Recombinant TAT-BMI-1 fusion protein induces ex vivo expansion of human umbilical cord blood-derived hematopoietic stem cells

Bruna Codispoti, Nicola Rinaldo, Emanuela Chiarella, Michela Lupia, Cristina Barbara Spoleti, Maria Grazia Marafioti, Annamaria Aloisio, Stefania Scicchitano, Marco Giordano, Giovanna Nappo, Valeria Lucchino, Malcolm A.S. Moore, Pengbo Zhou, Maria Mesuraca, Heather Mandy Bond, Giovanni Morrone

Research output: Contribution to journalArticle

Abstract

Transplantation of hematopoietic stem cells (HSCs) is a well-established therapeutic approach for numerous disorders. HSCs are typically derived from bone marrow or peripheral blood after cytokine-induced mobilization. Umbilical cord blood (CB) represents an appealing alternative HSC source, but the small amounts of the individual CB units have limited its applications. The availability of strategies for safe ex vivo expansion of CB-derived HSCs (CB-HSCs) may allow to extend the use of these cells in adult patients and to avoid the risk of insufficient engraftment or delayed hematopoietic recovery. Here we describe a system for the ex vivo expansion of CB-HSCs based on their transient exposure to a recombinant TAT-BMI-1 chimeric protein. BMI-1 belongs to the Polycomb family of epigenetic modifiers and is recognized as a central regulator of HSC self-renewal. Recombinant TAT-BMI-1 produced in bacteria was able to enter the target cells via the HIV TAT-derived protein transduction peptide covalently attached to BMI-1, and conserved its biological activity. Treatment of CB-CD34+ cells for 3 days with repeated addition of 10 nM purified TAT-BMI-1 significantly enhanced total cell expansion as well as that of primitive hematopoietic progenitors in culture. Importantly, TAT-BMI-1-treated CB-CD34+ cells displayed a consistently higher rate of multi-lineage long-term repopulating activity in primary and secondary xenotransplants in immunocompromised mice. Thus, recombinant TAT-BMI-1 may represent a novel, effective reagent for ex vivo expansion of CB-HSC for therapeutic purposes.

Original languageEnglish
Pages (from-to)43782-43798
Number of pages17
JournalOncotarget
Volume8
Issue number27
DOIs
Publication statusPublished - Jan 1 2017

Keywords

  • BMI-1
  • Ex vivo expansion
  • Hematopoietic stem cells (HSCs)
  • Protein transduction
  • TAT-fusion protein

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Codispoti, B., Rinaldo, N., Chiarella, E., Lupia, M., Spoleti, C. B., Marafioti, M. G., Aloisio, A., Scicchitano, S., Giordano, M., Nappo, G., Lucchino, V., Moore, M. A. S., Zhou, P., Mesuraca, M., Bond, H. M., & Morrone, G. (2017). Recombinant TAT-BMI-1 fusion protein induces ex vivo expansion of human umbilical cord blood-derived hematopoietic stem cells. Oncotarget, 8(27), 43782-43798. https://doi.org/10.18632/oncotarget.15156