Tracking erythroid progenitor cells in times of need and times of plenty
2015; Elsevier BV; Volume: 44; Issue: 8 Linguagem: Inglês
10.1016/j.exphem.2015.10.007
ISSN1873-2399
Autores Tópico(s)Blood properties and coagulation
Resumo•Erythroid progenitor populations during various states of erythropoietic demand are reviewed.•A model of erythropoietic changes based on the degree of demand for new RBCs is presented.•Clinical therapies of underproduction anemias based on erythropoietic stimulation are reviewed. Red blood cell production rates increase rapidly following blood loss or hemolysis, but the expansion of erythropoiesis in these anemic states is tightly regulated such that rebound polycythemia does not occur. The erythroid cells that respond to erythropoietic stimulation or suppression are the progenitor stages of burst-forming units–erythroid (BFU-Es) and colony-forming units–erythroid (CFU-Es). Results from an early study of the changes in the size, location, and cell cycling status of BFU-E and CFU-E populations in mice under normal conditions, erythropoietic stimulation, and erythropoietic suppression are used as reference points to review subsequent developments related to erythroid progenitor populations and regulation of their size. The review concerns development of erythroid progenitor populations mainly in mice and humans, with a focus on the mechanisms related to the rapid but highly regulated expansion of erythropoiesis in spleens of erythropoietically stimulated mice. Current knowledge is used as a model of erythroid progenitor populations in mice under normal, erythropoietically suppressed, and erythropoietically stimulated conditions. Clinical applications of information learned from studies of erythropoietic expansion, in terms of current therapies for anemia, are reviewed. Red blood cell production rates increase rapidly following blood loss or hemolysis, but the expansion of erythropoiesis in these anemic states is tightly regulated such that rebound polycythemia does not occur. The erythroid cells that respond to erythropoietic stimulation or suppression are the progenitor stages of burst-forming units–erythroid (BFU-Es) and colony-forming units–erythroid (CFU-Es). Results from an early study of the changes in the size, location, and cell cycling status of BFU-E and CFU-E populations in mice under normal conditions, erythropoietic stimulation, and erythropoietic suppression are used as reference points to review subsequent developments related to erythroid progenitor populations and regulation of their size. The review concerns development of erythroid progenitor populations mainly in mice and humans, with a focus on the mechanisms related to the rapid but highly regulated expansion of erythropoiesis in spleens of erythropoietically stimulated mice. Current knowledge is used as a model of erythroid progenitor populations in mice under normal, erythropoietically suppressed, and erythropoietically stimulated conditions. Clinical applications of information learned from studies of erythropoietic expansion, in terms of current therapies for anemia, are reviewed. Erythrocytes (RBCs) carry oxygen from the lungs to the other tissues, enabling aerobic cellular respiration. Numbers of circulating RBCs in the blood have a narrow range, with daily turnover rates of about 1%, as the oldest RBCs are recognized as senescent and removed by macrophages, while a similar number of their replacements, the reticulocytes, enter the blood from the bone marrow. Normally, humans produce is about 2.0–2.5 × 1011 RBCs per day, but when RBCs are lost from bleeding or destroyed by hemolysis, the resultant anemia causes tissue hypoxia, leading to rapid expansion of marrow erythropoiesis. In mice, acute anemia increases erythropoiesis mainly in the spleen because of limited space for erythroid expansion in the marrow. This "stress" erythropoiesis in times of need for more RBCs is regulated largely by erythropoietin (EPO), the renal hormone that is produced in small amounts under normal conditions, but increases rapidly in response to kidney hypoxia. The erythropoietic response in times of need is highly regulated such that overshoot polycythemia does not occur as recovery to baseline normal numbers of RBCs, a time of plenty, is