Review Article Diverse of Erythropoiesis Responding to

Review ArticleDiverse of Erythropoiesis Responding to Hypoxia andLow Environmental Temperature in Vertebrates

Shun Maekawa1 and Takashi Kato12

1Department of Biology School of Education Waseda University 2-2 Wakamatsu Shinjuku Tokyo 162-8480 Japan2Graduate School of Advanced Science and Engineering Waseda University 2-2 Wakamatsu Shinjuku Tokyo 162-8480 Japan

Correspondence should be addressed to Takashi Kato tkatowasedajp

Received 28 April 2015 Accepted 4 September 2015

Academic Editor Hasan Mahmud

Copyright copy 2015 S Maekawa and T Kato This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Erythrocytes are responsible for transporting oxygen to tissue and are essential for the survival of almost all vertebrate animalsCirculating erythrocyte counts are tightly regulated and respond to erythrocyte mass and oxygen tension Since the discovery oferythropoietin the erythropoietic responses to environment and tissue oxygen tension have been investigated in mice and humanMoreover it has recently become increasingly clear that various environmental stresses could induce the erythropoiesis via variousmodulating systems while all vertebrates live in various environments and habitually adapt to environmental stress Thereforeit is considered that investigations of erythropoiesis in vertebrates provide a lead to the various erythropoietic responses toenvironmental stressThis paper comparatively introduces the present understanding of erythropoiesis in vertebrates Indeed thereis a wide range of variations in vertebratesrsquo erythropoiesis This paper also focused on erythropoietic responses to environmentalstress hypoxia and lowered temperature in vertebrates

1 Introduction

Erythrocytes are responsible for transporting oxygen to tissueand are essential for the survival of almost all vertebrateanimals All vertebrates adapt to various environmentsTherefore investigations of erythropoiesis in vertebratesare considered vital to address the various erythropoieticresponses to environmental stress The vertebrates that lackhemoglobin and erythrocytes are the larvae of eels and a fewAntarctic fish of the family Channichthyidae [1] Moreoveronly mammalian species in vertebrates have anucleate ery-throcytes while erythrocytes of nonmammalian species havenuclei and a shape of an ellipse The advantage of anucleateerythrocyte is explained by flexibility in developed capillaryand incensement of surface area for oxygen binding More-over it has beendemonstrated that the erythropoietic systemsare diverse among vertebrates (Table 1) Although the sciencebehind them is less than clear-cut such a wide-rangingdifference should bring diversity to the hematopoietic sys-tems for responding to environmental stress To address thedescription of erythropoietic functions this paper introduces

the present understanding of erythropoiesis in vertebratesfocusing on erythropoietic responses to environmental stresshypoxia and lowered temperature

2 Diversity of Erythropoiesis

21 Erythropoietin In 1977 Miyake and his colleges isolatednative human erythropoietin (EPO) from urine of patientswith aplastic anemia [2] Inmammalian species EPO expres-sion and secretion in the kidney are induced by hypoxiaand then highly glycosylated EPO circulates to the bonemarrow in adult mammals to stimulate the proliferationand differentiation of EPO receptor expressing erythroidprogenitors in an endocrine manner [3ndash5] Subsequentlythis notion is widely understood as a central mechanismof the production of mammalian red blood cells [6 7]Long afterward EPO gene was identified for the first timein nonmammalian species and was reported in pufferfishFugu rubripes [8] and then zebrafish [9 10] The primarysites of EPO expression in fish was unexpectedly found in

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 747052 9 pageshttpdxdoiorg1011552015747052

2 BioMed Research International

Table 1 Diversity of erythropoiesis in nonmammal

Species EPO Erythropoietic organ Life spanProducing organ Site Cell identification Days Cell labeling

FishPufferfish(Takifugu rubripes) Heart [8]

Zebrafish(Danio rerio) Heart [9 10] Kidney gata1 reporter transgenesis [26 27]

progenitor assay [29]Brown trout(Salmo trutta)

Spleenkidney Cell morphology [19]

European perch(Perca fluviatilis) Spleen Cell morphology [19]

Common Roach(Rutilus rutilus) Kidney Cell morphology [19]

Common carp(Cyprinus carpio L) Kidney Cell morphology [25]

Ginbuna crucian carp(Carassius auratus langsdorfii) Kidney (stem cell) Kidney marrow cell transplantation [81] 270 PKH 26-GL [40]

AmphibianAfrican clawed frog(Xenopus laevis) Lung liver [12] Liver Progenitor assay [30]

immunohistochemistry [14] 220 Biotin in vivo [39]

Bullfrog(Lithobates catesbeianus)

Kidneybone marrow Immunohistochemistry [31]

Leopard frog(Lithobates pipiens) 200 DFP32 [82]

Great crested newts(Triturus cristatus)

Spleenheart

Cell morphology [20]PHZ-induced anemia [23]

Ezo salamander(Hynobius retardatus) Spleen In situ hybridization [83]

ReptilesPainted turtle(Chrysemys picta)

Bone marrowkidney spleen Fe59 incorporation [32]

European pond turtle(Emys orbicularis) Bone marrow Cell morphology [21]

Spanish lizard(Lacerta hispanica) Bone marrow Cell morphology [22]

Boa constrictor(Boa constrictor) Bone marrow Cell morphology [24]

Corn snake(Elaphe guttata) Bone marrow Cell morphology [24]

Brown house snake(Lamprophis fulaginosus) Bone marrow Cell morphology [24]

Bothrops jararaca(Bothrops jararaca)

Bone marrowspleen Cell morphology [24]

AvianChicken(Gallus gallus) Bone marrow Progenitor assay [33] 35 Na

2Cr51O

4[38]

White Carneaux pigeons(Columba livia) 35ndash45 Na

2Cr51O

4[38]

White Pekin duck(Anas platyrhynchos) 42 Na

2Cr51O

4[38]

BioMed Research International 3

the heart [8] however the biological function of the heartEPO has not been directly elucidated We have reported theidentification and biological properties of EPO [11 12] andEPO receptors (EPOR) [13 14] in the African clawed frogsXenopus laevis The highest expression of EPO in Xenopuslaevis was found in the lung and lesser in the liver [12] Itwas our surprise that Xenopus EPO unlike in human andmurine EPO lacks N-glycosylation that is essential for in vivostability and biological activity in the circulation When N-linked carbohydrates were artificially introduced to XenopusEPO however in vitro activity was not interfered [15] Wealso demonstrated that recombinant Xenopus EPO inducesproliferation of human cell lines expressing Xenopus EPORas well as human EPOR despite the 38 amino acid identityshared between Xenopus EPO and human EPO [12] Inaddition an essential tertiary structure of the ligand-receptor(EPO-EPOR) is reserved and shared among those species [11]Because of these findings the ligand specificity should not bedetermined solely by primary amino acid sequences

