Hematopoietic stem cells are regulated by Cripto, as an intermediary of HIF‐1α in the hypoxic bone marrow niche

Miharada, Kenichi; Karlsson, Göran; Rehn, Matilda; Rörby, Emma; Siva, Kavitha; Cammenga, Jörg; Karlsson, Stefán

doi:10.1111/j.1749-6632.2012.06564.x

Cited by 26 publications

(19 citation statements)

References 54 publications

(137 reference statements)

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“…These findings raise an intriguing possibility that cells matured in BM niches may be highly susceptible to aberrant increases in ROS. In support, disruption of ROS homeostasis has been shown to impede the quiescence of hematopoietic stem cells, a paradigm corroborated by our current investigations [21, 37, 38]. Alongside the current research, another recent publication showed that IEX-1 was a key to up regulate NF-kB and to activate Erk signaling resulting in repairing DNA breaks induced by gamma-irradiation in hematopoietic stem cells [39].…”

Section: Discussionsupporting

confidence: 85%

Mitoquinone restores platelet production in irradiation-induced thrombocytopenia

Ramsey

Zhang

2014

Platelets

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Myelodysplastic syndromes (MDS) are hallmarked by cytopenia and dysplasia of hematopoietic cells, often accompanied by mitochondrial dysfunction and increases of reactive oxygen species (ROS) within affected cells. However, it is not known whether the increase in ROS production is an instigator or a byproduct of the disease. The present investigation shows that mice lacking immediate early responsive gene X-1 (IEX-1) exhibit lineage specific increases in ROS production and abnormal cytology upon radiation in blood cell types commonly identified in MDS. These affected cell lineages chiefly have the bone marrow as a primary site of differentiation and maturation, while cells with extramedullary differentiation and maturation like B- and T-cells remain unaffected. Increased ROS production is likely to contribute significantly to irradiation-induced thrombocytopenia in the absence of IEX-1 as demonstrated by effective reversal of the disorder after mitoquinone (MitoQ) treatment, a mitochondria-specific antioxidant. MitoQ reduced intracellular ROS production within megakaryocytes and platelets. It also normalized mitochondrial membrane potential and superoxide production in platelets in irradiated, IEX-1 deficient mice. The lineage-specific effects of mitochondrial ROS may help us understand the etiology of thrombocytopenia in association with MDS in a subgroup of the patients.

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Section: Discussionsupporting

confidence: 85%

Mitoquinone restores platelet production in irradiation-induced thrombocytopenia

Ramsey

Zhang

2014

Platelets

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“…Researchers have also identified extracellular factors that regulate HIF1α activity in HSCs 52,53 . The soluble protein CRIPTO (also known as TDGF1), and its cell surface receptor 78 kDa glucose-regulated protein (GRP78), have crucial roles in promoting quiescence and in the maintenance of HSCs 52 .…”

Section: Glycolysis and The Hypoxic Nichementioning

confidence: 99%

Metabolic requirements for the maintenance of self-renewing stem cells

Ito

Suda

2014

Nat Rev Mol Cell Biol

879

841

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A distinctive feature of stem cells is their capacity to self-renew to maintain pluripotency. Studies of genetically-engineered mouse models and recent advances in metabolomic analysis, particularly in haematopoietic stem cells, have deepened our understanding of the contribution made by metabolic cues to the regulation of stem cell self-renewal. Many types of stem cells heavily rely on anaerobic glycolysis, and stem cell function is also regulated by bioenergetic signalling, the AKT–mTOR pathway, Gln metabolism and fatty acid metabolism. As maintenance of a stem cell pool requires a finely-tuned balance between self-renewal and differentiation, investigations into the molecular mechanisms and metabolic pathways underlying these decisions hold great therapeutic promise.

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“…53 The hypoxic microenvironment in the endosteum is a major factor in the integration of skeletal and haematopoietic functions, owing in part to the central role of hypoxia-inducible factor (HIF)-1α in HSC differentiation. 54,55 …”

Section: Biochemistry Of the Nichementioning

confidence: 99%

Navigating the bone marrow niche: translational insights and cancer-driven dysfunction

2015

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The bone marrow niche consists of stem and progenitor cells destined to become mature cells such as haematopoietic elements, osteoblasts or adipocytes. Marrow cells, influenced by endocrine, paracrine and autocrine factors, ultimately function as a unit to regulate bone remodelling and haematopoiesis. Current evidence highlights the bone marrow niche is not merely an anatomic compartment; rather, it integrates the physiology of two distinct organ systems, the skeleton and the marrow. The niche has a hypoxic microenvironment that maintains quiescent haematopoietic stem cells (HSCs) and supports glycolytic metabolism. In response to biochemical cues and under the influence of neural, hormonal, and biochemical factors, marrow stromal elements, such as mesenchymal stromal cells (MSCs), differentiate into mature, functioning cells. However, disruption of the niche can affect cellular differentiation, resulting in disorders ranging from osteoporosis to malignancy. In this Review, we propose that the niche reflects the vitality of two distinct tissues—bone and blood—by providing a unique environment for stem and stromal cells to flourish whilst simultaneously preventing disproportionate proliferation, malignant transformation or loss of the multipotent progenitors required for healing, functional immunity and growth throughout an organism’s lifetime. Through a fuller understanding of the complexity of the niche in physiologic and pathologic states, the successful development of more-effective therapeutic approaches to target the niche and its cellular components for the treatment of rheumatic, endocrine, neoplastic and metabolic diseases becomes achievable.

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Hematopoietic stem cells are regulated by Cripto, as an intermediary of HIF‐1α in the hypoxic bone marrow niche

Cited by 26 publications

References 54 publications

Mitoquinone restores platelet production in irradiation-induced thrombocytopenia

Mitoquinone restores platelet production in irradiation-induced thrombocytopenia

Metabolic requirements for the maintenance of self-renewing stem cells

Navigating the bone marrow niche: translational insights and cancer-driven dysfunction

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