achieved. In the rare cases of more than plenty RBCs, such as when an individual with polycythemia from acclimatization to high altitudes travels to sea level, erythropoiesis is suppressed until a smaller normal number of RBCs is achieved. Regulation of the erythropoietic process occurs mainly in the erythroid progenitor stages of differentiation. Examining the sizes and locations of these progenitor populations in times of need, times of plenty, and times of more than plenty, as reported nearly 40 years ago in Experimental Hematology [1Hara H. Ogawa M. Erythropoietic precursors in mice under erythropoietic stimulation and suppression.Exp Hematol. 1977; 5: 141-148PubMed Google Scholar], has advanced understanding of multiple factors that regulate RBC production and has helped in the development of clinical therapies for anemias. In 1977, Hiroshi Hara and Makio Ogawa published a study that examined the changes in erythroid progenitor cells, colony-forming units–erythroid (CFU-Es) and burst-forming units–erythroid (BFU-Es), in mice under normal conditions, reduced erythropoietic demand, and increased erythropoietic stress [1Hara H. Ogawa M. Erythropoietic precursors in mice under erythropoietic stimulation and suppression.Exp Hematol. 1977; 5: 141-148PubMed Google Scholar]. This report, like several others that followed soon after the original descriptions of CFU-Es [2Stephenson J.R. Axelrad A.A. McLeod D.L. Shreeve M.M. Induction of colonies of hemoglobin-synthesizing cells by erythropoietin in vitro.Proc Natl Acad Sci USA. 1971; 68: 1542-1546Crossref PubMed Scopus (379) Google Scholar] and BFU-Es [3Axelrad A. McLeod D. Shreeve M. Heath D. Properties of Cells that Produce Erythropoietic Colonies In Vitro.in: Robinson W. Hemopoiesis in Culture. U.S. Government Printing Office, Bethesda, MD1974: 226-237Google Scholar] from Axelrad's laboratory, indicated that erythropoietic stress increased CFU-E numbers modestly in the bone marrow and markedly in the spleen, whereas BFU-E numbers decreased about twofold in marrow and increased twofold in the spleen. Suppression of erythropoietic demand had opposite effects on erythroid progenitor numbers in these two organs. The new information reported by Hara and Ogawa included: (i) BFU-Es normally found in the blood increased with erythropoietic stress and decreased with erythropoietic suppression. (ii) Despite the large differences in numbers of BFU-Es and CFU-Es in normal, erythropoietically stressed, or erythropoietically suppressed mice, the cell cycle status of BFU-Es and CFU-Es was similar under all conditions in spleen and marrow [1Hara H. Ogawa M. Erythropoietic precursors in mice under erythropoietic stimulation and suppression.Exp Hematol. 1977; 5: 141-148PubMed Google Scholar]. These results indicated that BFU-Es migrate in the blood of mice from bone marrow to spleen, erythropoietic stress increases and erythropoietic suppression decreases BFU-E migration, and marked expansion of CFU-Es during erythropoietic stress involves more than simply an increased rate of erythroid cell proliferation. This review discusses some aspects of erythroid progenitor populations and their changes in response to erythropoietic demand that have been published since Hara and Ogawa's publication and that may help explain their original results and provide insights into the development of new approaches in treating anemia. In the few years before Hara and Ogawa's publication, knowledge about erythropoiesis had advanced rapidly following the characterization of two basic erythroid progenitor stages that precede microscopically identifiable erythroblasts, the CFU-E and the more immature BFU-E. These murine erythroid progenitors were detected by their growth, in semisolid or viscous medium containing EPO, into colonies of 8 to 64 morphologically identifiable erythroblasts after 2 days for CFU-Es [2Stephenson J.R. Axelrad A.A. McLeod D.L. Shreeve M.M. Induction of colonies of hemoglobin-synthesizing cells by erythropoietin in vitro.Proc Natl Acad Sci USA. 1971; 68: 1542-1546Crossref PubMed Scopus (379) Google Scholar] or much larger bursts or multiple colonies of erythroblasts after 8–14 days for BFU-Es [3Axelrad A. McLeod D. Shreeve M. Heath D. Properties of Cells that Produce Erythropoietic Colonies In Vitro.in: