Ectopic miR-125a Expression Induces Long-Term Repopulating Stem Cell Capacity in Mouse and Human Hematopoietic Progenitors
Umbilical cord blood (CB) is a convenient and broadly used source of hematopoietic stem cells (HSCs) for allogeneic stem cell transplantation. However, limiting numbers of HSCs remain a major constraint for its clinical application. Although one feasible option would be to expand HSCs to improve the...
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| Vydáno v: | Cell stem cell Ročník 19; číslo 3; s. 383 |
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| Hlavní autoři: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
01.09.2016
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| ISSN: | 1875-9777, 1875-9777 |
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| Abstract | Umbilical cord blood (CB) is a convenient and broadly used source of hematopoietic stem cells (HSCs) for allogeneic stem cell transplantation. However, limiting numbers of HSCs remain a major constraint for its clinical application. Although one feasible option would be to expand HSCs to improve therapeutic outcome, available protocols and the molecular mechanisms governing the self-renewal of HSCs are unclear. Here, we show that ectopic expression of a single microRNA (miRNA), miR-125a, in purified murine and human multipotent progenitors (MPPs) resulted in increased self-renewal and robust long-term multi-lineage repopulation in transplanted recipient mice. Using quantitative proteomics and western blot analysis, we identified a restricted set of miR-125a targets involved in conferring long-term repopulating capacity to MPPs in humans and mice. Our findings offer the innovative potential to use MPPs with enhanced self-renewal activity to augment limited sources of HSCs to improve clinical protocols. |
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| AbstractList | Umbilical cord blood (CB) is a convenient and broadly used source of hematopoietic stem cells (HSCs) for allogeneic stem cell transplantation. However, limiting numbers of HSCs remain a major constraint for its clinical application. Although one feasible option would be to expand HSCs to improve therapeutic outcome, available protocols and the molecular mechanisms governing the self-renewal of HSCs are unclear. Here, we show that ectopic expression of a single microRNA (miRNA), miR-125a, in purified murine and human multipotent progenitors (MPPs) resulted in increased self-renewal and robust long-term multi-lineage repopulation in transplanted recipient mice. Using quantitative proteomics and western blot analysis, we identified a restricted set of miR-125a targets involved in conferring long-term repopulating capacity to MPPs in humans and mice. Our findings offer the innovative potential to use MPPs with enhanced self-renewal activity to augment limited sources of HSCs to improve clinical protocols. Umbilical cord blood (CB) is a convenient and broadly used source of hematopoietic stem cells (HSCs) for allogeneic stem cell transplantation. However, limiting numbers of HSCs remain a major constraint for its clinical application. Although one feasible option would be to expand HSCs to improve therapeutic outcome, available protocols and the molecular mechanisms governing the self-renewal of HSCs are unclear. Here, we show that ectopic expression of a single microRNA (miRNA), miR-125a, in purified murine and human multipotent progenitors (MPPs) resulted in increased self-renewal and robust long-term multi-lineage repopulation in transplanted recipient mice. Using quantitative proteomics and western blot analysis, we identified a restricted set of miR-125a targets involved in conferring long-term repopulating capacity to MPPs in humans and mice. Our findings offer the innovative potential to use MPPs with enhanced self-renewal activity to augment limited sources of HSCs to improve clinical protocols.Umbilical cord blood (CB) is a convenient and broadly used source of hematopoietic stem cells (HSCs) for allogeneic stem cell transplantation. However, limiting numbers of HSCs remain a major constraint for its clinical application. Although one feasible option would be to expand HSCs to improve therapeutic outcome, available protocols and the molecular mechanisms governing the self-renewal of HSCs are unclear. Here, we show that ectopic expression of a single microRNA (miRNA), miR-125a, in purified murine and human multipotent progenitors (MPPs) resulted in increased self-renewal and robust long-term multi-lineage repopulation in transplanted recipient mice. Using quantitative proteomics and western blot analysis, we identified a restricted set of miR-125a targets involved in conferring long-term repopulating capacity to MPPs in humans and mice. Our findings offer the innovative potential to use MPPs with enhanced self-renewal activity to augment limited sources of HSCs to improve clinical protocols. |
| Author | Ritsema, Martha Bystrykh, Leonid V de Haan, Gerald Broekhuis, Mathilde J C Schoof, Erwin M Elzinga, Jantje Ignatchenko, Vladimir Wienholds, Erno Dethmers-Ausema, Bertien Hermans, Karin G Krivdova, Gabriela Dick, John E Trotman-Grant, Aaron Bader, Gary D Wojtowicz, Edyta E Kennedy, James Sinha, Ankit Alemdehy, Mir Farshid Lechman, Eric R van Veelen, Peter A de Looper, Hans W J Janssen, George M C Kislinger, Thomas Weersing, Ellen Erkeland, Stefan J Isserlin, Ruth Dobson, Stephanie M Gan, Olga I |
