Administration of PHD inhibitors boosts quiescence and lowers proliferation of HSCs in the bone tissue marrow in vivo, thereby protecting them from great dosages of irradiation and accelerating hematological recovery. Administration of PHD inhibitors boosts quiescence and reduces proliferation of HSCs in the bone tissue marrow in vivo, thus safeguarding them from high dosages of irradiation and accelerating hematological recovery. Latest findings also present that stabilization of HIF-1 boosts mobilization of HSCs in response to granulocyte colony-stimulating aspect and plerixafor, recommending that PHD inhibitors could possibly be useful agents to improve mobilization achievement in patients needing transplantation. These results highlight the need for the hypoxia-sensing pathway and HIFs in scientific hematology Launch Maintenance of air homeostasis is crucial for the success of organisms. On exposure to hypoxic conditions, a cellular response is usually mounted by hypoxia-inducible factors (HIFs). HIFs are a family of three transcription factors composed of one of three oxygen-sensitive subunitsHIF-1, HIF-2, and HIF-3and a constitutively expressed subunit HIF-1, also called aryl hydrocarbon receptor nuclear translocator (ARNT). Once the HIF-:ARNT complex is usually formed, it translocates to the nucleus and activates the transcription of genes made up of hypoxia-responsive elements (HREs) [1, 2]. Hematopoietic cells including hematopoietic stem cells (HSCs) express HIF-1 mRNA, which is usually expressed ubiquitously by all cells. In hypoxic conditions with oxygen (O2) concentration below 2%, HIF- proteins are stabilized and complex with ARNT to translocate to the nucleus and initiate transcription of HRE-containing genes. In normoxic conditions or when O2 concentration exceeds 2%, HIF-1 protein is usually degraded within 5 minutes by the proteasome [3], preventing the formation of the transcription factor and its translocation to the nucleus. The sensitization of HIF- proteins to proteasomal degradation in the presence of O2 is usually mediated by three prolyl hydroxylase domain name (PHD) enzymes that hydroxylate two proline residues within the oxygen-degradation domain name of HIF- proteins (Fig. 1A) [4, 5]. These hydroxylated proline residues then bind the von Hippel-Lindau tumor-suppressor protein to form an E3 ubiquitin ligase complex that ubiquinates and targets HIF- protein to the proteasome (Fig. 1B) [6, 7]. PHD enzymes are iron(II)-dependent and utilize 2-oxoglutarate and O2 as substrates to hydroxylate proline residues [8]. In cultured cells, PHDs are inactive when O2 is usually <2% in the extracellular milieu, resulting in HIF- protein stabilization. Open in a separate window Physique 1. Regulation of HIF- proteins. (A): Hydroxylation of two distinct proline residues is usually catalyzed by PHDs. (B): Regulation of the HIF- protein under hypoxic and normoxic conditions. PHD inhibitors block HIF- proline hydroxylation and subsequent ubiquitination. HIF- proteins are stabilized. Abbreviations: ARNT, aryl hydrocarbon receptor nuclear translocator; ATM, ataxia telangiectasia mutated; DMOG, dimethyloxalylglycine; HRE, hypoxia-responsive elements; PHD, prolyl hydroxylase domain name; pVHL, von Hippel-Lindau protein. As noted previously, the expression of HIF- subunits is usually predominantly regulated by PHD-mediated proline hydroxylation. There are three well known PHD isoforms, called PHD1, PHD2, and PHD3, and all are reported to hydroxylate HIF- subunits [9]. They are encoded by three distinct genes: for PHD1, for PHD2, and for PHD3. A fourth PHD enzyme is also thought to be involved in regulating HIF- subunits and has been reported to play a potential role in erythropoiesis [10, 11]. Role of HIFs in Controlling Hematopoietic Stem and Progenitor Cells HIF Expression in Hematopoietic Stem and Progenitor Cells The importance of HIFs in development and hematopoiesis has been demonstrated by genetic deletion of ARNT, which abrogates the function of both HIF-1 and HIF-2. In the developing embryo, ARNT is essential for multilineage hematopoietic progenitors, vasculogenesis, and angiogenesis [12, 13]. HIF-1 mRNA is usually ubiquitously expressed [14]. In steady state, HIF-1 protein is usually detected only in the endosteal region of the bone marrow (BM) and in