Pharmacologic stabilization of HIF-1α increases hematopoietic stem cell quiescence in vivo and accelerates blood recovery after severe irradiation

Abstract

Key Points• HIF-1␣ protein stabilization increases HSC quiescence in vivo.• HIF-1␣ protein stabilization increases HSC resistance to irradiation and accelerates recovery. IntroductionTo remain in an undifferentiated state, hematopoietic stem cells (HSCs) need be lodged in specific niches of the BM where they can preserve their essential capacity to self-renew and reconstitute the whole hematopoietic and immune systems on transplantation. 1-2 In mice 3 and humans, 4 the BM contains 2 pools of HSCs: (1) a quiescent pool that divides very infrequently approximately every 145 days to self-renew and maintain a genetic reserve and (2) an activated pool that divides more frequently for the daily replacement of hematopoietic progenitor cells (HPCs), blood leukocytes, erythrocytes, and platelets. Molecular components of HSC niches are critical to maintaining the correct balance among quiescence, self-renewing proliferation, and differentiation of HSCs. It has been found recently that, in addition to the stromal cells forming niches and the arrays of essential mediators they secrete, the physicochemical conditions within niches are critical to maintaining HSC quiescence and self-renewal. 5 For example, the most quiescent HSCs capable of serial reconstitution in serial transplantations reside in niches very poorly perfused by the circulating blood, whereas more active and proliferative HSCs capable of only a single round of transplantation or reconstitution reside in more perfused niches. 6 A direct consequence of low perfusion could be increased local hypoxia. Indeed, the oxygenation rate of a tissue is dependent on how rapidly oxygen solubilized in the circulating blood perfuses into the tissue and how rapidly this oxygen is consumed by cells in an active metabolic state. [7][8] Similar to the BM, solid tumors are sites of rapid regeneration and cell division. Analyses of blood perfusion and hypoxia in solid tumors have shown that areas that are poorly perfused are stained by the hypoxia sensitive marker pimonidazole, suggesting a hypoxic state, 9 and contain tumor stem cells. [10][11] Similarly, the endosteal region of the mouse BM, which is known to harbor niches containing quiescent HSCs,3,[12][13][14][15] is also stained by pimonidazole in steady-state conditions, also suggesting a hypoxic state. [16][17] A functional consequence of tissue hypoxia is the stabilization of a family of oxygen-labile transcription factors called hypoxiainducing factors (HIFs). HIFs are heterodimers of an O 2 -labile ␣-subunit, and a stable ␤-subunit called the aryl hydrocarbon receptor nuclear translocator (ARNT). Once the HIF-␣:ARNT complex is formed, it can then translocate to the nucleus and activate the transcription of genes containing hypoxia-responsive elements. Hematopoietic cells, including HSCs, express HIF-1␣ mRNA. 18 In hypoxic conditions with an oxygen concentration below 2%, the HIF-␣ protein is stable and the complex with ARNT is formed, translocates to the nucleus, and initiates transcription of hypoxia-responsive elemen...

Differential hypoxic regulation of the microRNA-146a/CXCR4 pathway in normal and leukemic monocytic cells: impact on response to chemotherapy

“…[23][24][25][26][27] Stabilization of HIF proteins by dimethyloxalyl glycine treatment, increases hematopoietic stem cell quiescence in vivo, improves blood recovery and enhances hematopoietic stem cell survival in the bone marrow of irradiated mice. 23 Echinomycin, a DNA-intercalating agent that blocks HIF DNA-binding activity, selectively eradicates cancer stem cells in mouse models of lymphoma and human AML 24 and selectively kills leukemia-initiating cells, inducing long-term remission in a murine model of relapsed AML. 25 The chemokine receptor CXCR4 and its ligand stromalderived factor-1α (SDF-1/CXCL12) are both major players in the cross-talk between leukemic cells and the bone marrow microenvironment.…”

“…This observation is in line with recent studies showing a key role of HIF-1α in maintaining the stemness of normal hematopoietic stem cells: in fact, in HIF-1α -/-mice hematopoietic stem cell numbers decrease during stress in association with a loss of quiescence. 23,46 Hematopoietic stem cells in their niche use glycolysis to meet their energy demand, which depends on a Meis1-induced HIF-1α-signaling network. 47 Associated with the differential HIF-1α and HIF-2α expression found in monocytic differentiating hematopoietic progenitor cells, we identified miR-146a as a new hypoxic-responsive microRNA.…”

The Adult Hematopoietic Niches — Cellular Composition, Histological Organization and Physiological Regulation

“…However, it is more difficult to demonstrate that endosteal and vascular niches represent functionally different environments housing quiescent HSC and cycling hematopoietic progenitors, respectively, as suggested by some authors [12,36]. The endosteal niche would house dormant, primitive HSCs due to its presumptive hypoxic condition [37,38].It has been reported that disruption of HIF 1α (hypoxia-inducible factor) coursed with loss of HSC quiescence and repopulating activity whereas stabilization of HIF-1α induced opposite effects [39,40], but CFU-S associated with endosteum has been described as non-quiescent cells and, indeed, endosteum is a highly vascularised and, therefore, presumably well-oxygenated area of the BM. Thus, it has been proposed that hematopoietic progenitors exhibit an intrinsic hypoxic profile independently of their location in the BM [41,42].…”

Structural-functional organisation of the bone marrow hematopoietic stem cells niches

“…Hypoxia-inducible transcription factors are also involved in the control of genes associated with HSCs self-renewal, including telomerase genes [210,211], Oct4 [49] and Notch [212]. Inhibition of HIF-1α synthesis leads to the loss of HSCs dormancy and decrease of repopulation activity, whereas stabilization of HIF-1α level induces dormancy and enhances repopulation activity of HSCs [213,214].…”