22 Erythropoietic Organ Erythropoietic organs in verte-brates are various Inmammals erythropoiesismainly occursin bone marrow at their adult stage Additionally the spleenalso causes erythropoiesis in some rodents [16ndash18] The stud-ies of searching hematopoietic organs in nonmammals havebeen performed through the ages [19ndash25] Although mostinvestigations are approached though cellular morphologicalobservation there are reports usingmolecular based technicsduring recent years

In teleost fish hematopoiesis occurs in the kidney Astudy of brown trout has indicated that the spleen is alsoan erythropoietic organ [19] In zebrafish study reportertransgenesis takes the advantage to isolate and characterizethe hematopoietic progenitor cells An approach using gata1reporter transgene and flow cytometry to separate the ery-throblastic cells from the kidney has been developed in thegata1 reporter transgenicmodels [26ndash28] Kidney of zebrafishcomprehends the erythroid progenitor cells that inducedproliferation and differentiation by recombinant EPO in vitro[29]

In aquatic amphibianXenopus laevis we recently demon-strated that erythropoiesis mainly occurs in the adult liverto reveal the presence of CFU-E [14 30] The EPOR positivecells are found predominantly on the inner wall of hepaticsinusoids and increased during erythropoietic stress [14] Innorthern crested newt erythroblastic cells are observed in theheart aside from the spleen after phenylhydrazine- (PHZ-)induced anemia Although we also observed erythroblasts inperiphery during erythropoietic stress induced by PHZ ery-throblasts could not be observed in periphery in normal state[13]Therefore it is suggested that these erythroblast cells thatare observed in periphery are released from erythropoieticorgan responding to erythropoietic stress

While in bullfrog (Lithobates catesbeianus) terrestrialamphibian de Abreu Manso and his colleagues reveal thathematopoietic cells expressing CD34 CD117 and EPOR existin the adult bone marrow of vertebrae femur and fingersand in the kidney detected by immunohistochemistry [31]

in reptiles and avian bonemarrow is the primary erythropoi-etic site [21 22 24 32 33] In chicken erythroid progenitorassay is developed well using bone marrow cells [33] Takentogether in aquatic amphibian erythropoiesis mainly occursin kidney spleen andor liver From terrestrial amphibianerythropoiesis is found in bone marrow while in aquaticmammalian bottlenose dolphins (Tursiops truncatus) bonemarrowmononuclear cells contain hematopoietic progenitorcells [34]

23 Fate of Circulating Erythrocytes Erythrocyte is damagedlittle by little during circulation and destructed eventuallyIn adult human the life span of erythrocyte is about 120days [35] The life span is not correlating with the directionof evolution The erythrocytes lifespans of mice [36] rabbit[37] and chickens [38] are about 40 55 and 35 daysrespectively which are shorter than human In amphibianand fish the life span tends to be longer compared withmammalian species The life span of erythrocytes in Xeno-pus laevis is about 220 days [39] longer than mouse andhuman In ginbuna crucian carp the erythrocyte lifespanis about 50 days and labeling erythrocytes are detectedin circulation up to 270 days [40] Biological implica-tion of difference in the erythrocyte life span is not wellunderstood

In mammals damaged or senescent erythrocytes aredegraded by phagocytes in the liver and spleen [41] Inves-tigations of erythrocyte destruction sites in nonmammalianspecies are limited Our recent work with Xenopus laevisshowed that erythrocyte destruction mainly occurred in theliver based on the expression of heme degrading enzymeshemeoxygenase-1 and biliverdin reductase A expression andthe accumulation of iron [39]

3 Erythropoiesis Response toEnvironmental Stress

31 Hypoxia The primary EPO producing organ is thekidney in adult mammal while most of the knowledge ofhypoxic EPO expression has been based on human hepatomacell lines The molecular mechanisms of hypoxia inducibleEPO gene expression involve hypoxia inducible transcriptionfactors (HIFs) which are primary transcriptional factors ofthe hypoxic response [7 42] and are negatively regulatedby the von Hippel-Lindau (VHL) factor [43 44] The VHLacts to ubiquitylate the catalytic 120572 subunit of HIF andinduce their turnover in normoxia due to recognition ofa prolyl hydroxylation motif which is oxygen dependenthydroxylases to modify 120572 subunit of HIF During hypoxiccondition the loss of hydroxylase activity causees the accu-mulation and transactivation function of HIF-120572 subunit[45] The most well characterized HIF regulatory regionis a liver-specific hypoxia response element (HRE) that isthe binding site of HIF-1 which is located within 07 kb 31015840of the polyadenylation signal [45] Recently the analysis ofrenal EPO expression has been performed and increasinglyobvious [46ndash48] There are also reports that EPO is detectedin various tissues (brain heart lung and testis) and exhibited


nonerythropoietic activity [49ndash51] Taken together we havea question if each EPO producing organ could responseto hypoxia and promote erythropoiesis or not To resolvethis issue conditional knockout experiments in which atarget gene can be specifically inactivated in specific tissue(s)were performed The deletion of VHL gene prevents theubiquitination of hydroxylated HIF-120572 proteins and causes ahypoxic phenotype due to accumulation of HIF-120572 proteinsTo demonstrate the contribution of each EPO producingorgan various mice in which VHL can be inactivated tissuespecifically were generated using conditional gene target-ing technology based on Cre-loxP mediated recombination[52] Hepatocytes specific deletion of VHL using albuminpromoter enhanced hepatic EPO expression and inducedpolycythemia [53] Mice with osteoblasts specific knockoutof VHL showed the enhancement of EPO expression inbone marrow and erythropoiesis [54] The expression levelof renal EPO was decreased in the mice Interestingly it hasbeen reported that renal EPO expression is induced by thevariation of oxygen partial pressure in other tissues Ratswith high cerebral pressure exhibit a significant increasein plasma EPO levels [55] This report suggested that EPOexpression in the kidney is induced by a brain stem-derivedhumoral factor at high intracranial pressure Boutin et alshowed that HIF-1120572 gene deletion in mice epidermis inhibitsrenal EPO synthesis in response to hypoxia and epidermalsensing of oxygen is important for the renal EPO synthesis[56] Based on these observations it is suggested that eachorgan have an oxygen sensor independently in mammalianspecies

