Regulation of dormant hematopoietic stem cells
Hematopoiesis is a hierarchically organized process. HSCs reside at the top of it, are highly quiescent and hold the unique potential to generate multipotent progenitors which can differentiate into lineage-committed populations and subsequently into mature blood cells. We have applied long-term labeling strategies to identify a sub-population of label-retaining cells within most refined HSCs1. These highly quiescent cells, termed dormant HSCs (dHSCs), divide only five times per lifetime of a healthy mouse, but harbor the highest long-term reconstitution potential within the hematopoietic system. The rest of HSCs -although still quiescent- are named active HSCs (aHSCs). dHSCs are an extremely rare population, that can be reversibly activated in response to stress signals such as interferons, lipopolysaccharide or chemotherapy. Recently, we established the first molecular fingerprint of HSC dormancy2. We found that stem cell dormancy is defined by a low biosynthetic state (low transcription, translation) which gets gradually up-regulated upon commitment. Further, we found that retinoic acid (RA)/ vitamin A signaling is highly expressed in dormant HSCs. Intriguingly, multipotent progenitors are negatively enriched for RA metabolism suggesting a specific role of this in regulating the most potent stem cells3,4,5. We performed proof-of principle experiments and showed that vitamin A plays an important role for the in vivo regulation of stem cell dormancy2. Currently, we are addressing the mechanisms on how stem cell dormancy is regulated.
1. Wilson, A., et al., Hematopoietic Stem Cells Reversibly Switch from Dormancy to Self-Renewal during Homeostasis and Repair. Cell, 2008. 135(6): p. 1118-1129.
2. Cabezas-Wallscheid N, et al., (2017). “Vitamin A/ retinoic acid signaling regulates hematopoietic stem cell dormancy”. Cell. 169:1-17.
3. Cabezas-Wallscheid N et al., (2014) “Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis”. Cell Stem Cell. 15(4):507-22.
4. Klimmeck D*, Cabezas-Wallscheid N*, et al., (2014) “Transcriptional landscape, long non-coding RNAs and post transcriptional regulation in hematopoietic stem/progenitor cell commitment”. Stem Cell Reports. 11;3(5):858-75.
5. Lipka DB*, Wang Q*, Cabezas-Wallscheid N* et al., (2014) “Identification of DNA methylation changes at cis-regulatory elements during early steps of HSC differentiation using tagmentation-based whole genome bisulfite sequencing”. Cell Cycle. 13(22):3476-3487.
Department of Cellular and Molecular Immunology, Max-Planck-Institute of Immunobiology and Epigenetics, Freiburg