Robinson W. Hemopoiesis in Culture. U.S. Government Printing Office, Bethesda, MD1974: 226-237Google Scholar]. Over the next few years, multiple studies by Eaves and colleagues characterized mouse and human CFU-Es, BFU-Es, and mature BFU-Es, intermediates with properties between those of the immature BFU-Es and CFU-Es [4Eaves C.J. Humphries R.K. Eaves A.C. In Vitro Characterization of Erythroid Precursor Cells and Erythropoietic Differentiation.in: Stamatoyannopoulos G. Nienhuis A.W. Cellular and Molecular Regulation of Hemogolobin Switching. Grune and Stratton, New York1979: 251-273Google Scholar]. Most of the properties of mouse and human erythroid progenitors were similar except for a relatively prolonged period of development in vitro for colonies (7–9 days) and immature bursts (17–20 days) of humans compared with those of mice [4Eaves C.J. Humphries R.K. Eaves A.C. In Vitro Characterization of Erythroid Precursor Cells and Erythropoietic Differentiation.in: Stamatoyannopoulos G. Nienhuis A.W. Cellular and Molecular Regulation of Hemogolobin Switching. Grune and Stratton, New York1979: 251-273Google Scholar]. Within a few years of their description, immature BFU-Es were found to have a close relationship with the megakaryocytic lineage, as 40% of BFU-Es displayed both megakaryocytic and erythroid potential [5McLeod D.L. Shreeve M.M. Axelrad A.A. Chromosome marker evidence for the bipotentiality of BFU-E.Blood. 1980; 56: 318-322PubMed Google Scholar]. Subsequent studies reported that later-stage erythroid progenitors, including those in spleens of mice with phenylhydrazine (PHZ)-induced hemolytic anemia [6Vannucchi A.M. Paoletti F. Linari S. et al.Identification and characterization of a bipotent (erythroid and megakaryocytic) cell precursor from the spleen of phenylhydrazine-treated mice.Blood. 2000; 95: 2559-2568Crossref PubMed Google Scholar] and those isolated from human blood [7Goldfarb A.N. Wong D. Racke F.K. Induction of megakaryocytic differentiation in primary human erythroblasts: a physiological basis for leukemic lineage plasticity.Am J Pathol. 2001; 158: 1191-1198Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar], retain megakaryocytic potential that is either lost or retained depending on their exposure in vitro to erythropoietic or thrombopoietic conditions. These bipotent megakaryocyte–erythroid progenitors (MEPs) differentiate along the erythroid lineage when increased expression of transcription factors that induce erythroid differentiation, including GATA1 [8Mancini E. Sanjuan-Pla A. Luciani L. et al.FOG-1 and GATA-1 act sequentially to specify definitive megakaryocytic and erythroid progenitors.EMBO J. 2012; 31: 351-365Crossref PubMed Scopus (68) Google Scholar], KLF1 [9Siatecka M. Bieker J.J. The multifunctional role of EKLF/KLF1 during erythropoiesis.Blood. 2011; 118: 2044-2054Crossref PubMed Scopus (206) Google Scholar, 10Bianchi E. Zini R. Salati S. et al.c-myb supports erythropoiesis through the transactivation of KLF1 and LMO2 expression.Blood. 2010; 116: e99-e110Crossref PubMed Scopus (86) Google Scholar], and LMO2 [10Bianchi E. Zini R. Salati S. et al.c-myb supports erythropoiesis through the transactivation of KLF1 and LMO2 expression.Blood. 2010; 116: e99-e110Crossref PubMed Scopus (86) Google Scholar], are accompanied by decreased expression of transcription factors that induce megakaryocytic differentiation, including KLF1 antagonism of FLI1 [9Siatecka M. Bieker J.J. The multifunctional role of EKLF/KLF1 during erythropoiesis.Blood. 2011; 118: 2044-2054Crossref PubMed Scopus (206) Google Scholar] and MYB-induced miR486-3p suppression of MAF translation [11Bianchi E. Bulgarelli J. Ruberti S. et al.MYB controls erythroid versus megakaryocyte lineage fate decision through the miR-486-3p-mediated downregulation of MAF.Cell Death Differ. 