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 languageEnglish
Pages (from-to)383-396
Number of pages14
JournalCell stem cell
Volume19
Issue number3
DOIs
Publication statusPublished - 1-Sept-2016

Keywords

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

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