some discrete cells in the central BM [15]. Consequently, HIF-1 protein is generally below detection in whole BM lysates [15, 16]; however, when HSCs are mobilized in the peripheral blood by administering granulocyte colony-stimulating factor (G-CSF) or cyclophosphamide, HIF-1 protein is usually stabilized and found throughout the BM cavity [15]. Unlike HIF-1, HIF-2 mRNA expression is restricted. HIF-2 is usually expressed by vascular endothelium, hepatocytes, and interstitial and glomerular cells of the kidney. In the BM, HIF-2 mRNA is primarily expressed by hematopoietic lineage-negative cells [14]. HIF-2 mRNA is detected at very low levels in HSCs; however, in these cells, HIF-2 protein is mainly localized to the cytoplasm [14], suggesting that it is not transcriptionally active [17]. The expression profile of HIF-3 has been largely uncharacterized; however, in the BM, HIF-3 is most highly expressed in HSCs and is expressed at low levels in more differentiated.Pharmacological stabilization of HIF-1 protein with PHD inhibitors is also emerging as an important regulator of HSC proliferation and self-renewal. Pharmacological stabilization of HIF-1 protein with PHD inhibitors is also emerging as an important regulator of HSC proliferation and self-renewal. Administration of PHD inhibitors increases quiescence and decreases proliferation of HSCs in the bone marrow in vivo, thereby protecting them from high doses of irradiation and accelerating hematological recovery. Recent findings also show that stabilization of HIF-1 increases mobilization of HSCs in response to granulocyte colony-stimulating factor and plerixafor, suggesting that PHD inhibitors could be useful agents to increase mobilization success in patients requiring transplantation. These findings highlight the importance of the hypoxia-sensing pathway and HIFs in clinical hematology Introduction Maintenance of oxygen homeostasis is critical for the survival of organisms. On exposure to hypoxic conditions, a cellular response is mounted by hypoxia-inducible factors (HIFs). HIFs are a family of three transcription factors composed of one of three oxygen-sensitive subunitsHIF-1, HIF-2, and HIF-3and a constitutively expressed subunit HIF-1, also called aryl hydrocarbon receptor nuclear translocator (ARNT). Once the HIF-:ARNT complex is formed, it translocates to the nucleus and activates the transcription of genes containing hypoxia-responsive elements (HREs) [1, 2]. Hematopoietic cells including hematopoietic stem cells (HSCs) express HIF-1 mRNA, which is expressed ubiquitously by all cells. In hypoxic conditions with oxygen (O2) concentration below 2%, HIF- proteins are stabilized and complex with ARNT to translocate to the nucleus and initiate transcription of HRE-containing genes. In normoxic conditions or when O2 concentration exceeds 2%, HIF-1 protein is degraded within 5 minutes by the proteasome [3], preventing the formation of the transcription factor and its translocation to the nucleus. The sensitization of HIF- proteins to proteasomal degradation in the presence of O2 is mediated by three prolyl hydroxylase domain (PHD) enzymes that hydroxylate two proline residues within the oxygen-degradation domain of HIF- proteins (Fig. 1A) [4, 5]. These hydroxylated proline residues then bind the von Hippel-Lindau tumor-suppressor protein to form an E3 ubiquitin ligase complex that ubiquinates and targets HIF- protein to the proteasome (Fig. 1B) [6, 7]. PHD enzymes are iron(II)-dependent and utilize 2-oxoglutarate and O2 as substrates to hydroxylate proline residues [8]. In cultured cells, PHDs are inactive when O2 is <2% in the extracellular milieu, resulting in HIF- protein stabilization. Open in a separate window Figure 1. Regulation of HIF- proteins. (A): Hydroxylation of two distinct proline residues is catalyzed by PHDs. (B): Regulation of the HIF- protein under hypoxic and normoxic conditions. PHD inhibitors block HIF- proline hydroxylation and subsequent ubiquitination. HIF- proteins are stabilized. Abbreviations: ARNT, aryl hydrocarbon receptor nuclear translocator; ATM, ataxia telangiectasia mutated; DMOG, dimethyloxalylglycine; HRE, hypoxia-responsive elements; PHD, prolyl hydroxylase domain; pVHL, von Hippel-Lindau protein. As noted previously, the expression of HIF- subunits is predominantly