2015; 22: 1906-1921Crossref PubMed Scopus (44) Google Scholar]. Thus, erythroid progenitor cells were defined as a continuum beginning with immature BFU-Es, which can be restricted to erythroid differentiation despite their megakaryocytic potential, and ending with CFU-Es. The immediate progeny of the CFU-Es, the pro-erythroblasts (ProEBs), are the first morphologically recognized stage of erythroid differentiation. Based on their appearance on Giemsa staining during terminal differentiation, ProEBs pass through basophilic, polychromatophilic, and orthochromatic erythroblast stages as they accumulate hemoglobin before enucleating to form reticulocytes. Erythroblasts in the terminal erythroid stages, termed erythroid precursor cells, are now often identified by flow cytometry-based surface expression of specific proteins, glycoproteins, and/or cell size [12Socolovsky M. Nam H. Fleming M.D. Haase V.H. Brugnara C. Lodish H.F. Ineffective erythropoiesis in Stat5a(−/−)5b(−/−) mice due to decreased survival of early erythroblasts.Blood. 2001; 98: 3261-3273Crossref PubMed Scopus (575) Google Scholar, 13Chen K. Liu J. Heck S. Chasis J.A. An X. Mohandas N. Resolving the distinct stages in erythroid differentiation based on dynamic changes in membrane protein expression during erythropoiesis.Proc Natl Acad Sci USA. 2009; 106: 17413-17418Crossref PubMed Scopus (331) Google Scholar, 14Hu J. Liu J. Xue F. et al.Isolation and functional characterization of human erythroblasts at distinct stages: implications for understanding of normal and disordered erythropoiesis in vivo.Blood. 2013; 121: 3246-3253Crossref PubMed Scopus (229) Google Scholar]. However, the transition between the operationally defined CFU-E and microscopically identified ProEB stages has been uncertain. Overlap in the CFU-E and ProEB populations is possible, as some ProEBs may complete three or four generations of cell divisions, giving rise to a colony of 8–16 cells in the CFU-E assay. Therefore, in some situations, these two closely related and potentially overlapping populations will be designated as CFU-E/ProEBs. More than a decade before the descriptions of the erythroid progenitor cells, Erslev noted that mitotic divisions in the erythroid precursors and the ratios of ProEBs to later stages of precursors were the same under conditions of suppressed and stimulated erythropoiesis [15Erslev A. Hematology: control of red cell production.Annu Rev Med. 1960; 11: 315-332Crossref PubMed Scopus (4) Google Scholar]. He concluded that erythropoiesis was controlled by either the rate of hematopoietic stem cell (HSC) differentiation into ProEBs or the rate of ProEB replication [15Erslev A. Hematology: control of red cell production.Annu Rev Med. 1960; 11: 315-332Crossref PubMed Scopus (4) Google Scholar]. Although bleeding has been reported to increase proliferation and self-renewal of phenotypically sorted HSCs [16Cheshier S.H. Prohaska S.S. Weissman I.L. The effect of bleeding on hematopoietic stem cell cycling and self-renewal.Stem Cells Dev. 2007; 16: 707-717Crossref PubMed Scopus (70) Google Scholar], and EPO administration has been reported to influence differentiation of multipotent HSC progeny toward the erythroid lineage [17Grover A. Mancini E. Moore S. et al.Erythropoietin guides multipotent hematopoietic progenitor cells toward an erythroid fate.J Exp Med. 2014; 211: 181-188Crossref PubMed Scopus (101) Google Scholar], the vast majority of studies have focused on the effects of erythropoietic stress or suppression on the erythroid progenitor cells. The importance of EPO in vivo as the principal hypoxia-inducible stimulator of erythropoietic responses was well recognized before identification of the CFU-E and the BFU-E [18Koury M.J. Erythropoietin: the story of hypoxia and a finely regulated hematopoietic hormone.Exp Hematol. 2005; 33: 1263-1270Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. Administration of an EPO preparation to mice increased erythroblast populations in the marrow, especially in the spleen, but no change in the radiolabeled mitoses in the populations could be detected, and a slightly shortened S phase calculated by double radiolabeling could not account for large increases in the erythroblast populations [19Papayannopoulou T. Finch C.A. On the in vivo action of erythropoietin: a quantitative analysis.J Clin Invest. 1972; 51: 1179-1185Crossref PubMed Scopus (52) Google Scholar]. The requirement for EPO in the media of CFU-E and BFU-E assays, the restriction of the effects of EPO to hematopoietic cells of the erythroid lineage, and the absence of an effect of high-EPO states on the proliferation of a specific stage of erythroblast differentiation indicated that the target cell populations for EPO's regulation of erythropoiesis were very likely the BFU-Es and/or CFU-Es. Therefore, several investigators examined the effects of increased or decreased EPO levels in vivo on the numbers, location, and proliferation status of BFU-E and CFU-E populations [1Hara H. Ogawa M. Erythropoietic precursors in mice under erythropoietic stimulation and suppression.Exp Hematol. 