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Small molecule-mediated modulation of ubiquitination and neddylation improves HSC function ex vivo

Esra Albayrak1, Merve Uslu1, Sezer Akgol1

  • 1Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, Istanbul, Turkey.

Journal of Cellular Physiology
|June 8, 2021
PubMed

Insights

Inhibiting ubiquitination and neddylation enhances hematopoietic stem cell (HSC) self-renewal and quiescence. These processes, involving SKP2 and CDKIs, are crucial for HSC maintenance and expansion.

Area of Science:

  • Hematology
  • Cell Biology
  • Biochemistry

Background:

  • Hematopoietic stem cells (HSCs) are vital for blood formation, characterized by quiescence and self-renewal.
  • Cell cycle regulators, including cyclin-dependent kinase inhibitors (CDKIs), are critical for maintaining HSC function.
  • Ubiquitination and neddylation pathways influence HSC behavior, with S-phase kinase-associated protein 2 (SKP2) mediating CDKI degradation.

Purpose of the Study:

  • To investigate the role of SKP2-associated ubiquitination and overall neddylation in HSC maintenance and self-renewal.
  • To determine the effects of inhibiting SKP2 and the NEDD8 system on hematopoietic stem and progenitor cell (HSPC) compartments.
  • To explore the impact of these modulations on HSC quiescence, proliferation, and mobilization.

Main Methods:

  • Utilized SKP2-C25 (an SKP2 inhibitor) and MLN4924 (a NEDD8 system inhibitor) to modulate ubiquitination and neddylation in murine and human HSCs.
  • Assessed changes in HSPC compartments, HSC quiescence (via p27 and p57 CDKIs), and in vitro self-renewal potential using colony-forming unit assays.
  • Monitored HSPC mobilization to peripheral blood and proliferation of other cell types, such as mesenchymal stem cells and endothelial cells.

Main Results:

  • Treatment with SKP2-C25 and MLN4924 significantly increased both murine and human HSPC compartments.
  • Inhibition of ubiquitination and neddylation led to improved quiescence in murine HSCs, associated with increased p27 and p57 CDKI levels.
  • Enhanced in vitro self-renewal capacity was observed post-treatment, and MLN4924 induced HSPC mobilization into peripheral blood.
  • MLN4924 also demonstrated a notable decrease in the proliferation of murine bone marrow mesenchymal stem cells and endothelial cells.

Conclusions:

  • SKP2, ubiquitination, and neddylation play significant roles in the maintenance, self-renewal, and expansion of HSCs.
  • Targeting these pathways offers potential therapeutic strategies for modulating HSC behavior.
  • The findings provide insights into the complex regulatory mechanisms governing HSC function and potential for stem cell expansion and mobilization.

Keywords:
HSCneddylationsmall moleculesubiquitination

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