PUBLICATION

Zebrafish In-Vivo Screening for Compounds Amplifying Hematopoietic Stem and Progenitor Cells: - Preclinical Validation in Human CD34+ Stem and Progenitor Cells

Authors
Arulmozhivarman, G., Kräter, M., Wobus, M., Friedrichs, J., Bejestani, E.P., Müller, K., Lambert, K., Alexopoulou, D., Dahl, A., Stöter, M., Bickle, M., Shayegi, N., Hampe, J., Stölzel, F., Brand, M., von Bonin, M., Bornhäuser, M.
ID
ZDB-PUB-170923-4
Date
2017
Source
Scientific Reports   7: 12084 (Journal)
Registered Authors
Brand, Michael
Keywords
Haematopoietic stem cells, High-throughput screening
MeSH Terms
  • Animals
  • Antigens, CD34/metabolism*
  • Cell Proliferation/drug effects*
  • Cells, Cultured
  • Drug Evaluation, Preclinical/methods*
  • Graft Survival/drug effects
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells/cytology
  • Hematopoietic Stem Cells/drug effects*
  • Hematopoietic Stem Cells/metabolism
  • Histone Deacetylase Inhibitors/pharmacology
  • Humans
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Small Molecule Libraries/pharmacology*
  • Transplantation, Heterologous
  • Valproic Acid/pharmacology
  • Zebrafish
PubMed
28935977 Full text @ Sci. Rep.
Abstract
The identification of small molecules that either increase the number and/or enhance the activity of human hematopoietic stem and progenitor cells (hHSPCs) during ex vivo expansion remains challenging. We used an unbiased in vivo chemical screen in a transgenic (c-myb:EGFP) zebrafish embryo model and identified histone deacetylase inhibitors (HDACIs), particularly valproic acid (VPA), as significant enhancers of the number of phenotypic HSPCs, both in vivo and during ex vivo expansion. The long-term functionality of these expanded hHSPCs was verified in a xenotransplantation model with NSG mice. Interestingly, VPA increased CD34+ cell adhesion to primary mesenchymal stromal cells and reduced their in vitro chemokine-mediated migration capacity. In line with this, VPA-treated human CD34+ cells showed reduced homing and early engraftment in a xenograft transplant model, but retained their long-term engraftment potential in vivo, and maintained their differentiation ability both in vitro and in vivo. In summary, our data demonstrate that certain HDACIs lead to a net expansion of hHSPCs with retained long-term engraftment potential and could be further explored as candidate compounds to amplify ex-vivo engineered peripheral blood stem cells.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping