c-Myc inhibitor 10074-G5 induces murine and human hematopoietic stem and progenitor cell expansion and HDR modulator Rad51 expression
Current Cancer Drug Targets, cilt.19, sa.6, ss.479-494, 2019 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 19 Sayı: 6
- Basım Tarihi: 2019
- Doi Numarası: 10.2174/1568009618666180905100608
- Dergi Adı: Current Cancer Drug Targets
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
- Sayfa Sayıları: ss.479-494
- Anahtar Kelimeler: Bone marrow, c-myc, Hematopoietic stem cells, Homology-directed repair, Mesenchymal stem cells, Small molecules
- Ondokuz Mayıs Üniversitesi Adresli: Hayır
Özet
Background: c-Myc plays a major role in the maintenance of glycolytic metabolism and hematopoietic stem cell (HSC) quiescence. Objective: Targeting modulators of HSC quiescence and metabolism could lead to HSC cell cycle entry with concomitant expansion. Methods and Results: Here we show that c-Myc inhibitor 10074-G5 treatment leads to 2-fold increase in murine LSKCD34low HSC compartment post 7 days. In addition, c-Myc inhibition increases CD34+ and CD133+ human HSC number. c-Myc inhibition leads to downregulation of glycolytic and cyclindependent kinase inhibitor (CDKI) gene expression ex vivo and in vivo. In addition, c-Myc inhibition upregulates major HDR modulator Rad51 expression in hematopoietic cells. Besides, c-Myc inhibition does not alter proliferation kinetics of endothelial cells, fibroblasts or adipose-derived mesenchymal stem cells, however, it limits bone marrow derived mesenchymal stem cell proliferation. We further demonstrate that a cocktail of c-Myc inhibitor 10074-G5 along with tauroursodeoxycholic acid (TUDCA) and i-NOS inhibitor L-NIL provides a robust HSC maintenance and expansion ex vivo as evident by induction of all stem cell antigens analyzed. Intriguingly, the cocktail of c-Myc inhibitor 10074-G5, TUDCA and L-NIL improves HDR related gene expression. Conclusion: These findings provide tools to improve ex vivo HSC maintenance and expansion, autologous HSC transplantation and gene editing through modulation of HSC glycolytic and HDR pathways.