Monika Zukowska

All Publications

• Proteomic analysis of young and old mouse hematopoietic stem cells and their progenitors reveals post-transcriptional regulation in stem cells. eLife Zaro, B. W., Noh, J. J., Mascetti, V. L., Demeter, J., George, B., Zukowska, M., Gulati, G. S., Sinha, R., Flynn, R. A., Banuelos, A., Zhang, A., Wilkinson, A. C., Jackson, P., Weissman, I. L. 2020; 9

  Abstract

  The balance of hematopoietic stem cell (HSC) self-renewal and differentiation is critical for a healthy blood supply; imbalances underlie hematological diseases. The importance of HSCs and their progenitors have led to their extensive characterization at genomic and transcriptomic levels. However, the proteomics of hematopoiesis remains incompletely understood. Here we report a proteomics resource from mass spectrometry of mouse young adult and old adult mouse HSCs, multipotent progenitors and oligopotent progenitors; 12 cell types in total. We validated differential protein levels, including confirmation that Dnmt3a protein levels are undetected in young adult mouse HSCs until forced into cycle. Additionally, through integrating proteomics and RNA-sequencing datasets, we identified a subset of genes with apparent post-transcriptional repression in young adult mouse HSCs. In summary, we report proteomic coverage of young and old mouse HSCs and progenitors, with broader implications for understanding mechanisms for stem cell maintenance, niche interactions and fate determination.

  View details for DOI 10.7554/eLife.62210

  View details for PubMedID 33236985

• Heme oxygenase-1 deficiency triggers exhaustion of hematopoietic stem cells. EMBO reports Szade, K., Zukowska, M., Szade, A., Nowak, W., Skulimowska, I., Ciesla, M., Bukowska-Strakova, K., Gulati, G. S., Kachamakova-Trojanowska, N., Kusienicka, A., Einwallner, E., Kijowski, J., Czauderna, S., Esterbauer, H., Benes, V., L Weissman, I., Dulak, J., Jozkowicz, A. 2019: e47895

  Abstract

  While intrinsic changes in aging hematopoietic stem cells (HSCs) are well characterized, it remains unclear how extrinsic factors affect HSC aging. Here, we demonstrate that cells in the niche-endothelial cells (ECs) and CXCL12-abundant reticular cells (CARs)-highly express the heme-degrading enzyme, heme oxygenase 1 (HO-1), but then decrease its expression with age. HO-1-deficient animals (HO-1-/- ) have altered numbers of ECs and CARs that produce less hematopoietic factors. HSCs co-cultured invitro with HO-1-/- mesenchymal stromal cells expand, but have altered kinetic of growth and differentiation of derived colonies. HSCs from young HO-1-/- animals have reduced quiescence and regenerative potential. Young HO-1-/- HSCs exhibit features of premature exhaustion on the transcriptional and functional level. HO-1+/+ HSCs transplanted into HO-1-/- recipients exhaust their regenerative potential early and do not reconstitute secondary recipients. In turn, transplantation of HO-1-/- HSCs to the HO-1+/+ recipients recovers the regenerative potential of HO-1-/- HSCs and reverses their transcriptional alterations. Thus, HSC-extrinsic activity of HO-1 prevents HSCs from premature exhaustion and may restore the function of aged HSCs.

  View details for DOI 10.15252/embr.201947895

  View details for PubMedID 31885181

• Neogenin-1 distinguishes between myeloid-biased and balanced Hoxb5+ mouse long-term hematopoietic stem cells. Proceedings of the National Academy of Sciences of the United States of America Gulati, G. S., Zukowska, M., Noh, J. J., Zhang, A., Wesche, D. J., Sinha, R., George, B. M., Weissman, I. L., Szade, K. 2019

  Abstract

  Hematopoietic stem cells (HSCs) self-renew and generate all blood cells. Recent studies with single cell transplants and lineage tracing suggest that adult HSCs are diverse in their reconstitution and lineage potentials. However, prospective isolation of these subpopulations has remained challenging. Here, we identify Neogenin-1 (NEO1) as a unique surface marker on a fraction of mouse HSCs labeled with Hoxb5, a specific reporter of long-term HSCs (LT-HSCs). We show that NEO1+ Hoxb5 + LT-HSCs expand with age and respond to myeloablative stress in young mice while NEO1- Hoxb5 + LT-HSCs exhibit no significant change in number. Furthermore, NEO1+ Hoxb5 + LT-HSCs are more often in the G2/S cell cycle phase compared to NEO1- Hoxb5 + LT-HSCs in both young and old bone marrow. Upon serial transplantation, NEO1+ Hoxb5 + LT-HSCs exhibit myeloid-biased differentiation and reduced reconstitution while NEO1- Hoxb5 + LT-HSCs are lineage-balanced and stably reconstitute recipients. Gene expression analysis reveals erythroid and myeloid priming in the NEO1+ fraction and association of quiescence and self-renewal-related transcription factors with NEO1- LT-HSCs. Finally, transplanted NEO1+ Hoxb5 + LT-HSCs rarely generate NEO1- Hoxb5 + LT-HSCs while NEO1- Hoxb5 + LT-HSCs repopulate both LT-HSC fractions. This supports a model in which dormant, balanced NEO1- Hoxb5 + LT-HSCs can hierarchically precede active, myeloid-biased NEO1+ Hoxb5 + LT-HSCs.

  View details for DOI 10.1073/pnas.1911024116

  View details for PubMedID 31754028