In nonmammalian species the knowledge of EPO geneexpressions responding to hypoxia is limited In zebrafishcardiac EPO mRNA expression is moderately upregulated65 h after being exposed at hypoxic environment [9] HREin teleost EPO gene locus of fugu has been reported [57]The fugu HRE is located in the 51015840 flanking region of EPOgene locus However the HRE is on the opposite strand ofDNA unlike the HRE of EPO gene locus in the humanand it is unclear whether the HRE contributes to responseto hypoxia and induces the EPO gene expression or not Werecently have showed that the expression of EPO gene inXenopus laevis is not induced by anemia investigated [12]The hypoxic response and diversity organs of EPO geneexpression in nonmammalian species are subject of futureinvestigation

Before indicating the existence of EPO Misher (1893)suggested that hypoxic stress directly stimulates bone mar-row and promotes erythropoiesis Although this hypoth-esis was rejected by the identification of EPO once theresponse of erythroid cells to hypoxia has been recentlyinvestigated Ex vivo erythrocytes production from periph-eral and cord blood CD34+ cells was enhanced by lowoxygen concentration (15ndash5) exposure [58] Under hypoxicconditions the mRNA and protein amounts of delta-aminolevulinate synthase 2 (ALAS2) and GATA-1 (erythroidspecific transcriptional factor) were elevated in human ery-throleukemic cell line K562 cells and erythroid induc-tion cultures of CD34+ hematopoietic stemprogenitor cells[59 60]

It has been reported that the type of hemoglobin ischanged by hypoxia stimuli In human embryonic fetal andadult hemoglobin is sequentially expressed in erythroblastsduring developing developments The binding affinity ofhemoglobin is different among the type of hemoglobinIncreasing the oxygen-binding affinity of fetal hemoglobinis relative to that of adult In erythroid differentiated culturefrom human hematopoietic progenitor cells the numberof cells with fetal hemoglobin increased exposed to lowO2[61] A moderate increase of circulating erythrocytes

with fetal hemoglobin was observed in human during andafter the hypoxia exposure [62] Erythrocytes with fetalhemoglobin have an advantage to bind more oxygen underhypoxic condition In amphibian species hemoglobin switchfrom the larval to the adult type of hemoglobin has beenshowed during metamorphosis (from aquatic to terrestriallife) [63 64] Because the oxygen dissociation curve intadpole shifts to left compared with that in adult [65] thetadpole erythrocyte more readily takes up oxygen so thatit is an advantage for tadpoles to live in water with loweroxygen These reports indicated that hemoglobin switch-ing is one of the important responses to adapt hypoxicenvironment

Recently a type of noncording RNA micro-RNA(miRNA) has attracted attention for the factor respondingto environmental stress miRNAs are single-strandedRNA molecules approximately 22 nucleotides in lengthEach miRNA recognizes target mRNAs via base-pairinginteractions and induces the gene silencing We comparedthe miRNA expression patterns in UT-7EPO UT-7GMand UT-7TPO cell lines which are all differentiated fromUT-7 cells by cytokine stimulation and exhibit the samegenotype with different phenotypes and demonstrated somespecific miRNAs expressed in erythroid cells [66] Oneof them miR-210 is expressed in the late stage erythroidcells in mouse [66] miR-210 is highly expressed by hypoxiccondition and regulates the iron homeostasis via targetingthe iron-sulfur cluster scaffold protein and transferrinreceptor [67] Recently Sarakul et al demonstrated thatmiR-210 induced erythroid differentiation in K562 cells andCD34+ hematopoietic stemprogenitor cells [68] Althoughseen mostly in vitro these results suggested that erythroidcells could be regulated by low O

2condition beyond the EPO

response

32 Low Temperature In birds and mammals endothermicanimals process the mechanisms to maintain the bodytemperature independent of the environmental temperatureUpon the initial exposure to low temperature endothermicanimals exhibit peripheral vasoconstriction to reduce heatloss from body Active thermogenesis occurs by meansof periodic shivering if heat dissipation exceeds metabolicheat generation [69] During prolonged exposure to lowtemperature nonshivering thermogenesis is enhanced bysynthesis and catalysis of ATP in the brown adipose tis-sue and muscle Additional metabolic heat generation isaccompanied by increased oxygen consumption [69] There-fore it is readily hypothesized that erythropoiesis would


respond and contribute to adaptation to low environmentaltemperature

There are many reports that showed the response ofhematopoiesis to environmental temperature Nine-bandedarmadillo (Dasypus novemcinctus) possesses the activehematopoiesis in the dermal bone marrow of the armorIn winter season the dermal bone marrow became fattyand showed less hematopoiesis compared with summerseason [70] The marrow of tailbone in new borne rats hasactive hematopoiesis and replaced the adipose with maturityTavassoli et al showed that the capability of hematopoiesiswas maintained in the tail vertebrae of newborn rats bytransposing the tail into the warmer environment of theabdomen [71] It has been demonstrated that the variationof blood cell counts is induced by low environmental tem-perature and season change in various vertebrates (Table 2)In rats and chickens acclimated to low temperature anincrease in the number erythrocytes was observed [7273] We have investigated whether increase in circulatingerythrocytes induced by low temperature exposure is causedby enhanced erythropoiesis in mice [74] Mice were exposedto a 5∘C environment for 56 days The blood hematocritlevels (HCT) gradually increased by day 14 and remainedhighat day 56 The proportion of proerythroblasts in the spleenand bone marrow increased greatly by day 5 of exposureto low temperature EPO mRNA levels increased in thekidneys and hypoxia inducible genes were enhanced in thekidney after being exposed to low-temperature environmentThese results indicated that erythropoiesis was enhancedexplaining the high level of EPO mRNA expression inthe kidney In addition the level of oxygen tension inthe kidney was decreased after low-temperature exposureElevated erythrocyte counts would increase oxygen supply toperipheral tissues for heat production after low-temperatureexposure