regulated by PHD-mediated proline hydroxylation. There are three well known PHD isoforms, called PHD1, PHD2, and PHD3, and all are reported to hydroxylate HIF- subunits [9]. They are encoded by three distinct genes: for PHD1, for PHD2, and for PHD3. A fourth PHD enzyme is also thought to be involved in regulating HIF- subunits and has been reported to play a potential role in erythropoiesis [10, 11]. Role of HIFs in Controlling Hematopoietic Stem and Progenitor Cells HIF Expression in Hematopoietic Stem and Progenitor Cells The importance of HIFs in development and hematopoiesis has been demonstrated by genetic deletion of ARNT, which abrogates the function of both HIF-1 and HIF-2. In the developing embryo, ARNT is essential for multilineage hematopoietic progenitors, vasculogenesis, and angiogenesis [12, 13]. HIF-1 mRNA is ubiquitously indicated [14]. In constant state, HIF-1 protein is definitely detected only in the endosteal region of the bone marrow (BM) and in some discrete cells in the central BM [15]. As a result, HIF-1 protein is generally below detection in whole BM lysates [15, 16]; however, when HSCs are mobilized in the peripheral blood by administering granulocyte colony-stimulating element (G-CSF) or cyclophosphamide, HIF-1 protein is definitely stabilized and found throughout the BM cavity [15]. Unlike HIF-1, HIF-2 mRNA manifestation is restricted. HIF-2 is definitely indicated by vascular endothelium, hepatocytes, and interstitial and glomerular cells of the kidney. In the BM, HIF-2 mRNA is definitely primarily indicated by hematopoietic lineage-negative cells [14]. HIF-2 mRNA is definitely detected at very low levels in HSCs; however, in these cells, HIF-2 protein is mainly localized to the cytoplasm [14], suggesting that it is not transcriptionally active [17]. The manifestation profile of HIF-3 has been largely uncharacterized; however, in the BM, HIF-3 is definitely most highly indicated in HSCs and is indicated at low levels in more differentiated progeny [14]. The function of HIF-3 is definitely unfamiliar because, unlike HIF-1 and HIF-2,.As a result, the recent discovery of small molecules that stabilize HIFs individually of tissue oxygenation opens the possibility of pharmacological interventions in the hematopoietic system, particularly to treat anemia, to enhance HSC mobilization for transplantation, and to increase HSC radioresistance. of HIF-1 raises mobilization of HSCs in response to granulocyte colony-stimulating element and plerixafor, suggesting that PHD inhibitors could be useful agents to increase mobilization success in patients requiring transplantation. These findings highlight the importance of the hypoxia-sensing pathway and HIFs in medical hematology Intro Maintenance of oxygen homeostasis is critical for the survival of organisms. On exposure to hypoxic conditions, a cellular response is definitely mounted by hypoxia-inducible factors (HIFs). HIFs are a family of three transcription factors composed of one of three oxygen-sensitive subunitsHIF-1, HIF-2, and HIF-3and a constitutively indicated subunit HIF-1, also called aryl hydrocarbon receptor nuclear translocator (ARNT). Once the HIF-:ARNT complex is definitely created, it translocates to the nucleus and activates the transcription of genes comprising hypoxia-responsive elements (HREs) [1, 2]. Hematopoietic cells including hematopoietic stem cells (HSCs) communicate HIF-1 mRNA, which is definitely indicated ubiquitously by all cells. In hypoxic conditions with oxygen (O2) concentration below 2%, HIF- proteins are stabilized and complex with ARNT to translocate to the nucleus and initiate transcription of HRE-containing genes. In normoxic conditions or when O2 concentration exceeds 2%, HIF-1 protein is definitely degraded within 5 minutes from the proteasome [3], preventing the formation of the transcription element and its translocation to the nucleus. The sensitization of HIF- proteins to proteasomal degradation in the presence of O2 is certainly mediated by three prolyl hydroxylase area (PHD) enzymes that hydroxylate two proline residues inside the oxygen-degradation area of HIF- proteins (Fig. 1A) [4, 5]. These hydroxylated proline residues after that bind the von Hippel-Lindau tumor-suppressor proteins to create an E3 ubiquitin ligase complicated that ubiquinates and goals