Ectopic miR-125a Expression Induces Long-Term Repopulating Stem Cell Capacity in Mouse and Human Hematopoietic Progenitors

Edyta E. Wojtowicz; Eric R. Lechman; Karin G. Hermans; Erwin M. Schoof; Erno Wienholds; Ruth Isserlin; Peter A. van Veelen; Mathilde J. C. Broekhuis; George M. C. Janssen; Aaron Trotman-Grant; Stephanie M. Dobson; Gabriela Krivdova; Jantje Elzinga; James Kennedy; Olga I. Gan; Ankit Sinha; Vladimir Ignatchenko; Thomas Kislinger; Bertien Dethmers-Ausema; Ellen Weersing; Mir Farshid Alemdehy; Hans W. J. de Looper; Gary D. Bader; Martha Ritsema; Stefan J. Erkeland; Leonid V. Bystrykh; John E. Dick; Gerald de Haan

doi:10.1016/j.stem.2016.06.008

Ectopic miR-125a Expression Induces Long-Term Repopulating Stem Cell Capacity in Mouse and Human Hematopoietic Progenitors

Edyta E. Wojtowicz, Eric R. Lechman, Karin G. Hermans, Erwin M. Schoof, Erno Wienholds, Ruth Isserlin, Peter A. van Veelen, Mathilde J. C. Broekhuis, George M. C. Janssen, Aaron Trotman-Grant, Stephanie M. Dobson, Gabriela Krivdova, Jantje Elzinga, James Kennedy, Olga I. Gan, Ankit Sinha, Vladimir Ignatchenko, Thomas Kislinger, Bertien Dethmers-Ausema, Ellen WeersingMir Farshid Alemdehy, Hans W. J. de Looper, Gary D. Bader, Martha Ritsema, Stefan J. Erkeland, Leonid V. Bystrykh, John E. Dick, Gerald de Haan

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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 selfrenewal 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.

Original language	English
Pages (from-to)	383-396
Number of pages	14
Journal	Cell stem cell
Volume	19
Issue number	3
DOIs	https://doi.org/10.1016/j.stem.2016.06.008
Publication status	Published - 1-Sept-2016

Keywords

UMBILICAL-CORD BLOOD
TYROSINE-PHOSPHATASE 1B
LIFE-SPAN
IN-VIVO
EXPANSION
TRANSPLANTATION
MICRORNAS
RECEPTOR
DIFFERENTIATION
PROLIFERATION

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10.1016/j.stem.2016.06.008

Ectopic miR-125a Expression Induces Long-Term Repopulating Stem Cell CapacityFinal publisher's version, 4.14 MBLicence: Elsevier

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Wojtowicz, E. E., Lechman, E. R., Hermans, K. G., Schoof, E. M., Wienholds, E., Isserlin, R., van Veelen, P. A., Broekhuis, M. J. C., Janssen, G. M. C., Trotman-Grant, A., Dobson, S. M., Krivdova, G., Elzinga, J., Kennedy, J., Gan, O. I., Sinha, A., Ignatchenko, V., Kislinger, T., Dethmers-Ausema, B., ... de Haan, G. (2016). Ectopic miR-125a Expression Induces Long-Term Repopulating Stem Cell Capacity in Mouse and Human Hematopoietic Progenitors. Cell stem cell, 19(3), 383-396. https://doi.org/10.1016/j.stem.2016.06.008

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title = "Ectopic miR-125a Expression Induces Long-Term Repopulating Stem Cell Capacity in Mouse and Human Hematopoietic Progenitors",

