Pharmacologic increase in HIF1α enhances hematopoietic stem and progenitor homing and engraftment

Speth, John D.; Hoggatt, Jonathan; Singh, Pratibha; Pelus, Louis M.

doi:10.1182/blood-2013-07-516336

Cited by 53 publications

(46 citation statements)

References 31 publications

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“…34 Moreover, the observed increase in surface CXCR4 could result from the translocation of intracellular stores of CXCR4 to the cell surface, which has been reported in hematopoietic progenitor cells. 82 Following radiation injury, the upregulation of MK surface CXCR4 could also be due to microenvironmental hypoxia through HIF-1a 83 ( Figure 4B). Our studies reveal spatial fluctuations in SDF-1 transcript production in the marrow following sublethal TBI that dynamically regulate MK location.…”

Section: Discussionmentioning

confidence: 99%

SDF-1 dynamically mediates megakaryocyte niche occupancy and thrombopoiesis at steady state and following radiation injury

Niswander

Fegan²,

Kingsley³

et al. 2014

Blood

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• SDF-1 acutely affects megakaryocyte spatial distribution in the bone marrow at steady state and in the setting of radiation injury.• SDF-1-directed localization of megakaryocytes into the vascular niche increases platelet output.Megakaryocyte (MK) development in the bone marrow progresses spatially from the endosteal niche, which promotes MK progenitor proliferation, to the sinusoidal vascular niche, the site of terminal maturation and thrombopoiesis. The chemokine stromal cellderived factor-1 (SDF-1), signaling through CXCR4, is implicated in the maturational chemotaxis of MKs toward sinusoidal vessels. Here, we demonstrate that both IV administration of SDF-1 and stabilization of endogenous SDF-1 acutely increase MKvasculature association and thrombopoiesis with no change in MK number. In the setting of radiation injury, we find dynamic fluctuations in marrow SDF-1 distribution that spatially and temporally correlate with variations in MK niche occupancy. Stabilization of altered SDF-1 gradients directly affects MK location. Importantly, these SDF-1-mediated changes have functional consequences for platelet production, as the movement of MKs away from the vasculature decreases circulating platelets, while MK association with the vasculature increases circulating platelets. Finally, we demonstrate that manipulation of SDF-1 gradients can improve radiation-induced thrombocytopenia in a manner additive with earlier TPO treatment. Taken together, our data support the concept that SDF-1 regulates the spatial distribution of MKs in the marrow and consequently circulating platelet numbers. This knowledge of the microenvironmental regulation of the MK lineage could lead to improved therapeutic strategies for thrombocytopenia. (Blood. 2014;124(2):277-286) Introduction Platelet-producing megakaryocytes (MKs) are derived from megakaryocyte progenitors (MKPs), which are defined functionally by their capacity to form colonies in vitro. 1,2 MKPs are thought to reside near the bone surface in an "endosteal niche," where environmental cues encourage expansion, but suppress terminal maturation.3-6 Polyploid MKs mature cytoplasmically, extrude proplatelets in association with sinusoidal vasculature, and shed platelets into the peripheral blood. [7][8][9] This process results in past-maturity "exhausted" MKs comprised of a nucleus with a thin layer of cytoplasm surrounded by a cell membrane. 10,11 Megakaryopoiesis is primarily regulated by the cytokine thrombopoietin (TPO), which signals through its receptor Mpl to promote MKP proliferation and MK maturation. [12][13][14] Although the physical association of MKs with sinusoidal vasculature was first appreciated several decades ago, 15-17 the functional significance of the "vascular niche" for MK maturation and thrombopoiesis has only more recently begun to be elucidated. 4,[18][19][20][21] Several studies have implicated the chemokine stromal cellderived factor-1 ([SDF-1] or CXCL12) signaling through receptor CXCR4 in the maturational localization of MKs to the vascular nic...

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Section: Discussionmentioning

confidence: 99%

SDF-1 dynamically mediates megakaryocyte niche occupancy and thrombopoiesis at steady state and following radiation injury

Niswander

Fegan²,

Kingsley³

et al. 2014

Blood

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“…Such a gradient is beneficial to stem cells since it limits oxidative stress and consequent risk of mutations, and also aids in the maintenance of totipotency. In addition, the culture of haematopoietic stem cells at low oxygen tension levels permits a better engraftment into mice models (Speth et al, 2014).…”

Section: Cell Biology and Oxygenmentioning

confidence: 99%

Oxygen and viruses: a breathing story

Morinet

Parent

Bergeron

et al. 2015

Journal of General Virology

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The effect of oxygen on virus replication is complex, and the role of hypoxia-inducible factor 1a (HIF-1a) in the metabolism of virus-infected cells remains uncertain. Solid tumours are hypoxic, and some viruses use this low oxygen tension level to facilitate their replication in tumour cells, thereby causing cell lysis. In addition, the interactions between viruses and HIF-1a may stimulate a trained immunity. However, the evolutionary basis for the oxygen regulatory mechanism of virus replication is ill-defined and requires further investigation.

