The BET inhibitor CPI203 promotes ex vivo expansion of cord blood long-term repopulating HSCs and megakaryocytes
Although cytokine-mediated expansion of human hematopoietic stem cells (HSCs) can result in high yields of hematopoietic progenitor cells, this generally occurs at the expense of reduced bone marrow HSC repopulating ability thereby limiting potential therapeutic applications. As Bromodomain-containi...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Society of Hematology
2020
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| _version_ | 1797086191172976640 |
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| author | Hua, P Hester, J Adigbli, G Li, R Psaila, B Roy, A Bataille, CJR Wayne, GM Jackson, T Milne, TA Russell, AJ Davies, J Roberts, I Issa, F Watt, SM |
| author_facet | Hua, P Hester, J Adigbli, G Li, R Psaila, B Roy, A Bataille, CJR Wayne, GM Jackson, T Milne, TA Russell, AJ Davies, J Roberts, I Issa, F Watt, SM |
| author_sort | Hua, P |
| collection | OXFORD |
| description | Although cytokine-mediated expansion of human hematopoietic stem cells (HSCs) can result in high yields of hematopoietic progenitor cells, this generally occurs at the expense of reduced bone marrow HSC repopulating ability thereby limiting potential therapeutic applications. As Bromodomain-containing proteins (BCPs) have been demonstrated to regulate mouse HSC self-renewal and stemness, we screened small molecules targeting various BCPs as potential agents for ex vivo expansion of human HSCs. Of 10 compounds tested, only the Bromodomain and Extra-terminal Motif (BET) inhibitor CPI203 enhanced the expansion of human cord blood HSCs without losing cell viability in vitro. The expanded cells also demonstrated improved engraftment and repopulation in serial transplantation assays. Transcriptomic and functional studies showed that the expansion of long-term repopulating HSCs was accompanied by synchronized expansion and maturation of megakaryocytes consistent with CPI203-mediated reprogramming of cord blood hematopoietic stem and progenitor cells (HSPCs). This approach may therefore prove beneficial for ex vivo gene editing, for enhanced platelet production, and for the improved usage of cord blood for transplantation research and therapy. |
| first_indexed | 2024-03-07T02:18:34Z |
| format | Journal article |
| id | oxford-uuid:a31bd8ec-46c2-4e4a-bd45-779f8ec913e9 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:18:34Z |
| publishDate | 2020 |
| publisher | American Society of Hematology |
| record_format | dspace |
| spelling | oxford-uuid:a31bd8ec-46c2-4e4a-bd45-779f8ec913e92022-03-27T02:24:42ZThe BET inhibitor CPI203 promotes ex vivo expansion of cord blood long-term repopulating HSCs and megakaryocytesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a31bd8ec-46c2-4e4a-bd45-779f8ec913e9EnglishSymplectic ElementsAmerican Society of Hematology2020Hua, PHester, JAdigbli, GLi, RPsaila, BRoy, ABataille, CJRWayne, GMJackson, TMilne, TARussell, AJDavies, JRoberts, IIssa, FWatt, SMAlthough cytokine-mediated expansion of human hematopoietic stem cells (HSCs) can result in high yields of hematopoietic progenitor cells, this generally occurs at the expense of reduced bone marrow HSC repopulating ability thereby limiting potential therapeutic applications. As Bromodomain-containing proteins (BCPs) have been demonstrated to regulate mouse HSC self-renewal and stemness, we screened small molecules targeting various BCPs as potential agents for ex vivo expansion of human HSCs. Of 10 compounds tested, only the Bromodomain and Extra-terminal Motif (BET) inhibitor CPI203 enhanced the expansion of human cord blood HSCs without losing cell viability in vitro. The expanded cells also demonstrated improved engraftment and repopulation in serial transplantation assays. Transcriptomic and functional studies showed that the expansion of long-term repopulating HSCs was accompanied by synchronized expansion and maturation of megakaryocytes consistent with CPI203-mediated reprogramming of cord blood hematopoietic stem and progenitor cells (HSPCs). This approach may therefore prove beneficial for ex vivo gene editing, for enhanced platelet production, and for the improved usage of cord blood for transplantation research and therapy. |
| spellingShingle | Hua, P Hester, J Adigbli, G Li, R Psaila, B Roy, A Bataille, CJR Wayne, GM Jackson, T Milne, TA Russell, AJ Davies, J Roberts, I Issa, F Watt, SM The BET inhibitor CPI203 promotes ex vivo expansion of cord blood long-term repopulating HSCs and megakaryocytes |
| title | The BET inhibitor CPI203 promotes ex vivo expansion of cord blood long-term repopulating HSCs and megakaryocytes |
| title_full | The BET inhibitor CPI203 promotes ex vivo expansion of cord blood long-term repopulating HSCs and megakaryocytes |
| title_fullStr | The BET inhibitor CPI203 promotes ex vivo expansion of cord blood long-term repopulating HSCs and megakaryocytes |
| title_full_unstemmed | The BET inhibitor CPI203 promotes ex vivo expansion of cord blood long-term repopulating HSCs and megakaryocytes |
| title_short | The BET inhibitor CPI203 promotes ex vivo expansion of cord blood long-term repopulating HSCs and megakaryocytes |
| title_sort | bet inhibitor cpi203 promotes ex vivo expansion of cord blood long term repopulating hscs and megakaryocytes |
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