SHIPi Enhances Autologous and Allogeneic Hematopoietic Stem Cell Transplantation
Hematopoietic stem cell transplantation (HSCT) is a highly effective procedure enabling long-term survival for patients with hematologic malignancy or heritable defects. Although there has been a dramatic increase in the success rate of HSCT over the last two decades, HSCT can result in serious, som...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2015-03-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S235239641500047X |
| _version_ | 1818292057772392448 |
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| author | Sandra Fernandes Robert Brooks Matthew Gumbleton Mi-Young Park Christopher M. Russo Kyle T. Howard John D. Chisholm William G. Kerr |
| author_facet | Sandra Fernandes Robert Brooks Matthew Gumbleton Mi-Young Park Christopher M. Russo Kyle T. Howard John D. Chisholm William G. Kerr |
| author_sort | Sandra Fernandes |
| collection | DOAJ |
| description | Hematopoietic stem cell transplantation (HSCT) is a highly effective procedure enabling long-term survival for patients with hematologic malignancy or heritable defects. Although there has been a dramatic increase in the success rate of HSCT over the last two decades, HSCT can result in serious, sometimes untreatable disease due to toxic conditioning regimens and Graft-versus-Host-Disease. Studies utilizing germline knockout mice have discovered several candidate genes that could be targeted pharmacologically to create a more favorable environment for transplant success. SHIP1 deficiency permits improved engraftment of hematopoietic stem-progenitor cells (HS-PCs) and produces an immunosuppressive microenvironment ideal for incoming allogeneic grafts. The recent development of small molecule SHIP1 inhibitors has opened a different therapeutic approach by creating transient SHIP1-deficiency. Here we show that SHIP1 inhibition (SHIPi) mobilizes functional HS-PC, accelerates hematologic recovery, and enhances donor HS-PC engraftment in both allogeneic and autologous transplant settings. We also observed the expansion of key cell populations known to suppress host-reactive cells formed during engraftment. Therefore, SHIPi represents a non-toxic, new therapeutic that has significant potential to improve the success and safety of therapies that utilize autologous and allogeneic HSCT. |
| first_indexed | 2024-12-13T02:53:55Z |
| format | Article |
| id | doaj.art-803f7a54adcc4a47933a44e24a5b299d |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-13T02:53:55Z |
| publishDate | 2015-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-803f7a54adcc4a47933a44e24a5b299d2022-12-22T00:01:59ZengElsevierEBioMedicine2352-39642015-03-012320521310.1016/j.ebiom.2015.02.004SHIPi Enhances Autologous and Allogeneic Hematopoietic Stem Cell TransplantationSandra Fernandes0Robert Brooks1Matthew Gumbleton2Mi-Young Park3Christopher M. Russo4Kyle T. Howard5John D. Chisholm6William G. Kerr7Dept. of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USADept. of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USADept. of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USADept. of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USADept. of Chemistry, Syracuse University, Syracuse, NY 13210, USADept. of Chemistry, Syracuse University, Syracuse, NY 13210, USADept. of Chemistry, Syracuse University, Syracuse, NY 13210, USADept. of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USAHematopoietic stem cell transplantation (HSCT) is a highly effective procedure enabling long-term survival for patients with hematologic malignancy or heritable defects. Although there has been a dramatic increase in the success rate of HSCT over the last two decades, HSCT can result in serious, sometimes untreatable disease due to toxic conditioning regimens and Graft-versus-Host-Disease. Studies utilizing germline knockout mice have discovered several candidate genes that could be targeted pharmacologically to create a more favorable environment for transplant success. SHIP1 deficiency permits improved engraftment of hematopoietic stem-progenitor cells (HS-PCs) and produces an immunosuppressive microenvironment ideal for incoming allogeneic grafts. The recent development of small molecule SHIP1 inhibitors has opened a different therapeutic approach by creating transient SHIP1-deficiency. Here we show that SHIP1 inhibition (SHIPi) mobilizes functional HS-PC, accelerates hematologic recovery, and enhances donor HS-PC engraftment in both allogeneic and autologous transplant settings. We also observed the expansion of key cell populations known to suppress host-reactive cells formed during engraftment. Therefore, SHIPi represents a non-toxic, new therapeutic that has significant potential to improve the success and safety of therapies that utilize autologous and allogeneic HSCT.http://www.sciencedirect.com/science/article/pii/S235239641500047XSHIP13ACAllogeneic BMTAutologous BMTStem cell mobilizationSDF-1MMP-9NK cellsSHIPi |
| spellingShingle | Sandra Fernandes Robert Brooks Matthew Gumbleton Mi-Young Park Christopher M. Russo Kyle T. Howard John D. Chisholm William G. Kerr SHIPi Enhances Autologous and Allogeneic Hematopoietic Stem Cell Transplantation EBioMedicine SHIP1 3AC Allogeneic BMT Autologous BMT Stem cell mobilization SDF-1 MMP-9 NK cells SHIPi |
| title | SHIPi Enhances Autologous and Allogeneic Hematopoietic Stem Cell Transplantation |
| title_full | SHIPi Enhances Autologous and Allogeneic Hematopoietic Stem Cell Transplantation |
| title_fullStr | SHIPi Enhances Autologous and Allogeneic Hematopoietic Stem Cell Transplantation |
| title_full_unstemmed | SHIPi Enhances Autologous and Allogeneic Hematopoietic Stem Cell Transplantation |
| title_short | SHIPi Enhances Autologous and Allogeneic Hematopoietic Stem Cell Transplantation |
| title_sort | shipi enhances autologous and allogeneic hematopoietic stem cell transplantation |
| topic | SHIP1 3AC Allogeneic BMT Autologous BMT Stem cell mobilization SDF-1 MMP-9 NK cells SHIPi |
| url | http://www.sciencedirect.com/science/article/pii/S235239641500047X |
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