1977; 5: 141-148PubMed Google Scholar, 3Axelrad A. McLeod D. Shreeve M. Heath D. Properties of Cells that Produce Erythropoietic Colonies In Vitro.in: Robinson W. Hemopoiesis in Culture. U.S. Government Printing Office, Bethesda, MD1974: 226-237Google Scholar, 20Gregory C.J. Tepperman A.D. McCulloch E.A. Till J.E. Erythropoietic progenitors capable of colony formation in culture: response of normal and genetically anemic W-W-V mice to manipulations of the erythron.J Cell Physiol. 1974; 84: 1-12Crossref PubMed Scopus (54) Google Scholar, 21Iscove N.N. The role of erythropoietin in regulation of population size and cell cycling of early and late erythroid precursors in mouse bone marrow.Cell Tissue Kinet. 1977; 10: 323-334PubMed Google Scholar, 22Pannacciulli I.M. Massa G.G. Saviane A.G. Ghio R.L. Bianchi G.L. Bogliolo G.V. Effect of bleeding on in vivo in vitro colony-forming hemopoietic cells.Acta Haematol. 1977; 58: 27-33Crossref PubMed Scopus (12) Google Scholar, 23Peschle C. Magli M.C. Cillo C. et al.Kinetics of erythroid and myeloid stem cells in post-hypoxia polycythaemia.Br J Haematol. 1977; 37: 345-352Crossref PubMed Scopus (26) Google Scholar]. Marrow and spleen were hematopoietic sites examined in these investigations, but Hara and Ogawa, who had established that BFU-Es, but not CFU-Es, circulated in the blood [24Hara H. Ogawa M. Erthropoietic precursors in mice with phenylhydrazine-induced anemia.Am J Hematol. 1976; 1: 453-458Crossref PubMed Scopus (100) Google Scholar], also examined BFU-Es in the blood [1Hara H. Ogawa M. Erythropoietic precursors in mice under erythropoietic stimulation and suppression.Exp Hematol. 1977; 5: 141-148PubMed Google Scholar]. About the same time as Hara and Ogawa's publication, the purification of EPO was reported [25Miyake T. Kung C.K. Goldwasser E. Purification of human erythropoietin.J Biol Chem. 1977; 252: 5558-5564Abstract Full Text PDF PubMed Google Scholar], but several more years were required before the cloning of EPO and availability of large quantities of purified EPO. Therefore, in addition to using partially purified EPO preparations, investigators frequently increased endogenous EPO by inducing hemolytic anemia or blood-loss anemia. They suppressed endogenous EPO by hypertransfusing erythrocytes or creating a posthypoxia condition. Hara and Ogawa had previously found that PHZ-induced hemolytic anemia in mice increased CFU-Es modestly in the marrow and markedly in the spleen, whereas BFU-Es decreased modestly in the marrow and increased modestly in the spleen [24Hara H. Ogawa M. Erthropoietic precursors in mice with phenylhydrazine-induced anemia.Am J Hematol. 1976; 1: 453-458Crossref PubMed Scopus (100) Google Scholar]. Importantly, they reported that the splenic increases in BFU-Es were preceded by increases in the normally low levels of circulating BFU-Es [24Hara H. Ogawa M. Erthropoietic precursors in mice with phenylhydrazine-induced anemia.Am J Hematol. 1976; 1: 453-458Crossref PubMed Scopus (100) Google Scholar]. However, PHZ causes direct oxidant stress in erythroid progenitors, as well as inducing hemolytic anemia. Thus, confirmation of increased circulating BFU-Es with administration of an EPO preparation or with blood loss provided evidence that the increase in splenic BFU-Es and the maintenance of elevated splenic CFU-Es at later times in erythropoietically stressed mice were potentially related to an influx of migrating BFU-Es, which likely originated in the marrow, where BFU-E numbers declined [1Hara H. Ogawa M. Erythropoietic precursors in mice under erythropoietic stimulation and suppression.Exp Hematol. 1977; 5: 141-148PubMed Google Scholar]. Hypertransfusion-induced polycythemia had the opposite effects of acute anemia on BFU-E and CFU-E populations in marrow, spleen, and blood, indicating that EPO very likely mediated these changes [1Hara H. Ogawa M. Erythropoietic precursors in mice under erythropoietic stimulation and suppression.Exp Hematol. 