HIF- proteins towards the proteasome (Fig. 1B) [6, 7]. PHD enzymes are iron(II)-reliant and make use of 2-oxoglutarate and O2 as substrates to hydroxylate proline residues [8]. In cultured cells, PHDs are inactive when O2 is certainly <2% in the extracellular milieu, leading to HIF- proteins stabilization. Open up in another window Body 1. Legislation of HIF- proteins. (A): Hydroxylation of two specific proline residues is certainly catalyzed by PHDs. (B): Legislation from the HIF- proteins under hypoxic and normoxic circumstances. PHD inhibitors stop HIF- proline hydroxylation and following ubiquitination. HIF- proteins are stabilized. Abbreviations: ARNT, aryl hydrocarbon receptor nuclear translocator; ATM, ataxia telangiectasia mutated; DMOG, dimethyloxalylglycine; HRE, hypoxia-responsive components; PHD, prolyl hydroxylase area; pVHL, von Hippel-Lindau proteins. As observed previously, the appearance of HIF- subunits is certainly predominantly governed by PHD-mediated proline hydroxylation. You can find three popular PHD isoforms, known as PHD1, PHD2, and PHD3, and each is reported to hydroxylate HIF- subunits [9]. These are encoded by three specific genes: for PHD1, for PHD2, as well as for PHD3. A 4th PHD enzyme can be regarded as involved with regulating HIF- subunits and continues to be reported to try out a potential function in erythropoiesis [10, 11]. Function of HIFs in Managing Hematopoietic Stem and Progenitor Cells HIF Appearance in Hematopoietic Stem and Progenitor Cells The need for HIFs in advancement and hematopoiesis continues to be demonstrated by hereditary deletion of ARNT, which abrogates the function of both HIF-1 and HIF-2. In the developing embryo, ARNT is vital for multilineage hematopoietic progenitors, vasculogenesis, and angiogenesis [12, 13]. HIF-1 mRNA is certainly ubiquitously portrayed [14]. In regular state, HIF-1 proteins is certainly detected just in the endosteal area from the bone tissue marrow (BM) and in a few discrete cells in the central BM [15]. Therefore, HIF-1 proteins is normally below detection entirely BM lysates [15, 16]; nevertheless, when HSCs are mobilized in the peripheral bloodstream by administering granulocyte colony-stimulating aspect (G-CSF) or cyclophosphamide, HIF-1 proteins is certainly stabilized and discovered through the entire BM cavity [15]. Unlike HIF-1, HIF-2 mRNA appearance is fixed. HIF-2 is certainly portrayed by vascular endothelium, hepatocytes, and interstitial and glomerular cells from the kidney. In the BM, HIF-2 mRNA is certainly primarily portrayed by hematopoietic lineage-negative cells [14]. HIF-2 mRNA is certainly detected at suprisingly low amounts in HSCs; nevertheless, in these cells, HIF-2 proteins Rabbit polyclonal to BNIP2 is principally localized towards the cytoplasm [14], recommending that it’s not transcriptionally energetic [17]. The appearance profile of HIF-3 continues to be largely uncharacterized; nevertheless, in the BM, HIF-3 is certainly most highly portrayed in HSCs and it is portrayed at low amounts in even more differentiated progeny [14]. The function of HIF-3 is certainly unidentified because, unlike HIF-1 and HIF-2, HIF-3 will not include a DNA-binding area. Furthermore,.Mice treated using the PHD inhibitor dimethyloxalylglycine or FG-4497 ahead of irradiation had 100% of their HSCs surviving in the BM after 9.0-Gy irradiation, whereas in charge saline-treated mice, the real amount of long-term competitive repopulating HSCs was reduced 27-fold by 9.0-Gy irradiation. them from high dosages of irradiation and accelerating hematological recovery. Latest findings also present that stabilization of HIF-1 boosts mobilization of HSCs in response to granulocyte colony-stimulating aspect and plerixafor, recommending that PHD inhibitors could possibly be useful agents to improve mobilization achievement in patients needing transplantation. These results highlight the need for the hypoxia-sensing pathway and HIFs in scientific hematology Launch Maintenance of air homeostasis is crucial for the success of microorganisms. On contact with hypoxic circumstances, a mobile response is certainly installed by hypoxia-inducible elements (HIFs). HIFs certainly are a category of three transcription elements composed of among three oxygen-sensitive subunitsHIF-1, HIF-2, and HIF-3and