Inflammation as a regulator of hematopoietic stem cell function in disease, aging, and clonal selection

Caiado, Francisco; Pietras, Eric M.; Manz, Markus G.

doi:10.1084/jem.20201541

Cited by 127 publications

(112 citation statements)

References 191 publications

(219 reference statements)

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“…Together with this decreased iron availability for erythropoiesis, IFN-γ, TNF-α and IL-1 directly inhibit the production of erythropoietin in the kidney and impair the differentiation and proliferation of erythroid progenitor cells in the bone marrow [ 30 , 31 , 32 ]. Finally, the quickest acting inflammation-related mechanism causing a reduction in circulating erythrocytes is the upregulation of erythrophagocytosis by hepatic and especially splenic macrophages, thus decreasing the erythrocyte half-life [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Dynamics in Anemia Development and Dysregulation of Iron Homeostasis in Hospitalized Patients with COVID-19

et al. 2021

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Anemia and disturbances of iron metabolism are frequently encountered in patients with COVID-19 and associated with an adverse clinical course. We retrospectively analyzed 645 consecutive COVID-19 patients hospitalized at the Innsbruck University Hospital. Pre-existing anemia was associated with increased risk for in-hospital death. We further found that the decline in hemoglobin levels during hospital stay is more pronounced in patients with signs of hyperinflammation upon admission, the latter being associated with a nearly two-fold higher risk for new onset anemia within one week. Anemia prevalence increased from 44.3% upon admission to 87.8% in patients who were still hospitalized after two weeks. A more distinct decrease in hemoglobin levels was observed in subjects with severe disease, and new-onset anemia was associated with a higher risk for ICU admission. Transferrin levels decreased within the first week of hospitalization in all patients, however, a continuous decline was observed in subjects who died. Hemoglobin, ferritin, and transferrin levels normalized in a median of 122 days after discharge from hospital. This study uncovers pre-existing anemia as well as low transferrin concentrations as risk factors for mortality in hospitalized COVID-19 patients, whereas new-onset anemia during hospitalization is a risk factor for ICU admission. Anemia and iron disturbances are mainly driven by COVID-19 associated inflammation, and cure from infection results in resolution of anemia and normalization of dysregulated iron homeostasis.

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Section: Discussionmentioning

confidence: 99%

Dynamics in Anemia Development and Dysregulation of Iron Homeostasis in Hospitalized Patients with COVID-19

et al. 2021

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“…Inflammation-related EPO reduction thus aggravates hepcidin-mediated iron limitation to erythroid progenitor cells [2]. Moreover, several cytokines including type I interferons, IFN-γ, TNF or IL-1β have been shown to inhibit erythroid progenitor cell proliferation or differentiation directly or via induction of radical formation of ceramide mediated apoptotic processes [180][181][182]. Erythrophagocytosis by hepatic and especially splenic macrophages is also upregulated during inflammation resulting in a decreased erythrocyte half-life [2,47].…”

Section: Erythropoiesis Suppression and Decreased Erythrocyte Survival By Inflammationmentioning

confidence: 99%

Physiology and Inflammation Driven Pathophysiology of Iron Homeostasis—Mechanistic Insights into Anemia of Inflammation and Its Treatment

et al. 2021

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Anemia is very common in patients with inflammatory disorders. Its prevalence is associated with severity of the underlying disease, and it negatively affects quality of life and cardio-vascular performance of patients. Anemia of inflammation (AI) is caused by disturbances of iron metabolism resulting in iron retention within macrophages, a reduced erythrocyte half-life, and cytokine mediated inhibition of erythropoietin function and erythroid progenitor cell differentiation. AI is mostly mild to moderate, normochromic and normocytic, and characterized by low circulating iron, but normal and increased levels of the storage protein ferritin and the iron hormone hepcidin. The primary therapeutic approach for AI is treatment of the underlying inflammatory disease which mostly results in normalization of hemoglobin levels over time unless other pathologies such as vitamin deficiencies, true iron deficiency on the basis of bleeding episodes, or renal insufficiency are present. If the underlying disease and/or anemia are not resolved, iron supplementation therapy and/or treatment with erythropoietin stimulating agents may be considered whereas blood transfusions are an emergency treatment for life-threatening anemia. New treatments with hepcidin-modifying strategies and stabilizers of hypoxia inducible factors emerge but their therapeutic efficacy for treatment of AI in ill patients needs to be evaluated in clinical trials.

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“…In response to different demands of the organism (such as infection, blood loss, acute inflammatory conditions, and other stress conditions), HSCs typically exit their quiescence and undergo proliferation and differentiation; this process is termed demand, stress, or emergency hematopoiesis [ 18 ]. The different HSC and HSPC functional states are associated with distinct metabolic demands and metabolic states [ 19 ].…”

Section: Metabolic Changes In the Hspc Poolmentioning

confidence: 99%

“…Taken together, the combination of dysregulated metabolism and pro-inflammatory alterations generates a complex immunometabolic network in the bone marrow, which contributes to the pathogenesis of CHIP and MDS [ 10 , 18 ].…”

Section: Metabolic Pathways In Non-hematopoietic Cells Of the Mds Niche And Beyondmentioning

confidence: 99%

Myelodysplastic Syndromes and Metabolism

Balaian

Wobus

Bornhäuser

et al. 2021

IJMS

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Myelodysplastic syndromes (MDS) are acquired clonal stem cell disorders exhibiting ineffective hematopoiesis, dysplastic cell morphology in the bone marrow, and peripheral cytopenia at early stages; while advanced stages carry a high risk for transformation into acute myeloid leukemia (AML). Genetic alterations are integral to the pathogenesis of MDS. However, it remains unclear how these genetic changes in hematopoietic stem and progenitor cells (HSPCs) occur, and how they confer an expansion advantage to the clones carrying them. Recently, inflammatory processes and changes in cellular metabolism of HSPCs and the surrounding bone marrow microenvironment have been associated with an age-related dysfunction of HSPCs and the emergence of genetic aberrations related to clonal hematopoiesis of indeterminate potential (CHIP). The present review highlights the involvement of metabolic and inflammatory pathways in the regulation of HSPC and niche cell function in MDS in comparison to healthy state and discusses how such pathways may be amenable to therapeutic interventions.

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Inflammation as a regulator of hematopoietic stem cell function in disease, aging, and clonal selection

Cited by 127 publications

References 191 publications

Dynamics in Anemia Development and Dysregulation of Iron Homeostasis in Hospitalized Patients with COVID-19

Dynamics in Anemia Development and Dysregulation of Iron Homeostasis in Hospitalized Patients with COVID-19

Physiology and Inflammation Driven Pathophysiology of Iron Homeostasis—Mechanistic Insights into Anemia of Inflammation and Its Treatment

Myelodysplastic Syndromes and Metabolism

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