In the studies of nine-banded armadillo and newborn ratsas described previously it is considered that hematopoieticeffects are caused by hematopoietic organ itself exposed tolow temperature Moreover cases of anemia or pancytope-nia in hypothermic patients have been reported [75ndash79]Establishing the hypothermic model in small mammals hasbeen hampered by practical difficulties We used the Africanclawed frog Xenopus laevis was used to investigate the causeof hypothermia-induced anemia [39] Frogs were exposedto low temperature (5∘C) for five days and then were putback to 22∘C immediately afterwards One day after exposureto 5∘C erythrocyte count decreased by approximately 30and then remained at this level for 5 days Two days afterthe return to 22∘C erythrocyte count had recovered toinitial levels The rate of destruction of erythrocytes in adultXenopus laeviswas estimated to be about 045per day undernormal conditions from 220-day erythrocyte lifespan It washypothesized that enhancement of erythrocyte degradationcaused erythrocytopenia after low-temperature exposurePrimary organ of erythrocyte degradation is the liver inadult Xenopus laevis In the liver heme oxygenase (HOMX1)and biliverdin reductase (BLVRA) mRNA increased afterexposure to low temperature and then accumulation of ironas a result of heme degradation was observed in the liver

These results indicated that hypothermic anemia was initi-ated by enhanced peripheral erythrocyte destruction It ishypothesized that the cause of anemia under hypothermicconditions is a downregulation of erythropoiesis However incontrast we found that EPO mRNA expression was elevatedin lung and liver after low-temperature exposure and hepaticerythropoiesis was upregulated Despite upregulation of ery-thropoiesis newly produced erythrocytes are not released tothe circulation but appear to remain in the hepatic sinusoidwhich could explain the prolonged anemia observed duringlow-temperature exposure To investigate the modulatedmolecules responding to low temperature moreover weattempted the proteomics to profile the hepatic proteomein Xenopus laevis after exposure to low temperature [80]Our proteome data suggested that glycolytic and antioxalatesystems acted after the accumulation of hepatic iron causedby low-temperature exposure

The signal passway from sensitive environmental lowtemperature to erythropoietic change is unclear Howeverwe demonstrated that the rule of erythropoiesis respond-ing to low environmental temperature is different betweenendothermic and ectothermic animals through our compar-ative study

4 Conclusion and Perspective

Since the discovery of EPO it has been investigated thatthe expression and secretion of renal EPO which respondto environment and tissue oxygen tension could regulatethe circulating erythrocyte counts Through the study ofvarious vertebrates it has become increasingly clear thatvertebrates possess the unique erythropoietic responses toindividual habitat and environmental stress Recently themany experimental technologies such as gene editing andomics have been developed and are available to not only lab-oratory animals but also nonlaboratory animals Thereforecomparative study holds the more potential for enhancingour knowledge of erythropoietic systems Furthermore tounderstand the physiology of the whole organism andorcell analyzing cyclopedic modulating molecules inducedby environmental stress and understanding the networkrelationship among thesemoleculeswere attemptedThroughthis analysis the various systems to link to erythropoiesis willbecome known

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper No financial inter-estrelationships with financial interest relating to the topicof this paper has been declared

Acknowledgments

This work was supported in part by a Grant-in-Aid forScientific Research from the Japan Society for the Promotionof Science by Strategic Foundation Grant-Aided Project for


Table 2 Hematopoietic responses to low environmental temperature and seasons in vertebrates

Stress Species Experimentalcondition

Peripheral blood cell counts Hematopoietic observation ReferenceIncrease Decrease

Seasonalchange

Nine-banded armadillo(Dasypus novemcinctus) Winter Decrease hematopoietic cells

in armor dermal bone marrow [70]

Edible frog(Rana esculenta) Winter RBC HGB [84]

Wisent European bison(Bison bonasus) Summer RBC size [85]

Grass snake(Natrix natrix) Winter RBC HGB

HCT [86]

Bottlenose dolphin(Tursiops truncatus) Winter RBC HGB

HCT [87]

Lowtemperature

Leopard frog(Rana pipiens) 5∘C HCT RBC lifespan extends [88]

Painted turtle(Chrysemys picta) 2∘C HCT [89]

Cunninghamrsquos skink(Egernia cunninghami) 8∘C HCT HGB [90]

Sidewinder(Crotalus cerastes) 20∘C RBC HGB

HCT [91]

Fossil catfish(Heteropneustes fossilis) 18∘C RBC HGB

HCT WBC [92]

American bullfrog(Rana catesbeiana) 5∘C RBC WBC

TBC [93]

Rat(Rattus norvegicus) 5∘C RBC HGB

HCT [72]

Chicken(Gallus domesticus) 10∘C HGB HCT [73]

Zebrafish(Danio rerio) 17∘C Downregulate erythropoietic

genes expression level [94]

African clawed frog(Xenopus laevis) 5∘C RBC WBC

TBC

Enhanced hepatic erythrocytedestructionNewly produced erythrocytesare confined to the liver

[39]

Mouse(Mus musculus) 5∘C HCT HGB Upregulate erythropoiesis [74]

Other

European hamster(Cricetus cricetus) Hibernation WBC TBC [95]

Syrian hamster(Mesocricetus auratus) Hibernation TBC [72]

Rat(Rattus norvegicus)

Transposing the tailinto the abdomen

Maintain the hematopoiesis inbone marrow of tail vein [71]

RBC erythrocyte HGB hemoglobin HCT hematocrit WBC leukocyte TBC thrombocyte

Private Universities from The Japanese Ministry of Edu-cation Culture Sports Science and Technology (MEXT)(2012ndash2017) and by Waseda University grants for specialresearch projects Part of this study was performed as acomponent of a Private University ldquoHigh-Tech ResearchCenterrdquo project supported by MEXT (2007ndash2011)

References

[1] K Schmidt-Nielsen Animal Physiology Adaptation and Envi-ronment Cambridge University Press Cambridge UK 1997

[2] T Miyake C K H Kung and E Goldwasser ldquoPurification ofhuman erythropoietinrdquoThe Journal of Biological Chemistry vol252 no 15 pp 5558ndash5564 1977

[3] V C Broudy N Lin M Brice B Nakamoto and TPapayannopoulou ldquoErythropoietin receptor characteristics onprimary human erythroid cellsrdquo Blood vol 77 no 12 pp 2583ndash2590 1991

[4] C Dame H Fahnenstich P Freitag et al ldquoErythropoietinmRNA expression in human fetal and neonatal tissuerdquo Bloodvol 92 no 9 pp 3218ndash3225 1998

