Heme oxygenase-1 deficiency affects bone marrow niche and triggers premature exhaustion of hematopoietic stem cells.

Szade, K.; Zukowska, M.; Szade, A.; Nowak, W. N.; Ciesla, M.; Bukowska-Strakova, K.; Gulati, G. S.; Kachamakova-Trojanowska, N.; Kusienicka, A.; Einwallner, E.; Kijowski, J.; Czauderna, S.; Esterbauer, H.; Weissman, I. L.; Dulak, J.; Jozkowicz, A.

doi:10.1101/492850

bioRxiv · 10.1101/492850

Heme oxygenase-1 deficiency affects bone marrow niche and triggers premature exhaustion of hematopoietic stem cells.

Szade, K.·Zukowska, M.·Szade, A.·Nowak, W. N.·Ciesla, M.·Bukowska-Strakova, K.·Gulati, G. S.·Kachamakova-Trojanowska, N.·Kusienicka, A.·Einwallner, E.·Kijowski, J.·Czauderna, S.·Esterbauer, H.·Weissman, I. L.·Dulak, J.·Jozkowicz, A.

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Abstract

While intrinsic changes in aging hematopoietic stem cells (HSCs) are well-characterized, it remains unclear how hematopoietic niche affects 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. RNA-sequencing shows that ECs and CARs from HO-1-deficient animals (HO-1-/-) produce less hematopoietic factors. Consequently, HSCs from young HO-1-/- animals lose quiescence and regenerative potential. Young HO-1-/- HSCs exhibit features of premature aging 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 aging and may restore the function of aged HSCs.

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Szade, K., Zukowska, M., Szade, A., Nowak, W. N., Ciesla, M., Bukowska-Strakova, K., Gulati, G. S., Kachamakova-Trojanowska, N., Kusienicka, A., Einwallner, E., Kijowski, J., Czauderna, S., Esterbauer, H., Weissman, I. L., Dulak, J., Jozkowicz, A.. 2018-12-10. Heme oxygenase-1 deficiency affects bone marrow niche and triggers premature exhaustion of hematopoietic stem cells.. https://doi.org/10.1101/492850

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