncbi.nlm.nih.gov/pubmed/33413613 http://dx.doi.org/10.1186/s13287-020-02073-z |
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author | Fang, Xiao Fang, Xiong Mao, Yujia Ciechanover, Aaron Xu, Yan An, Jing Huang, Ziwei |
author_facet | Fang, Xiao Fang, Xiong Mao, Yujia Ciechanover, Aaron Xu, Yan An, Jing Huang, Ziwei |
author_sort | Fang, Xiao |
collection | PubMed |
description | BACKGROUND: Hematopoietic stem cell (HSC) transplantation is an effective treatment strategy for many types of diseases. Peripheral blood (PB) is the most commonly used source of bone marrow (BM)-derived stem cells for current HSC transplantation. However, PB usually contains very few HSCs under normal conditions, as these cells are normally retained within the BM. This retention depends on the interaction between the CXC chemokine receptor 4 (CXCR4) expressed on the HSCs and its natural chemokine ligand, stromal cell-derived factor (SDF)-1α (also named CXCL12) present in the BM stromal microenvironment. In clinical practice, blocking this interaction with a CXCR4 antagonist can induce the rapid mobilization of HSCs from the BM into the PB. METHODS: C3H/HEJ, DBA/2, CD45.1(+), and CD45.2(+) mice and monkeys were employed in colony-forming unit (CFU) assays, flow cytometry assays, and competitive/noncompetitive transplantation assays, to assess the short-term mobilization efficacy of HF51116 and the long-term repopulating (LTR) ability of HSCs. Kinetics of different blood cells and the concentration of HF51116 in PB were also explored by blood routine examinations and pharmacokinetic assays. RESULTS: In this paper, we report that a novel small molecule CXCR4 antagonist, HF51116, which was designed and synthesized by our laboratory, can rapidly and potently mobilize HSCs from BM to PB in mice and monkeys. HF51116 not only mobilized HSCs when used alone but also synergized with the mobilizing effects of granulocyte colony-stimulating factor (G-CSF) after co-administration. Following mobilization by HF51116 and G-CSF, the long-term repopulating (LTR) and self-renewing HSCs were sufficiently engrafted in primary and secondary lethally irradiated mice and were able to rescue and support long-term mouse survival. In monkeys, HF51116 exhibited strong HSC mobilization activity and quickly reached the highest in vivo blood drug concentration. CONCLUSIONS: These results demonstrate that HF51116 is a new promising stem cell mobilizer which specifically targets CXCR4 and merits further preclinical and clinical studies. |
format | Online Article Text |
id | pubmed-7791974 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-77919742021-01-11 A novel small molecule CXCR4 antagonist potently mobilizes hematopoietic stem cells in mice and monkeys Fang, Xiao Fang, Xiong Mao, Yujia Ciechanover, Aaron Xu, Yan An, Jing Huang, Ziwei Stem Cell Res Ther Research BACKGROUND: Hematopoietic stem cell (HSC) transplantation is an effective treatment strategy for many types of diseases. Peripheral blood (PB) is the most commonly used source of bone marrow (BM)-derived stem cells for current HSC transplantation. However, PB usually contains very few HSCs under normal conditions, as these cells are normally retained within the BM. This retention depends on the interaction between the CXC chemokine receptor 4 (CXCR4) expressed on the HSCs and its natural chemokine ligand, stromal cell-derived factor (SDF)-1α (also named CXCL12) present in the BM stromal microenvironment. In clinical practice, blocking this interaction with a CXCR4 antagonist can induce the rapid mobilization of HSCs from the BM into the PB. METHODS: C3H/HEJ, DBA/2, CD45.1(+), and CD45.2(+) mice and monkeys were employed in colony-forming unit (CFU) assays, flow cytometry assays, and competitive/noncompetitive transplantation assays, to assess the short-term mobilization efficacy of HF51116 and the long-term repopulating (LTR) ability of HSCs. Kinetics of different blood cells and the concentration of HF51116 in PB were also explored by blood routine examinations and pharmacokinetic assays. RESULTS: In this paper, we report that a novel small molecule CXCR4 antagonist, HF51116, which was designed and synthesized by our laboratory, can rapidly and potently mobilize HSCs from BM to PB in mice and monkeys. HF51116 not only mobilized HSCs when used alone but also synergized with the mobilizing effects of granulocyte colony-stimulating factor (G-CSF) after co-administration. Following mobilization by HF51116 and G-CSF, the long-term repopulating (LTR) and self-renewing HSCs were sufficiently engrafted in primary and secondary lethally irradiated mice and were able to rescue and support long-term mouse survival. In monkeys, HF51116 exhibited strong HSC mobilization activity and quickly reached the highest in vivo blood drug concentration. CONCLUSIONS: These results demonstrate that HF51116 is a new promising stem cell mobilizer which specifically targets CXCR4 and merits further preclinical and clinical studies. BioMed Central 2021-01-07 /pmc/articles/PMC7791974/ /pubmed/33413613 http://dx.doi.org/10.1186/s13287-020-02073-z Text en © The Author(s) 2021 Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Fang, Xiao Fang, Xiong Mao, Yujia Ciechanover, Aaron Xu, Yan An, Jing Huang, Ziwei A novel small molecule CXCR4 antagonist potently mobilizes hematopoietic stem cells in mice and monkeys |
title | A novel small molecule CXCR4 antagonist potently mobilizes hematopoietic stem cells in mice and monkeys |
title_full | A novel small molecule CXCR4 antagonist potently mobilizes hematopoietic stem cells in mice and monkeys |
title_fullStr | A novel small molecule CXCR4 antagonist potently mobilizes hematopoietic stem cells in mice and monkeys |
title_full_unstemmed | A novel small molecule CXCR4 antagonist potently mobilizes hematopoietic stem cells in mice and monkeys |
title_short | A novel small molecule CXCR4 antagonist potently mobilizes hematopoietic stem cells in mice and monkeys |
title_sort | novel small molecule cxcr4 antagonist potently mobilizes hematopoietic stem cells in mice and monkeys |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791974/ https://www.ncbi.nlm.nih.gov/pubmed/33413613 http://dx.doi.org/10.1186/s13287-020-02073-z |
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