[5] S Elliott E Pham and I C Macdougall ldquoErythropoietins acommon mechanism of actionrdquo Experimental Hematology vol36 no 12 pp 1573ndash1584 2008


[6] W Jelkmann ldquoErythropoietin after a century of researchyounger than everrdquo European Journal of Haematology vol 78no 3 pp 183ndash205 2007

[7] B L Ebert and H F Bunn ldquoRegulation of the erythropoietingenerdquo Blood vol 94 no 6 pp 1864ndash1877 1999

[8] C-F Chou S Tohari S Brenner and B Venkatesh ldquoErythro-poietin gene from a teleost fish Fugu rubripesrdquo Blood vol 104no 5 pp 1498ndash1503 2004

[9] N Paffett-Lugassy N Hsia P G Fraenkel et al ldquoFunctionalconservation of erythropoietin signaling in zebrafishrdquo Bloodvol 110 no 7 pp 2718ndash2726 2007

[10] C-Y Chu C-H Cheng G-D Chen et al ldquoThe zebrafisherythropoietin functional identification and biochemical char-acterizationrdquo FEBS Letters vol 581 no 22 pp 4265ndash4271 2007

[11] M Meguro M Adachi K Nagasawa et al ldquoImplication ofmolecular diversity and functional conservation of erythropoi-etin based on a comparison of tertiary structures of humans andfrogsrdquo Blood (ASH Annual Meeting Abstracts) vol 118 no 21 p3396 2011

[12] N Nogawa-Kosaka T Hirose N Kosaka et al ldquoStructuraland biological properties of erythropoietin in Xenopus laevisrdquoExperimental Hematology vol 38 no 5 pp 363ndash372 2010

[13] Y Aizawa N Nogawa N Kosaka et al ldquoExpression of erythro-poietin receptor-likemolecule inXenopus laevis and erythrocy-topenia upon administration of its recombinant soluble formrdquoJournal of Biochemistry vol 138 no 2 pp 167ndash175 2005

[14] T Okui Y Yamamoto S Maekawa et al ldquoQuantification andlocalization of erythropoietin-receptor-expressing cells in theliver of Xenopus laevisrdquo Cell and Tissue Research vol 353 no1 pp 153ndash164 2013

[15] K Nagasawa M Meguro K Sato Y Tanizaki N Nogawa-Kosaka and T Kato ldquoThe influence of artificially introducedN-glycosylation sites on the in vitro activity of Xenopus laevisErythropoietinrdquo PLoS ONE vol 10 no 4 Article ID e01246762015

[16] H Hara and M Ogawa ldquoErythropoietic precursors in micewith phenylhydrazine-induced anemiardquo American Journal ofHematology vol 1 no 4 pp 453ndash458 1976

[17] H Hara and M Ogawa ldquoErythropoietic precursors in miceunder erythropoietic stimulation and suppressionrdquo Experimen-tal Hematology vol 5 no 2 pp 141ndash148 1977

[18] H Y Kam L C Ou C D Thron R P Smith and J C LeiterldquoRole of the spleen in the exaggerated polycythemic response tohypoxia in chronicmountain sickness in ratsrdquo Journal of AppliedPhysiology vol 87 no 5 pp 1901ndash1908 1999

[19] W T Catton ldquoBlood cell formation in certain teleost fishesrdquoBlood vol 6 no 1 pp 39ndash60 1951

[20] C Garavini and A Scandellari ldquoErythropoiesis insplenecto-mized Triturus cristatusrdquo Bollettino della Societa Italiana diBiologia Sperimentale vol 50 no 23-24 pp 2105ndash2110 1974

[21] J Vasse and D Beaupain ldquoErythropoiesis and haemoglobinontogeny in the turtleEmys orbicularisLrdquo Journal of Embryologyand Experimental Morphology vol 62 pp 129ndash138 1981

[22] A Zapata J Leceta andA Villena ldquoReptilian bonemarrow Anultrastructural study in the Spanish lizard Lacerta hispanicardquoJournal of Morphology vol 168 no 2 pp 137ndash149 1981

[23] G Frangioni and G Borgioli ldquoSites and trend of erythropoiesisin anemic normal and splenectomized newtsrdquo Journal ofExperimental Zoology vol 247 no 3 pp 244ndash250 1988

[24] Z Dbrowski I S Sano Martins Z Tabarowski et alldquoHaematopoiesis in snakes (Ophidia) in early postnatal devel-opmentrdquo Cell and Tissue Research vol 328 no 2 pp 291ndash2992007

[25] E Kondera ldquoHaematopoiesis in the head kidney of commoncarp (Cyprinus carpio L) a morphological studyrdquo Fish Physiol-ogy and Biochemistry vol 37 no 3 pp 355ndash362 2011

[26] Q Long A Meng M Wang J R Jessen M J Farrell and SLin ldquoGATA-1 expression pattern can be recapitulated in livingtransgenic zebrafish using GFP reporter generdquo Developmentvol 124 no 20 pp 4105ndash4111 1997

[27] D Traver B H Paw K D Poss W T Penberthy S Lin andL I Zon ldquoTransplantation and in vivo imaging of multilineageengraftment in zebrafish bloodless mutantsrdquo Nature Immunol-ogy vol 4 no 12 pp 1238ndash1246 2003

[28] L J McReynolds J Tucker M C Mullins and T EvansldquoRegulation of hematopoiesis by the BMP signaling pathway inadult zebrafishrdquo Experimental Hematology vol 36 no 12 pp1604ndash1615e3 2008

[29] D L Stachura J R Reyes P Bartunek B H Paw L I Zonand D Traver ldquoZebrafish kidney stromal cell lines supportmultilineage hematopoiesisrdquo Blood vol 114 no 2 pp 279ndash2892009

[30] N Nogawa-Kosaka T Sugai K Nagasawa et al ldquoIdentificationof erythroid progenitors induced by erythropoietic activity inXenopus laevisrdquo The Journal of Experimental Biology vol 214no 6 pp 921ndash927 2011

[31] P P de Abreu Manso L de Brito-Gitirana and M Pelajo-Machado ldquoLocalization of hematopoietic cells in the bullfrog(Lithobates catesbeianus)rdquo Cell and Tissue Research vol 337 no2 pp 301ndash312 2009

[32] R H Meints F J Carver J W Gerst and D W McLaughlinldquoErythropoietic activity in the turtle the influence of hemolyticanemia hypoxia and hemorrhage on hemopoietic functionrdquoComparative Biochemistry and PhysiologymdashPart A Physiologyvol 50 no 2 pp 419ndash422 1975