1977; 5: 141-148PubMed Google Scholar]. Decreases in marrow BFU-Es during stimulated erythropoiesis and increases in marrow BFU-Es during suppressed erythropoiesis were about twofold compared with the normal baseline numbers. However, the changes in CFU-Es were severalfold in the marrow and more than an order of magnitude in the spleen. Other early investigations reported similar patterns in the BFU-E and/or CFU-E populations in murine marrow and spleen with increased or decreased erythropoiesis [3Axelrad A. McLeod D. Shreeve M. Heath D. Properties of Cells that Produce Erythropoietic Colonies In Vitro.in: Robinson W. Hemopoiesis in Culture. U.S. Government Printing Office, Bethesda, MD1974: 226-237Google Scholar, 20Gregory C.J. Tepperman A.D. McCulloch E.A. Till J.E. Erythropoietic progenitors capable of colony formation in culture: response of normal and genetically anemic W-W-V mice to manipulations of the erythron.J Cell Physiol. 1974; 84: 1-12Crossref PubMed Scopus (54) Google Scholar, 21Iscove N.N. The role of erythropoietin in regulation of population size and cell cycling of early and late erythroid precursors in mouse bone marrow.Cell Tissue Kinet. 1977; 10: 323-334PubMed Google Scholar, 22Pannacciulli I.M. Massa G.G. Saviane A.G. Ghio R.L. Bianchi G.L. Bogliolo G.V. Effect of bleeding on in vivo in vitro colony-forming hemopoietic cells.Acta Haematol. 1977; 58: 27-33Crossref PubMed Scopus (12) Google Scholar, 23Peschle C. Magli M.C. Cillo C. et al.Kinetics of erythroid and myeloid stem cells in post-hypoxia polycythaemia.Br J Haematol. 1977; 37: 345-352Crossref PubMed Scopus (26) Google Scholar]. The prominent role of the spleen in mice during erythropoietic stress is due to the rapid increase in CFU-Es and their progeny, but Hara and Ogawa's demonstration that circulating BFU-E numbers increased with erythropoietic stress provided a mechanism for sustaining the expanded erythropoiesis. The relationship between circulating BFU-Es, their homing to the hematopoietic tissues, and their subsequent differentiation to the CFU-E stage in hematopoietic tissues remains relatively unexamined compared with the later differentiation stages of CFU-Es through reticulocytes. The prominence of splenic stress erythropoiesis in mice has facilitated investigation into the response to erythropoietic stimulation, as compared with studies with humans in which the marrow is the site of both normal and stress erythropoiesis. In the same year as Hara and Ogawa's article, BFU-Es were reported to circulate in human blood [26Ogawa M. Grush O.C. O'Dell R.F. Hara H. MacEachern M.D. Circulating erythropoietic precursors assessed in culture: characterization in normal men and patients with hemoglobinopathies.Blood. 1977; 50: 1081-1092PubMed Google Scholar, 27Clarke B.J. Housman D. Characterization of an erythroid precursor cell of high proliferative capacity in normal human peripheral blood.Proc Natl Acad Sci USA. 1977; 74: 1105-1109Crossref PubMed Scopus (116) Google Scholar]. The circulating BFU-Es lodge in the marrow through an interaction of p67 non-integrin laminin-binding protein expressed on their surface with non-integrin laminins expressed by the bone marrow stroma [28Bonig H. Chang K.H. Nakamoto B. Papayannopoulou T. The p67 laminin receptor identifies human erythroid progenitor and precursor cells and is functionally important for their bone marrow lodgment.Blood. 2006; 108: 1230-1233Crossref PubMed Scopus (12) Google Scholar]. Table 1 lists growth factors and adhesion proteins that play a role in localization, proliferation, and differentiation of erythroid progenitor and precursor cells during normal and stress erythropoiesis. Stem cell factor (SCF) expression on the surface of stromal cells plays a key role in the lodging of circulating BFU-E in both marrow and spleen following PHZ-induce anemia [29Broudy V.C. Lin N.L. Priestley G.V. Nocka K. Wolf N.S. Interaction of stem cell factor and its receptor c-kit mediates lodgment and acute expansion of hematopoietic cells in the murine spleen.Blood. 