| Author_xml | – sequence: 1 givenname: Edyta E surname: Wojtowicz fullname: Wojtowicz, Edyta E organization: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan 1, 9700 AV Groningen, the Netherlands – sequence: 2 givenname: Eric R surname: Lechman fullname: Lechman, Eric R organization: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada – sequence: 3 givenname: Karin G surname: Hermans fullname: Hermans, Karin G organization: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada – sequence: 4 givenname: Erwin M surname: Schoof fullname: Schoof, Erwin M organization: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada – sequence: 5 givenname: Erno surname: Wienholds fullname: Wienholds, Erno organization: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada – sequence: 6 givenname: Ruth surname: Isserlin fullname: Isserlin, Ruth organization: The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada – sequence: 7 givenname: Peter A surname: van Veelen fullname: van Veelen, Peter A organization: Departments of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands – sequence: 8 givenname: Mathilde J C surname: Broekhuis fullname: Broekhuis, Mathilde J C organization: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan 1, 9700 AV Groningen, the Netherlands – sequence: 9 givenname: George M C surname: Janssen fullname: Janssen, George M C organization: Departments of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands – sequence: 10 givenname: Aaron surname: Trotman-Grant fullname: Trotman-Grant, Aaron organization: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada – sequence: 11 givenname: Stephanie M surname: Dobson fullname: Dobson, Stephanie M organization: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada – sequence: 12 givenname: Gabriela surname: Krivdova fullname: Krivdova, Gabriela organization: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada – sequence: 13 givenname: Jantje surname: Elzinga fullname: Elzinga, Jantje organization: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada – sequence: 14 givenname: James surname: Kennedy fullname: Kennedy, James organization: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada – sequence: 15 givenname: Olga I surname: Gan fullname: Gan, Olga I organization: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada – sequence: 16 givenname: Ankit surname: Sinha fullname: Sinha, Ankit organization: Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada – sequence: 17 givenname: Vladimir surname: Ignatchenko fullname: Ignatchenko, Vladimir organization: Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada – sequence: 18 givenname: Thomas surname: Kislinger fullname: Kislinger, Thomas organization: Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada – sequence: 19 givenname: Bertien surname: Dethmers-Ausema fullname: Dethmers-Ausema, Bertien organization: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan 1, 9700 AV Groningen, the Netherlands – sequence: 20 givenname: Ellen surname: Weersing fullname: Weersing, Ellen organization: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan 1, 9700 AV Groningen, the Netherlands – sequence: 21 givenname: Mir Farshid surname: Alemdehy fullname: Alemdehy, Mir Farshid organization: Department of Hematology, Erasmus University Medical Center Cancer Institute, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands – sequence: 22 givenname: Hans W J surname: de Looper fullname: de Looper, Hans W J organization: Department of Hematology, Erasmus University Medical Center Cancer Institute, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands – sequence: 23 givenname: Gary D surname: Bader fullname: Bader, Gary D organization: The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada – sequence: 24 givenname: Martha surname: Ritsema fullname: Ritsema, Martha organization: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan 1, 9700 AV Groningen, the Netherlands – sequence: 25 givenname: Stefan J surname: Erkeland fullname: Erkeland, Stefan J organization: Department of Immunology, Erasmus University Medical Center, Wytemaweg 80, 3015CN Rotterdam, the Netherlands – sequence: 26 givenname: Leonid V surname: Bystrykh fullname: Bystrykh, Leonid V organization: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan 1, 9700 AV Groningen, the Netherlands – sequence: 27 givenname: John E surname: Dick fullname: Dick, John E email: jdick@uhnres.utoronto.ca organization: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: jdick@uhnres.utoronto.ca – sequence: 28 givenname: Gerald surname: de Haan fullname: de Haan, Gerald email: g.de.haan@umcg.nl organization: Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan 1, 9700 AV Groningen, the Netherlands. Electronic address: g.de.haan@umcg.nl |
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| SubjectTerms | ADP-ribosyl Cyclase 1 - metabolism Animals Antigens, CD34 - metabolism Cell Proliferation Cell Self Renewal - genetics Gene Expression Regulation Gene Regulatory Networks Hematopoietic Stem Cell Transplantation Hematopoietic Stem Cells - cytology Hematopoietic Stem Cells - metabolism Humans Isotope Labeling Male Mice, Inbred C57BL MicroRNAs - genetics MicroRNAs - metabolism Models, Biological Multipotent Stem Cells - cytology Multipotent Stem Cells - metabolism Multipotent Stem Cells - transplantation Reproducibility of Results Time Factors |
| Title | Ectopic miR-125a Expression Induces Long-Term Repopulating Stem Cell Capacity in Mouse and Human Hematopoietic Progenitors |
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