[33] C Schroeder L Gibson C Nordstrom and H Beug ldquoTheestrogen receptor cooperates with the TGF120572 receptor (c-erbB)in regulation of chicken erythroid progenitor self-renewalrdquoTheEMBO Journal vol 12 no 3 pp 951ndash960 1993

[34] T Segawa T Itou M Suzuki T Moritomo T Nakanishiand T Sakai ldquoHematopoietic cell populations in dolphin bonemarrow analysis of colony formation and differentiationrdquoResults in Immunology vol 1 no 1 pp 1ndash5 2011

[35] C A Finch J G Gibson W C Peacock and R G FluhartyldquoIron metabolism utilization of intravenous radioactive ironrdquoBlood vol 4 no 8 pp 905ndash927 1949

[36] L M Van Putten ldquoThe life span of red cells in the rat and themouse as determined by labeling with DFP32 in vivordquo Bloodvol 13 no 8 pp 789ndash794 1958

[37] T Suzuki and G L Dale ldquoBiotinylated erythrocytes in vivosurvival and in vitro recoveryrdquo Blood vol 70 no 3 pp 791ndash7951987

[38] G P Rodnan F G Ebaugh Jr and M R Fox ldquoThe life span ofthe red blood cell and the red blood cell volume in the chickenpigeon and duck as estimated by the use of Na

2Cr51O

4 with

observations on red cell turnover rate in the mammal bird andreptilerdquo Blood vol 12 no 4 pp 355ndash366 1957

[39] S Maekawa H Iemura Y Kuramochi et al ldquoHepatic con-finement of newly produced erythrocytes caused by low-temperature exposure in Xenopus laevisrdquoThe Journal of Exper-imental Biology vol 215 part 17 pp 3087ndash3095 2012


[40] U Fischer M Ototake and T Nakanishi ldquoLife span of circu-lating blood cells in ginbuna crucian carp (Carassius auratuslangsdorfii)rdquo Fish amp Shellfish Immunology vol 8 no 5 pp 339ndash349 1998

[41] G J C G M Bosman F L A Willekens and J M WerreldquoErythrocyte aging a more than superficial resemblance toapoptosisrdquo Cellular Physiology and Biochemistry vol 16 no 1ndash3 pp 1ndash8 2005

[42] G L Semenza ldquoO2-regulated gene expression transcriptional

control of cardiorespiratory physiology by HIF-1rdquo Journal ofApplied Physiology vol 96 no 3 pp 1173ndash1177 2004

[43] P H Maxwell M S Wlesener G-W Chang et al ldquoThe tumoursuppressor protein VHL targets hypoxia-inducible factors foroxygen-dependent proteolysisrdquo Nature vol 399 no 6733 pp271ndash275 1999

[44] M Ivan K Kondo H Yang et al ldquoHIF120572 targeted for VHL-mediated destruction by proline hydroxylation implications forO2sensingrdquo Science vol 292 no 5516 pp 464ndash468 2001

[45] G L Semenza and G L Wang ldquoA nuclear factor induced byhypoxia via de novo protein synthesis binds to the human ery-thropoietin gene enhancer at a site required for transcriptionalactivationrdquo Molecular and Cellular Biology vol 12 no 12 pp5447ndash5454 1992

[46] N Suzuki N Obara X Pan et al ldquoSpecific contribution of theerythropoietin gene 31015840 enhancer to hepatic erythropoiesis afterlate embryonic stagesrdquo Molecular and Cellular Biology vol 31no 18 pp 3896ndash3905 2011

[47] N Obara N Suzuki K Kim T Nagasawa S Imagawa and MYamamoto ldquoRepression via theGATAbox is essential for tissue-specific erythropoietin gene expressionrdquo Blood vol 111 no 10pp 5223ndash5232 2008

[48] S Frede P Freitag L Geuting R Konietzny and J FandreyldquoOxygen-regulated expression of the erythropoietin gene in thehuman renal cell line REPCrdquo Blood vol 117 no 18 pp 4905ndash4914 2011

[49] C C Tan K-U Eckardt J D Firth and P J Ratcliffe ldquoFeedbackmodulation of renal and hepatic erythropoietin mRNA inresponse to graded anemia and hypoxiardquoThe American Journalof PhysiologymdashRenal Fluid and Electrolyte Physiology vol 263no 3 pp F474ndashF481 1992

[50] M Sakanaka T-C Wen S Matsuda et al ldquoIn vivo evidencethat erythropoietin protects neurons from ischemic damagerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 95 no 8 pp 4635ndash4640 1998

[51] J Fandrey and H F Bunn ldquoIn vivo and in vitro regulationof erythropoietin mRNA measurement by competitive poly-merase chain reactionrdquo Blood vol 81 no 3 pp 617ndash623 1993

[52] V H Haase J N Glickman M Socolovsky and R JaenischldquoVascular tumors in livers with targeted inactivation of the vonHippel-Lindau tumor suppressorrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 98 no4 pp 1583ndash1588 2001

[53] Y A Minamishima and W G Kaelin Jr ldquoReactivation ofhepatic EPO synthesis in mice after PHD lossrdquo Science vol 329no 5990 p 407 2010

[54] E B Rankin CWu RKhatri et al ldquoTheHIF signaling pathwayin osteoblasts directly modulates erythropoiesis through theproduction of EPOrdquo Cell vol 149 no 1 pp 63ndash74 2012

[55] U von Wussow J Klaus and H Pagel ldquoIs the renal productionof erythropoietin controlled by the brain stemrdquo AmericanJournal of Physiology Endocrinology and Metabolism vol 289no 1 pp E82ndashE86 2005

[56] A T Boutin A Weidemann Z Fu et al ldquoEpidermal sensing ofoxygen is essential for systemic hypoxic responserdquo Cell vol 133no 2 pp 223ndash234 2008

[57] R P Kulkarni S Tohari A Ho S Brenner and B VenkateshldquoCharacterization of a hypoxia-response element in the Epolocus of the pufferfishTakifugu rubripesrdquoMarineGenomics vol3 no 2 pp 63ndash70 2010

