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| Status |
Public on Nov 01, 2017 |
| Title |
In Vivo Chemical Screen Nominates Valproic Acid as Pharmacologic Modulator of Hematopoietic Stem and Progenitor Cell Activity |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
The identification of small molecules which either increase the number and/or enhance the activity of CD34+ hematopoietic stem and progenitor cells (HSPCs) during ex-vivo expansion has remained challenging. Applying an unbiased in vivo chemical screen in a transgenic (c-myb:EGFP) zebrafish embryo model, histone deacetylase inhibitors (HDACI) (valproic acid, resminostat and entinostat) were shown to significantly amplify the number of phenotypic hematopoietic precursors. The identified HDACIs were confirmed to significantly enhance also the expansion of human HSPCs during ex vivo treatment. Long-term functionality of ex vivo expanded human HSPCs was verified in a xenotransplantation model using NSG mice. However, the HDACI induced proliferation of HSPCs was associated with short-term functional changes. One of the identified hits, valproic acid (VPA), increased the adhesion capacity of CD34+ cells on primary mesenchymal stromal cells and reduced their chemokine-mediated migration capacity in vitro. In line with the reduced migratory potential in vitro, homing as well as early engraftment of VPA treated human CD34+ cells was significantly impaired in the xenotransplantation model. Our data confirms that HDACI treatment leads to a net expansion of HSPCs cells with long-term engraftment potential across different species. However impaired homing and short-term-engraftment has to be kept in mind when designing clinical transplantation protocols. In addition, our gene expression analysis (RNA-Seq) revealed expression of several genes that were altered in CD34+ cells by VPA treatment including cell adhesion molecules and Notch and wnt genes which has been shown to be involved in preservation of stem cell properties.
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| Overall design |
Gene expression analysis of in vitro expanded human HSPCs (CD34+ cells) by valproic acid
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| Contributor(s) |
Arulmozhivarman G, Alexopoulou D, Dahl A, Bornhäuser M |
| Citation(s) |
28935977 |
| |
| Submission date |
Nov 26, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
Guruchandar Arulmozhivarman |
| E-mail(s) |
[email protected]
|
| Organization name |
TU Dresden - Faculty of Medicine
|
| Department |
Hematology department
|
| Lab |
Dresden Stem Cell Lab
|
| Street address |
Fetscherstraße 74
|
| City |
Dresden |
| ZIP/Postal code |
01307 |
| Country |
Germany |
| |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA355003 |
| SRA |
SRP093978 |
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