1996; 88: 75-81Crossref PubMed Google Scholar]. KIT, the surface transmembrane receptor for SCF, has intrinsic kinase activity, which, on binding of SCF (in either the fixed stromal form or soluble form), leads to activation of several intracellular pathways that regulate survival, proliferation, and differentiation of both BFU-Es and CFU-Es. These pathways include those involving RAS, Raf-1, mitogen-associated protein kinase (RAS-Raf-MAPK); phosphatidylinositol-3 kinase, protein kinase B (PI3K-AKT); and phospholipase Cγ, protein kinase C, inositol trisphosphate (PLC-PKC-IP3) [30Munugalavadla V. Kapur R. Role of c-Kit and erythropoietin receptor in erythropoiesis.Crit Rev Oncol Hematol. 2005; 54: 63-75Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar]. The importance of integrins containing the β1 component for interactions of BFU-Es with their microenvironment was illustrated in β1-integrin knockout mice by decreases in splenic BFU-E populations, with essentially no increase in response to erythropoietic stress [31Ulyanova T. Jiang Y. Padilla S. Nakamoto B. Papayannopoulou T. Combinatorial and distinct roles of alpha(5) and alpha(4) integrins in stress erythropoiesis in mice.Blood. 2011; 117: 975-985Crossref PubMed Scopus (43) Google Scholar].Table 1Growth factors and adhesion proteins that regulate normal and stress erythropoiesisGrowth factor/adhesion proteinSourceErythroid progenitor/precursorErythroid cell receptor/signalingEffect on erythroid cellsSCF (KIT ligand)Hematopoietic stromal cellsBFU-E and CFU-EKIT/PI3K-AKTRAS-Raf-MAPKPLC-PKC-IP3Lodgment in hematopoietic tissue; Survival and proliferationNon-integrin lamininsHematopoietic stromal cellsBFU-Ep67 Non-integrin- binding proteinLodgment in hematopoietic tissueβ1-integrins and binding partnersHematopoietic stromal cellsBFU-Eβ1-Integrins and binding partnersProliferation during stress erythropoiesisHedgehog and BMP4Hematopoietic stromal cellsBFU-EBMP4 receptor/Smad5Proliferation during stress erythropoiesisGlucocorticoid hormonesPlasma (adrenal cortex)BFU-E and CFU-EGlucocorticoid receptor/PPAR-αProliferation during stress erythropoiesisEPOPlasma (renal cortex)CFU-E, ProEB, early BasoEBEPO-R-JAK2/Stat5RAS-Raf-MAPKPI3K-AKTSurvival and differentiationFAS ligandErythroblastsCFU-E, ProEB, early BasoEBFAS-CaspasesSurvival inhibition and differentiationGas6Erythroblasts and hematopoietic stromal cellsProEBs and differentiating EBsTAM receptors (Axl)/ GATA1Survival and differentiation during stress erythropoiesisVCAM-1EBI central macrophagesCFU-E, ProEBs, and differentiating EBsα4β1-IntegrinAdherence to EBI central macrophagesαv-IntegrinsEBI central macrophagesCFU-E, ProEBs, and differentiating EBsICAM-4Adherence to EBI central macrophagesErythroblast-macrophage proteinEBI central macrophagesCFU-E, ProEBs, and differentiating EBsErythroblast-macrophage proteinAdherence to EBI central macrophagesCD169 (Siglec1)EBI central macrophagesCFU-E, ProEBs, and differentiating EBsSialylated glycoproteinsAdherence to EBI central macrophagesCD163EBI central macrophagesCFU-E, ProEBs, and differentiating EBsUnknownAdherence to EBI central macrophagesTGF-β superfamily ligandsHematopoietic stromal cellsDifferentiating erythroblastsTGF-β superfamily receptors/Smad2,3Differentiation inhibition Open table in a new tab During their differentiation into CFU-Es, the interactions of BFU-Es with the hematopoietic micro-environment are not well characterized, but several regulatory factors are known. These regulatory factors and the erythroid progenitors that they affect are illustrated in Figure 1 for mice in states of normal, suppressed, and stimulated erythropoiesis. Eaves and her colleagues helped identify factors in BFU-E development under normal and erythropoietically stressed conditions using W/Wv mice, which are chronically anemic and have deficiencies in Kit, the SCF receptor, and f/f mice, which are impaired in responding to erythropoietic stress and have a deficiency of Smad5, a signaling pathway protein for bone morphogenetic proteins [20Gregory C.J. Tepperman A.D. McCulloch E.A. Till J.E. Erythropoietic progenitors capable of colony formation in culture: response of normal and genetically anemic W-W-V mice to manipulations of the erythron.J Cell Physiol. 1974; 84: 1-12Crossref PubMed Scopus (54) Google Scholar, 32Gregory C.J. Eaves A.C. Three stages of erythropoietic progenitor cell differentiation distinguished by a
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