[58] M Vlaski X Lafarge J Chevaleyre P Duchez J-M Boironand Z Ivanovic ldquoLow oxygen concentration as a generalphysiologic regulator of erythropoiesis beyond the EPO-relateddownstream tuning and a tool for the optimization of red bloodcell production ex vivordquo Experimental Hematology vol 37 no5 pp 573ndash584 2009

[59] F-L Zhang G-M Shen X-L Liu et al ldquoHypoxic inductionof human erythroid-specific 120575-aminolevulinate synthase medi-ated by hypoxia-inducible factor 1rdquo Biochemistry vol 50 no 7pp 1194ndash1202 2011

[60] F-L Zhang G-M Shen X-L Liu F Wang Y-Z Zhaoand J-W Zhang ldquoHypoxia-inducible factor 1-mediated humanGATA1 induction promotes erythroid differentiation underhypoxic conditionsrdquo Journal of Cellular andMolecularMedicinevol 16 no 8 pp 1889ndash1899 2012

[61] H M Rogers X Yu J Wen R Smith E Fibach and C TNoguchi ldquoHypoxia alters progression of the erythroid pro-gramrdquo Experimental Hematology vol 36 no 1 pp 17ndash27 2008

[62] A RissoD FabbroGDamante andGAntonutto ldquoExpressionof fetal hemoglobin in adult humans exposed to high altitudehypoxiardquo Blood Cells Molecules and Diseases vol 48 no 3 pp147ndash153 2012

[63] R Weber B Blum and P R Muller ldquoThe switch from larval toadult globin gene expression in Xenopus laevis is mediated byerythroid cells from distinct compartmentsrdquo Development vol112 no 4 pp 1021ndash1029 1991

[64] M Yamaguchi and M Wakahara ldquoContribution of ventral anddorsal mesoderm to primitive and definitive erythropoiesis inthe Salamander Hynobius retardatusrdquo Developmental Biologyvol 230 no 2 pp 204ndash216 2001

[65] A Riggs ldquoThe metamorphosis of hemoglobin in the bullfrogrdquoJournal of General Physiology vol 35 no 1 pp 23ndash40 1951

[66] N Kosaka K Sugiura Y Yamamoto et al ldquoIdentificationof erythropoietin-induced microRNAs in haematopoietic cellsduring erythroid differentiationrdquo British Journal of Haematol-ogy vol 142 no 2 pp 293ndash300 2008

[67] Y Yoshioka N Kosaka T Ochiya and T Kato ldquoMicro-managing iron homeostasis hypoxia-induciblemicro-RNA-210suppresses iron homeostasis-related proteinsrdquo The Journal ofBiological Chemistry vol 287 no 41 pp 34110ndash34119 2012

[68] O Sarakul P Vattanaviboon Y Tanaka et al ldquoEnhancederythroid cell differentiation in hypoxic condition is in partcontributed by miR-210rdquo Blood Cells Molecules and Diseasesvol 51 no 2 pp 98ndash103 2013

[69] C J Gordon ldquoThermal biology of the laboratory ratrdquoPhysiologyamp Behavior vol 47 no 5 pp 963ndash991 1990

[70] L P Weiss and G B Wislocki ldquoSeasonal variations inhematopoiesis in the dermal bones of therdquo The AnatomicalRecord vol 126 no 2 pp 143ndash163 1956

[71] M Tavassoli L R Watson and R Khademi ldquoRetention ofhemopoiesis in tail vertebrae of newborn ratsrdquo Cell and TissueResearch vol 200 no 2 pp 215ndash222 1979

[72] D Deveci P CW Stone and S Egginton ldquoDifferential effect ofcold acclimation on blood composition in rats and hamstersrdquo


Journal of Comparative Physiology B vol 171 no 2 pp 135ndash1432001

[73] J Blahova R Dobsıkova E Strakova and P Suchy ldquoEffectof low environmental temperature on performance and bloodsystem in broiler chickens (Gallus domesticus)rdquoActaVeterinariaBrno vol 76 no 8 pp S17ndashS23 2007

[74] S Maekawa H Iemura and T Kato ldquoEnhanced erythropoiesisin mice exposed to low environmental temperaturerdquo Journal ofExperimental Biology vol 216 part 5 pp 901ndash908 2013

[75] F Sadikali and R Owor ldquoHypothermia in the tropics A reviewof 24 casesrdquo Tropical and Geographical Medicine vol 26 no 3pp 265ndash270 1974

[76] H OrsquoBrien J A L Amess and D L Mollin ldquoRecurrent throm-bocytopenia erythroid hypoplasia and sideroblastic anaemiaassociated with hypothermiardquo British Journal of Haematologyvol 51 no 3 pp 451ndash456 1982

[77] M P Daly and C H Rosenfarb ldquoPancytopenia associated withhypothermiardquo Journal of the American Board of Family Practicevol 4 no 2 pp 123ndash124 1991

[78] L Lo S T Singer and E Vichinsky ldquoPancytopenia induced byhypothermiardquo Journal of Pediatric HematologyOncology vol24 no 8 pp 681ndash684 2002

[79] A M Collins and D F Danzl ldquoHypothermia with pro-found anemia and pancreatitisrdquoWilderness and EnvironmentalMedicine vol 17 no 1 pp 31ndash35 2006

[80] K Nagasawa Y Tanizaki T Okui A Watarai S Ueda and TKato ldquoSignificant modulation of the hepatic proteome inducedby exposure to low temperature in Xenopus laevisrdquo BiologyOpen vol 2 no 10 pp 1057ndash1069 2013

[81] I Kobayashi M Sekiya T Moritomo M Ototake and TNakanishi ldquoDemonstration of hematopoietic stem cells inginbuna carp (Carassius auratus langsdorfii) kidneyrdquo Develop-mental and Comparative Immunology vol 30 no 11 pp 1034ndash1046 2006

[82] M J Cline and T A Waldmann ldquoEffect of temperature onerythropoiesis and red cell survival in the frogrdquo The AmericanJournal of Physiology vol 203 pp 401ndash403 1962

[83] M Yamaguchi H Takahashi and M Wakahara ldquoErythro-poiesis and unexpected expression pattern of globin genes inthe salamander Hynobius retardatusrdquo Development Genes andEvolution vol 210 no 4 pp 180ndash189 2000

[84] R C Sinha ldquoHaematological studies on the prewintering andwintering frog Rana esculentardquo Comparative Biochemistry andPhysiology Part A Physiology vol 74 no 2 pp 311ndash314 1983