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 selfrenewal 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.",

keywords = "UMBILICAL-CORD BLOOD, TYROSINE-PHOSPHATASE 1B, LIFE-SPAN, IN-VIVO, EXPANSION, TRANSPLANTATION, MICRORNAS, RECEPTOR, DIFFERENTIATION, PROLIFERATION",

author = "Wojtowicz, {Edyta E.} and Lechman, {Eric R.} and Hermans, {Karin G.} and Schoof, {Erwin M.} and Erno Wienholds and Ruth Isserlin and {van Veelen}, {Peter A.} and Broekhuis, {Mathilde J. C.} and Janssen, {George M. C.} and Aaron Trotman-Grant and Dobson, {Stephanie M.} and Gabriela Krivdova and Jantje Elzinga and James Kennedy and Gan, {Olga I.} and Ankit Sinha and Vladimir Ignatchenko and Thomas Kislinger and Bertien Dethmers-Ausema and Ellen Weersing and Alemdehy, {Mir Farshid} and {de Looper}, {Hans W. J.} and Bader, {Gary D.} and Martha Ritsema and Erkeland, {Stefan J.} and Bystrykh, {Leonid V.} and Dick, {John E.} and {de Haan}, Gerald",

year = "2016",

month = sep,

day = "1",

doi = "10.1016/j.stem.2016.06.008",

language = "English",

volume = "19",

pages = "383--396",

journal = "Cell stem cell",

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Wojtowicz, EE, Lechman, ER, Hermans, KG, Schoof, EM, Wienholds, E, Isserlin, R, van Veelen, PA, Broekhuis, MJC, Janssen, GMC, Trotman-Grant, A, Dobson, SM, Krivdova, G, Elzinga, J, Kennedy, J, Gan, OI, Sinha, A, Ignatchenko, V, Kislinger, T, Dethmers-Ausema, B , Weersing, E, Alemdehy, MF, de Looper, HWJ, Bader, GD, Ritsema, M, Erkeland, SJ, Bystrykh, LV, Dick, JE & de Haan, G 2016, 'Ectopic miR-125a Expression Induces Long-Term Repopulating Stem Cell Capacity in Mouse and Human Hematopoietic Progenitors', Cell stem cell, vol. 19, no. 3, pp. 383-396. https://doi.org/10.1016/j.stem.2016.06.008

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T1 - Ectopic miR-125a Expression Induces Long-Term Repopulating Stem Cell Capacity in Mouse and Human Hematopoietic Progenitors

AU - Wojtowicz, Edyta E.

AU - Lechman, Eric R.

AU - Hermans, Karin G.

AU - Schoof, Erwin M.

AU - Wienholds, Erno

AU - Isserlin, Ruth

AU - van Veelen, Peter A.

AU - Broekhuis, Mathilde J. C.

AU - Janssen, George M. C.

AU - Trotman-Grant, Aaron

AU - Dobson, Stephanie M.

AU - Krivdova, Gabriela

AU - Elzinga, Jantje

AU - Kennedy, James

AU - Gan, Olga I.

AU - Sinha, Ankit

AU - Ignatchenko, Vladimir

AU - Kislinger, Thomas

AU - Dethmers-Ausema, Bertien

AU - Weersing, Ellen

AU - Alemdehy, Mir Farshid

AU - de Looper, Hans W. J.

AU - Bader, Gary D.

AU - Ritsema, Martha

AU - Erkeland, Stefan J.

AU - Bystrykh, Leonid V.

AU - Dick, John E.

AU - de Haan, Gerald

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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 selfrenewal 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.

AB - 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 selfrenewal 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.

KW - UMBILICAL-CORD BLOOD

KW - TYROSINE-PHOSPHATASE 1B

KW - LIFE-SPAN

KW - IN-VIVO

KW - EXPANSION

KW - TRANSPLANTATION

KW - MICRORNAS

KW - RECEPTOR

KW - DIFFERENTIATION

KW - PROLIFERATION

U2 - 10.1016/j.stem.2016.06.008

DO - 10.1016/j.stem.2016.06.008

M3 - Article

C2 - 27424784

SN - 1934-5909

VL - 19

SP - 383

EP - 396

JO - Cell stem cell

JF - Cell stem cell

IS - 3

ER -

Ectopic miR-125a Expression Induces Long-Term Repopulating Stem Cell Capacity in Mouse and Human Hematopoietic Progenitors

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