Hypoxia Pathway Proteins in Normal and Malignant Hematopoiesis

Wielockx, Ben; Grinenko, Tatyana; Mirtschink, Peter; Chavakis, Triantafyllos

doi:10.3390/cells8020155

Cited by 39 publications

(35 citation statements)

References 82 publications

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“…In support of such a model, we found that activation of Nrf2-and Hif-driven gene programs are maintained in EPCR + /CD34 − SLAM cells. Notably, Nrf2 and Hif pathways are also required for HSC quiescence, and their deletion leads to HSC mobilization from the BM [43,53]. Thus, further studies can assess the degree to which EPCR cooperates and/or converges with metabolic control mechanisms like Nrf2 and Hif to enforce quiescence and localization of EPCR + HSCs in the BM niche, particularly under inflammatory stress conditions.…”

Section: Discussionmentioning

confidence: 99%

CD34 and EPCR coordinately enrich functional murine hematopoietic stem cells under normal and inflammatory conditions

Rabe

Hernández

Mills

et al. 2020

Experimental Hematology

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Section: Discussionmentioning

confidence: 99%

CD34 and EPCR coordinately enrich functional murine hematopoietic stem cells under normal and inflammatory conditions

Rabe

Hernández

Mills

et al. 2020

Experimental Hematology

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“…Hypoxia and a low ROS level are required for HSCs self-renewal and maintenance. [1][2][3][4] Optimization of the levels of environmental factors such as oxygen, cytokines, and fatty acids enables maintenance of HSCs quiescence ex vivo. 5 Small molecules that can maintain low ROS levels 6 and inhibit cell apoptosis or autophagy 7 are also useful for maintenance or expansion of HSCs.…”

Section: Introductionmentioning

confidence: 99%

“…Besides intrinsic transcriptional regulation, the birth of hematopoietic stem cells (HSCs) is regulated by multiple exogenous factors, such as hypoxic and extracellular components. Hypoxia and a low ROS level are required for HSCs self‐renewal and maintenance 1–4 . Optimization of the levels of environmental factors such as oxygen, cytokines, and fatty acids enables maintenance of HSCs quiescence ex vivo 5 .…”

Section: Introductionmentioning

confidence: 99%

Alpha lipoic acid promotes development of hematopoietic progenitors derived from human embryonic stem cells by antagonizing ROS signals

Dong

Bai

Zhang

et al. 2020

Journal of Leukocyte Biology

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Antagonism of ROS signaling can inhibit cell apoptosis and autophagy, thus favoring the maintenance and expansion of hematopoietic stem cells. Alpha lipoic acid (ALA), a small antioxidant molecule, affects cell apoptosis by lowering the ROS level. In this study, we show that ALA promoted production of human pluripotent stem cells (hPSCs) derived hemogenic endothelial cells and hematopoietic stem/progenitor cells in vitro. Transcriptome analysis of hPSCs derived hemogenic endothelial cells showed that ALA promoted endothelial-to-hematopoietic transition by up-regulating RUNX1, GFI1, GFI1B, MEIS2, and HIF1A and down-regulating SOX17, TGFB1, TGFB2, TGFB3, TGFBR1, and TGFBR2. ALA also up-regulated sensor genes of ROS signals, including HIF1A, FOXO1, FOXO3, ATM, PETEN, SIRT1, and SIRT3, during the process of hPSCs derived hemogenic endothelial cells generation. However, in more mature hPSC-derived hematopoietic stem/progenitor cells, ALA reduced ROS levels and inhibited apoptosis. In particular, ALA enhanced development of hPSCs derived hematopoietic stem/progenitor cells by up-regulating HIF1A in response to a hypoxic environment. Furthermore, addition of ALA in ex vivo culture greatly improved the maintenance of functional cord blood HSCs by in vivo transplantation assay. Our findings support the conjecture that ALA plays an important role in efficient regeneration of hematopoietic stem/progenitor cells from hPSCs and maintenance of functional HSCs, providing insight into understanding of regeneration of early hematopoiesis for engineering clinically useful hPSCs derived hematopoietic stem/progenitor cells transplantation. Thus, ALA can be used in the study of hPSCs derived HSCs. K E Y W O R D S alpha lipoic acid, endothelial-to-hematopoietic transition (EHT), hematopoiesis, hematopoietic stem/progenitor cells, human pluripotent stem cells (hPSCs), ROS Abbreviations: AGM-S3, aorta-gonad-mesonephros (AGM)-S3 cells; ALA, alpha lipoic acid; hESCs, human embryonic stem cells; hPSCs, human pluripotent stem cells; HSCs, hematopoietic stem cells; ROS, reactive oxygen species. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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“…Another important characteristic of the niches is the distribution of oxygen in the BM microenvironment. The oxygen concentration controls essential cellular processes for the maintenance of the physiological behavior of tissues and organs and is considered a key parameter in the regulation of the survival and quiescence of HSCs in the BM niches [ 15 ]. The oxygen concentration is not distributed evenly in the microenvironment of the niches: it is lower in the endosteal niche and gradually increases towards the perivascular niche [ 16 ] because of proximity of blood vessels that provide oxygen supply.…”

Section: Introductionmentioning

confidence: 99%

Microfluidics and organ-on-a-chip technologies: A systematic review of the methods used to mimic bone marrow

et al. 2020

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Bone marrow (BM) is an organ responsible for crucial processes in living organs, e. g., hematopoiesis. In recent years, Organ-on-a-Chip (OoC) devices have been used to satisfy the need for in vitro systems that better mimic the phenomena occurring in the BM microenvironment. Given the growing interest in these systems and the diversity of developed devices, an integrative systematic literature review is required. We have performed this review, following the PRISMA method aiming to identify the main characteristics and assess the effectiveness of the devices that were developed to represent the BM. A search was performed in the Scopus, PubMed, Web of Science and Science Direct databases using the keywords ((“bone marrow” OR “hematopoietic stem cells” OR “haematopoietic stem cells”) AND (“organ in a” OR “lab on a chip” OR “microfluidic” OR “microfluidic*” OR (“bioreactor” AND “microfluidic*”))). Original research articles published between 2009 and 2020 were included in the review, giving a total of 21 papers. The analysis of these papers showed that their main purpose was to study BM cells biology, mimic BM niches, model pathological BM, and run drug assays. Regarding the fabrication protocols, we have observed that polydimethylsiloxane (PDMS) material and soft lithography method were the most commonly used. To reproduce the microenvironment of BM, most devices used the type I collagen and alginate. Peristaltic and syringe pumps were mostly used for device perfusion. Regarding the advantages compared to conventional methods, there were identified three groups of OoC devices: perfused 3D BM; co-cultured 3D BM; and perfused co-cultured 3D BM. Cellular behavior and mimicking their processes and responses were the mostly commonly studied parameters. The results have demonstrated the effectiveness of OoC devices for research purposes compared to conventional cell cultures. Furthermore, the devices have a wide range of applicability and the potential to be explored.

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Hypoxia Pathway Proteins in Normal and Malignant Hematopoiesis

Cited by 39 publications

References 82 publications

CD34 and EPCR coordinately enrich functional murine hematopoietic stem cells under normal and inflammatory conditions

CD34 and EPCR coordinately enrich functional murine hematopoietic stem cells under normal and inflammatory conditions

Alpha lipoic acid promotes development of hematopoietic progenitors derived from human embryonic stem cells by antagonizing ROS signals

Microfluidics and organ-on-a-chip technologies: A systematic review of the methods used to mimic bone marrow

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