[85] J Gill ldquoSeasonal changes in the red blood cell system in theEuropean bison Bison bonasus Lrdquo Comparative Biochemistryand Physiology Part A Physiology vol 92 no 3 pp 291ndash2981989

[86] J S Wojtaszek ldquoSeasonal changes of circulating blood param-eters in the grass snake Natrix natrix natrix Lrdquo ComparativeBiochemistry and PhysiologymdashPart A Physiology vol 103 no3 pp 461ndash471 1992

[87] A J Hall R S Wells J C Sweeney et al ldquoAnnual seasonaland individual variation in hematology and clinical bloodchemistry profiles in bottlenose dolphins (Tursiops truncatus)from Sarasota Bay Floridardquo Comparative Biochemistry andPhysiology Part AMolecular and Integrative Physiology vol 148no 2 pp 266ndash277 2007

[88] M J Cline and T A Waldmann ldquoEffect of temperature onerythropoiesis and red cell survival in the frogrdquo AmericanJournal of Physiology vol 203 pp 401ndash403 1962

[89] X J Musacchia and M L Sievers ldquoEffects of induced coldtorpor on blood of Chrysemys pictardquo American Journal ofPhysiology vol 187 no 1 pp 99ndash102 1956

[90] G S Maclean A K Lee and P C Withers ldquoHaematologicaladjustments with diurnal changes in body temperature in alizard and a mouserdquo Comparative Biochemistry and PhysiologyPart A Physiology vol 51 no 1 pp 241ndash249 1975

[91] J A MacMahon and A Hamer ldquoEffects of temperature andphotoperiod on oxygenation and other blood parameters of thesidewinder (Crotalus cerastes) adaptive significancerdquoCompara-tive Biochemistry and Physiology A Physiology vol 51 no 1 pp59ndash69 1975

[92] B N Pandey ldquoHaematological studies in relation to environ-mental temperature and different periods of breeding cycle inan air breathing fish Heteropneustes fossilisrdquo Folia Haemato-logica vol 104 no 1 pp 69ndash74 1977

[93] X Wang and C Herman ldquoChanges in blood cell numbersand formation of eicosanoids during clotting in warm- andcold-acclimated bullfrogs (Rana catesbeiana)rdquo General andComparative Endocrinology vol 101 no 2 pp 211ndash219 1996

[94] K Kulkeaw T Ishitani T Kanemaru S Fucharoen and DSugiyama ldquoCold exposure down-regulates zebrafish hemato-poiesisrdquoBiochemical and Biophysical Research Communicationsvol 394 no 4 pp 859ndash864 2010

[95] G Reznik H R Schueller A Emminger and U Mohr ldquoCom-parative studies of blood from hibernating and nonhibernatingEuropean hamsters (Cricetus cricetus L)rdquo Laboratory AnimalScience vol 25 no 2 pp 210ndash215 1975

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table 1 Diversity of erythropoiesis in nonmammal

Species EPO Erythropoietic organ Life spanProducing organ Site Cell identification Days Cell labeling

FishPufferfish(Takifugu rubripes) Heart [8]

Zebrafish(Danio rerio) Heart [9 10] Kidney gata1 reporter transgenesis [26 27]

progenitor assay [29]Brown trout(Salmo trutta)

Spleenkidney Cell morphology [19]

European perch(Perca fluviatilis) Spleen Cell morphology [19]

Common Roach(Rutilus rutilus) Kidney Cell morphology [19]

Common carp(Cyprinus carpio L) Kidney Cell morphology [25]

Ginbuna crucian carp(Carassius auratus langsdorfii) Kidney (stem cell) Kidney marrow cell transplantation [81] 270 PKH 26-GL [40]

AmphibianAfrican clawed frog(Xenopus laevis) Lung liver [12] Liver Progenitor assay [30]

immunohistochemistry [14] 220 Biotin in vivo [39]

Bullfrog(Lithobates catesbeianus)

Kidneybone marrow Immunohistochemistry [31]

Leopard frog(Lithobates pipiens) 200 DFP32 [82]

Great crested newts(Triturus cristatus)

Spleenheart

Cell morphology [20]PHZ-induced anemia [23]

Ezo salamander(Hynobius retardatus) Spleen In situ hybridization [83]

ReptilesPainted turtle(Chrysemys picta)

Bone marrowkidney spleen Fe59 incorporation [32]

European pond turtle(Emys orbicularis) Bone marrow Cell morphology [21]

Spanish lizard(Lacerta hispanica) Bone marrow Cell morphology [22]

Boa constrictor(Boa constrictor) Bone marrow Cell morphology [24]

Corn snake(Elaphe guttata) Bone marrow Cell morphology [24]

Brown house snake(Lamprophis fulaginosus) Bone marrow Cell morphology [24]

Bothrops jararaca(Bothrops jararaca)

Bone marrowspleen Cell morphology [24]

AvianChicken(Gallus gallus) Bone marrow Progenitor assay [33] 35 Na

2Cr51O

4[38]

White Carneaux pigeons(Columba livia) 35ndash45 Na

2Cr51O

4[38]

White Pekin duck(Anas platyrhynchos) 42 Na

2Cr51O

4[38]




















response












Acknowledgments






Seasonalchange






HCT [86]


HCT [87]

Lowtemperature





HCT [91]


HCT WBC [92]


TBC [93]


HCT [72]





TBC


[39]


Other








References








































2Cr51O

4 with




































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



































response












Acknowledgments






Seasonalchange






HCT [86]


HCT [87]

Lowtemperature





HCT [91]


HCT WBC [92]


TBC [93]


HCT [72]





TBC


[39]


Other








References








































2Cr51O

4 with




































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























response












Acknowledgments






Seasonalchange






HCT [86]


HCT [87]

Lowtemperature





HCT [91]


HCT WBC [92]


TBC [93]


HCT [72]





TBC


[39]


Other








References








































2Cr51O

4 with




































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























Acknowledgments






Seasonalchange






HCT [86]


HCT [87]

Lowtemperature





HCT [91]


HCT WBC [92]


TBC [93]


HCT [72]





TBC


[39]


Other








References








































2Cr51O

4 with




































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















Seasonalchange






HCT [86]


HCT [87]

Lowtemperature





HCT [91]


HCT WBC [92]


TBC [93]


HCT [72]





TBC


[39]


Other








References








































2Cr51O

4 with




































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















































2Cr51O

4 with




































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of














































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article Diverse of Erythropoiesis Responding to