a constitutively indicated subunit HIF-1, also known as aryl hydrocarbon receptor nuclear translocator (ARNT). After the HIF-:ARNT complicated can be shaped, it translocates towards the nucleus and activates the transcription of genes including hypoxia-responsive components (HREs) [1, 2]. Hematopoietic cells including hematopoietic stem cells (HSCs) communicate HIF-1 mRNA, which can be indicated ubiquitously by all cells. In hypoxic circumstances with air (O2) focus below 2%, HIF- proteins are stabilized and complicated with ARNT to translocate towards the nucleus and start transcription of HRE-containing genes. In normoxic circumstances or when O2 focus surpasses 2%, HIF-1 proteins can be degraded within five minutes from the proteasome [3], avoiding the formation from the transcription element and its own translocation towards the nucleus. The sensitization of HIF- proteins to proteasomal degradation in the current presence of O2 can be mediated by three prolyl hydroxylase site (PHD) enzymes that hydroxylate two proline residues inside the oxygen-degradation site of HIF- proteins (Fig. 1A) [4, 5]. These hydroxylated proline residues after that bind the von Hippel-Lindau tumor-suppressor proteins to create an E3 ubiquitin ligase complicated that ubiquinates and focuses on HIF- proteins towards the proteasome (Fig. 1B) [6, 7]. PHD enzymes are iron(II)-reliant and use 2-oxoglutarate and O2 as substrates to hydroxylate proline residues [8]. In cultured cells, PHDs are inactive when O2 can be <2% in the extracellular milieu, leading to HIF- proteins stabilization. Open up in another window Shape 1. Rules of HIF- proteins. (A): Hydroxylation of two specific proline residues can be catalyzed by PHDs. (B): Rules from the HIF- proteins under hypoxic and normoxic circumstances. PHD inhibitors stop HIF- proline hydroxylation and following ubiquitination. HIF- proteins are stabilized. Abbreviations: ARNT, aryl hydrocarbon receptor nuclear translocator; ATM, ataxia telangiectasia mutated; DMOG, dimethyloxalylglycine; HRE, hypoxia-responsive components; PHD, prolyl hydroxylase site; pVHL, von Hippel-Lindau proteins. As mentioned previously, the manifestation of HIF- subunits can be predominantly controlled by PHD-mediated proline hydroxylation. You can find three popular PHD isoforms, known as PHD1, PHD2, and PHD3, and each Pyrimethamine is reported to hydroxylate HIF- subunits [9]. They may be encoded by three specific genes: for PHD1, for PHD2, as well as for PHD3. A 4th PHD enzyme can be regarded as involved with regulating HIF- subunits and continues to be reported to try out a potential part in erythropoiesis [10, 11]. Part of HIFs in Managing Hematopoietic Stem and Progenitor Cells HIF Manifestation in Hematopoietic Stem and Progenitor Cells The need for HIFs in advancement and hematopoiesis continues to be demonstrated by hereditary deletion of ARNT, which abrogates the function of both HIF-1 and HIF-2. In the developing embryo, ARNT is vital for multilineage hematopoietic progenitors, vasculogenesis, and angiogenesis [12, 13]. HIF-1 mRNA can be ubiquitously indicated [14]. In stable state, HIF-1 proteins can be detected just in the endosteal area from the bone tissue marrow (BM) and in a few discrete cells in the central BM [15]. As a result, HIF-1 proteins.As a result, HIF-1 protein is normally below detection entirely BM lysates [15, 16]; nevertheless, when HSCs are mobilized in the peripheral bloodstream by administering granulocyte colony-stimulating element (G-CSF) or cyclophosphamide, HIF-1 proteins can be stabilized and discovered through the entire BM cavity [15]. Unlike HIF-1, HIF-2 mRNA expression is fixed. raises quiescence and reduces proliferation of HSCs in the bone tissue marrow in vivo, therefore safeguarding them from high dosages of irradiation and accelerating hematological recovery. Latest findings also display that stabilization of HIF-1 raises mobilization of HSCs in response to granulocyte colony-stimulating element and plerixafor, recommending that PHD inhibitors could possibly be useful agents to improve mobilization achievement in patients needing transplantation. These results highlight the need for the hypoxia-sensing pathway and HIFs in medical hematology Intro Maintenance of air homeostasis is crucial for the success of microorganisms. On