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“…Because HIF regulates expression of Cxcr4, an essential receptor for HSC homing, we evaluated the homing capacity of ARNTdeficient progenitor cells. 28,29 Importantly, no defect in KO cell homing to either the BM or spleen ( Figure 3E-F) was observed, suggesting that this does not contribute to the phenotypes detected in our BMT studies.BMT is a test of HSC functional stem cell properties but also subjects them to stress conditions, because they must rapidly proliferate to reconstitute the recipient BM. The myelosuppressant 5-FU induces a similar stress in HSCs and can be used to evaluate HSC exhaustion.…”

mentioning

confidence: 80%

mentioning

confidence: 80%

The aryl hydrocarbon receptor nuclear translocator is an essential regulator of murine hematopoietic stem cell viability

Krock

Eisinger-Mathason

Giannoukos

et al. 2015

Blood

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Key Points• ARNT promotes adult hematopoietic stem cell viability through regulation of BCL-2 and VEGF-A expression.• Fetal liver hematopoietic progenitors experience hypoxia and loss of hypoxiainduced transcription decreases their survival.Hypoxia-inducible factors (HIFs) are master regulators of the transcriptional response to low oxygen and play essential roles in embryonic development, tissue homeostasis, and disease. Recent studies have demonstrated that hematopoietic stem cells (HSCs) within the bone marrow localize to a hypoxic niche and that HIF-1a promotes HSC adaptation to stress. Because the related factor HIF-2a is also expressed in HSCs, the combined role of HIF-1a and HIF-2a in HSC maintenance is unclear. To this end, we have conditionally deleted the HIF-a dimerization partner, the aryl hydrocarbon receptor nuclear translocator (ARNT) in the hematopoietic system to ablate activity of both HIF-1a and HIF-2a and assessed the functional consequence of ARNT deficiency on fetal liver and adult hematopoiesis. We determined that ARNT is essential for adult and fetal HSC viability and homeostasis. Importantly, conditional knockout of both Hif-1a and Hif-2a phenocopied key aspects of these HSC phenotypes, demonstrating that the impact of Arnt deletion is primarily HIF dependent. ARNT-deficient long-term HSCs underwent apoptosis, potentially because of reduced B-cell lymphoma 2 (BCL-2) and vascular endothelial growth factor A (VEGF-A) expression. Our results suggest that HIF activity may regulate HSC homeostasis through these prosurvival factors. (Blood. 2015;125(21):3263-3272) IntroductionHematopoietic stem cells (HSCs) reside in the bone marrow (BM), where they balance both cell-intrinsic and cell-extrinsic cues to achieve self-renewal and appropriate hematologic differentiation throughout the mammalian lifespan.1 HSCs are regulated by their microenvironment, which consists of endothelial, 2 perivascular, 2 adipocyte, 3 and osteoblast 4 support cells; secreted factors; and oxygen (O 2 ) availability. 5Hypoxia has become increasingly recognized as a critical regulator of stem cells, during both embryonic development and adulthood. 6 Importantly, HSCs reside in a poorly perfused hypoxic niche, [7][8][9][10] and recent data suggest that HSC oxygenation levels may be partially regulated by cell-specific mechanisms. 10 Although the biological importance of these observations is not entirely clear, hypoxia clearly imposes phenotypic consequences for HSCs. For instance, long-term HSCs (LT-HSCs) are highly quiescent, a cell cycle status often associated with O 2 -and nutrient-deprived cells. Although many pathways converge on metabolism, the primary transcriptional response to hypoxia is mediated by hypoxia-inducible factors (HIFs).HIFs are heterodimeric transcription factors composed of a HIF-a subunit ) and their common b subunit, HIF-1b or the aryl hydrocarbon receptor nuclear translocator (ARNT).13 HIFa/ARNT heterodimers stimulate the transcription of many genes, which promote survival and adaptation to ...

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Pharmacologic increase in HIF1α enhances hematopoietic stem and progenitor homing and engraftment

Cited by 53 publications

References 31 publications

SDF-1 dynamically mediates megakaryocyte niche occupancy and thrombopoiesis at steady state and following radiation injury

SDF-1 dynamically mediates megakaryocyte niche occupancy and thrombopoiesis at steady state and following radiation injury

Oxygen and viruses: a breathing story

The aryl hydrocarbon receptor nuclear translocator is an essential regulator of murine hematopoietic stem cell viability

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