Heme oxygenase 1 affects granulopoiesis in mice through control of myelocyte proliferation

Żukowska

et al. 2018

Preprint

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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 in vitro 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.

Section: Discussioncontrasting

confidence: 55%

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

Żukowska

et al. 2018

Preprint

Self Cite

“…Even though it is essential for preventing carcinogenesis in healthy cells through maintaining redox homeostasis [35], under the ongoing process of tumorigenesis, its activation becomes deleterious for patients, since its antioxidant, antiapoptotic, and anti-inflammatory properties promote proliferation and invasiveness of malignant cells, leading ultimately to protection of neoplastic cells from apoptosis [36], which was also observed in AML [29]. Furthermore, HO-1 regulates proliferation and differentiation of many cell types [37][38][39][40][41][42][43][44], and recently we have demonstrated that it also affects granulocytic development through influencing myelocyte proliferation [45], suggesting its potential role in regulating granulopoiesis under stress-induced conditions, such as chemotherapy.…”

Section: Introductionmentioning

confidence: 91%

Role of HMOX1 Promoter Genetic Variants in Chemoresistance and Chemotherapy Induced Neutropenia in Children with Acute Lymphoblastic Leukemia

Bukowska-Straková

Włodek

Pitera

et al. 2021

IJMS

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Whilst the survival rates of childhood acute lymphoblastic leukemia (ALL) have increased remarkably over the last decades, the therapy resistance and toxicity are still the major causes of treatment failure. It was shown that overexpression of heme oxygenase-1 (HO-1) promotes proliferation and chemoresistance of cancer cells. In humans, the HO-1 gene (HMOX1) expression is modulated by two polymorphisms in the promoter region: (GT)n-length polymorphism and single-nucleotide polymorphism (SNP) A(−413)T, with short GT repeat sequences and 413-A variants linked to an increased HO-1 inducibility. We found that the short alleles are significantly more frequent in ALL patients in comparison to the control group, and that their presence may be associated with a higher risk of treatment failure, reflecting the role of HO-1 in chemoresistance. We also observed that the presence of short alleles may predispose to develop chemotherapy-induced neutropenia. In case of SNP, the 413-T variant co-segregated with short or long alleles, while 413-A almost selectively co-segregated with long alleles, hence it is not possible to determine if SNPs are actually of phenotypic significance. Our results suggest that HO-1 can be a potential target to overcome the treatment failure in ALL patients.

“…Specific deletion of HO‐1 in myeloid lineage (Lyz‐Cre:Hmox1 fl/fl ) partially blocks differentiation of myeloid progenitors toward macrophages (Wegiel et al , ). We showed that lack of HO‐1 also affects granulopoiesis (Bukowska‐Strakova et al , ). HO‐1 −/− mice have more granulocytes in the peripheral blood (PB), what is connected with increased myelocyte proliferation in the bone marrow (BM).…”

Section: Introductionmentioning

confidence: 91%

Cobalt protoporphyrin IX increases endogenous G‐ CSF and mobilizes HSC and granulocytes to the blood

Nowak

et al. 2019

EMBO Mol Med

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Granulocyte colony‐stimulating factor (G‐CSF) is used in clinical practice to mobilize cells from the bone marrow to the blood; however, it is not always effective. We show that cobalt protoporphyrin IX (CoPP) increases plasma concentrations of G‐CSF, IL‐6, and MCP‐1 in mice, triggering the mobilization of granulocytes and hematopoietic stem and progenitor cells (HSPC). Compared with recombinant G‐CSF, CoPP mobilizes higher number of HSPC and mature granulocytes. In contrast to G‐CSF, CoPP does not increase the number of circulating T cells. Transplantation of CoPP‐mobilized peripheral blood mononuclear cells (PBMC) results in higher chimerism and faster hematopoietic reconstitution than transplantation of PBMC mobilized by G‐CSF. Although CoPP is used to activate Nrf2/HO‐1 axis, the observed effects are Nrf2/HO‐1 independent. Concluding, CoPP increases expression of mobilization‐related cytokines and has superior mobilizing efficiency compared with recombinant G‐CSF. This observation could lead to the development of new strategies for the treatment of neutropenia and HSPC transplantation.