contact with hypoxic circumstances, a mobile response can be installed by hypoxia-inducible elements (HIFs). HIFs certainly are a category of Pyrimethamine three transcription elements composed of among three oxygen-sensitive subunitsHIF-1, HIF-2, and HIF-3and a constitutively portrayed subunit HIF-1, Pyrimethamine also known as aryl hydrocarbon receptor nuclear translocator (ARNT). After the HIF-:ARNT complicated is normally produced, it translocates towards the nucleus and activates the transcription of genes filled with hypoxia-responsive components (HREs) [1, 2]. Hematopoietic cells including hematopoietic stem cells (HSCs) exhibit HIF-1 mRNA, which is normally portrayed ubiquitously by all cells. In hypoxic circumstances with air (O2) focus below 2%, HIF- proteins are stabilized and complicated with ARNT to translocate towards the nucleus and start transcription of HRE-containing genes. In normoxic circumstances or when O2 focus surpasses 2%, HIF-1 proteins is normally degraded within five minutes with the proteasome [3], avoiding the formation from the transcription aspect and its own translocation towards the nucleus. The sensitization of HIF- proteins to proteasomal degradation in the current presence of O2 is normally mediated by three prolyl hydroxylase domains (PHD) enzymes that hydroxylate two proline residues inside the oxygen-degradation domains of HIF- proteins (Fig. 1A) [4, 5]. These hydroxylated proline residues after that bind the von Hippel-Lindau tumor-suppressor proteins to create an E3 ubiquitin ligase complicated that ubiquinates and goals HIF- proteins towards the proteasome (Fig. 1B) [6, 7]. PHD enzymes are iron(II)-reliant and make use of 2-oxoglutarate and O2 as substrates to hydroxylate proline residues [8]. In cultured cells, PHDs are inactive when O2 is normally <2% in the extracellular milieu, leading to HIF- proteins stabilization. Open up in another window Amount 1. Legislation of HIF- proteins. (A): Hydroxylation of two distinctive proline residues is normally catalyzed by PHDs. (B): Legislation from the HIF- proteins under hypoxic and normoxic circumstances. PHD inhibitors stop HIF- proline hydroxylation and following ubiquitination. HIF- proteins are stabilized. Abbreviations: ARNT, aryl hydrocarbon receptor nuclear translocator; ATM, ataxia telangiectasia mutated; DMOG, dimethyloxalylglycine; HRE, hypoxia-responsive components; PHD, prolyl hydroxylase domains; pVHL, von Hippel-Lindau proteins. As observed previously, the appearance of HIF- subunits is normally predominantly governed by PHD-mediated proline hydroxylation. A couple of three popular PHD isoforms, known as PHD1, PHD2, and PHD3, and each is reported to hydroxylate HIF- subunits [9]. These are encoded by three distinctive genes: for PHD1, for PHD2, as well as for PHD3. A 4th PHD enzyme can be regarded as involved with regulating HIF- subunits and continues to be reported to try out a potential function in erythropoiesis [10, 11]. Function of HIFs in Managing Hematopoietic Stem and Progenitor Cells HIF Appearance in Hematopoietic Stem and Progenitor Cells The need for HIFs in advancement and hematopoiesis continues to be demonstrated by hereditary deletion of ARNT, which abrogates the function of both HIF-1 and HIF-2. In the developing embryo, ARNT is vital for multilineage hematopoietic progenitors, vasculogenesis, and angiogenesis [12, 13]. HIF-1 mRNA is normally ubiquitously portrayed [14]. In continuous state, HIF-1 proteins is normally detected just in the endosteal area from the bone tissue marrow (BM) and in a few discrete cells in the central BM [15]. Therefore, HIF-1 proteins is normally below detection entirely BM lysates [15, 16]; nevertheless, when HSCs are mobilized in the peripheral bloodstream by administering granulocyte colony-stimulating aspect (G-CSF) or cyclophosphamide, HIF-1 proteins is normally stabilized and discovered through the entire BM cavity [15]. Unlike HIF-1, HIF-2 mRNA appearance is fixed. HIF-2 is normally portrayed by vascular endothelium, hepatocytes, and interstitial and glomerular cells from the kidney. In the BM, HIF-2 mRNA is certainly primarily portrayed by hematopoietic lineage-negative cells [14]. HIF-2 mRNA is certainly detected at suprisingly low amounts in HSCs; nevertheless, in these cells, HIF-2 proteins is certainly.