{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T07:31:25Z","timestamp":1790753485647,"version":"4.1.0"},"reference-count":114,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2020,7,24]],"date-time":"2020-07-24T00:00:00Z","timestamp":1595548800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-11-LABX-0051"],"award-info":[{"award-number":["ANR-11-LABX-0051"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["No. 665850"],"award-info":[{"award-number":["No. 665850"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"name":"undefined  &lt;span style=&quot;color:gray;font-size:10px;&quot;&gt;undefined&lt;\/span&gt;","award":["MSc scholarshipp CGRF"],"award-info":[{"award-number":["MSc scholarshipp CGRF"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Human erythropoiesis is a complex process leading to the production of mature, enucleated erythrocytes (RBCs). It occurs mainly at bone marrow (BM), where hematopoietic stem cells (HSCs) are engaged in the early erythroid differentiation to commit into erythroid progenitor cells (burst-forming unit erythroid (BFU-E) and colony-forming unit erythroid (CFU-E)). Then, during the terminal differentiation, several erythropoietin-induced signaling pathways trigger the differentiation of CFU-E on successive stages from pro-erythroblast to reticulocytes. The latter are released into the circulation, finalizing their maturation into functional RBCs. This process is finely regulated by the physiological environment including the erythroblast-macrophage interaction in the erythroblastic island (EBI). Several human diseases have been associated with ineffective erythropoiesis, either by a defective or an excessive production of RBCs, as well as an increase or a hemoglobinization defect. Fully understanding the production of mature red blood cells is crucial for the comprehension of erythroid pathologies as well as to the field of transfusion. Many experimental approaches have been carried out to achieve a complete differentiation in vitro to produce functional biconcave mature RBCs. However, the various protocols usually fail to achieve enough quantities of completely mature RBCs. In this review, we focus on the evolution of erythropoiesis studies over the years, taking special interest in efforts that were made to include the microenvironment and erythroblastic islands paradigm. These more physiological approaches will contribute to a deeper comprehension of erythropoiesis, improve the treatment of dyserythropoietic disorders, and break through the barriers in massive RBCs production for transfusion.<\/jats:p>","DOI":"10.3390\/ijms21155263","type":"journal-article","created":{"date-parts":[[2020,7,24]],"date-time":"2020-07-24T09:06:09Z","timestamp":1595581569000},"page":"5263","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["An Overview of Different Strategies to Recreate the Physiological Environment in Experimental Erythropoiesis"],"prefix":"10.3390","volume":"21","author":[{"given":"C\u00e9cile","family":"Deleschaux","sequence":"first","affiliation":[{"name":"INSERM, Biologie Int\u00e9gr\u00e9e du Globule Rouge\/UMR_S1134\/BIGR, Universit\u00e9 de Paris, F-75006 Paris, France"},{"name":"INSERM, Biologie Int\u00e9gr\u00e9e du Globule Rouge\/UMR_S1134\/BIGR, Universit\u00e9 des Antilles, F-75006 Paris, France"},{"name":"INTS, D\u00e9partement de Recherche sur les Globules Rouges\/DRGR, F-75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Moras","sequence":"additional","affiliation":[{"name":"INSERM, Biologie Int\u00e9gr\u00e9e du Globule Rouge\/UMR_S1134\/BIGR, Universit\u00e9 de Paris, F-75006 Paris, France"},{"name":"INSERM, Biologie Int\u00e9gr\u00e9e du Globule Rouge\/UMR_S1134\/BIGR, Universit\u00e9 des Antilles, F-75006 Paris, France"},{"name":"INTS, D\u00e9partement de Recherche sur les Globules Rouges\/DRGR, F-75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7504-1881","authenticated-orcid":false,"given":"Sophie D.","family":"Lefevre","sequence":"additional","affiliation":[{"name":"INSERM, Biologie Int\u00e9gr\u00e9e du Globule Rouge\/UMR_S1134\/BIGR, Universit\u00e9 de Paris, F-75006 Paris, France"},{"name":"INSERM, Biologie Int\u00e9gr\u00e9e du Globule Rouge\/UMR_S1134\/BIGR, Universit\u00e9 des Antilles, F-75006 Paris, France"},{"name":"INTS, D\u00e9partement de Recherche sur les Globules Rouges\/DRGR, F-75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6769-3786","authenticated-orcid":false,"given":"Mariano A.","family":"Ostuni","sequence":"additional","affiliation":[{"name":"INSERM, Biologie Int\u00e9gr\u00e9e du Globule Rouge\/UMR_S1134\/BIGR, Universit\u00e9 de Paris, F-75006 Paris, France"},{"name":"INSERM, Biologie Int\u00e9gr\u00e9e du Globule Rouge\/UMR_S1134\/BIGR, Universit\u00e9 des Antilles, F-75006 Paris, France"},{"name":"INTS, D\u00e9partement de Recherche sur les Globules Rouges\/DRGR, F-75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Dzierzak, E., and Philipsen, S. (2013). Erythropoiesis: Development and differentiation. Cold Spring Harb. Perspect. Med., 3.","DOI":"10.1101\/cshperspect.a011601"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1111\/bjh.13938","article-title":"Advances in understanding erythropoiesis: Evolving perspectives","volume":"173","author":"Nandakumar","year":"2016","journal-title":"Br. J. Haematol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"20181","DOI":"10.1074\/jbc.M603226200","article-title":"Absence of erythroblast macrophage protein (Emp) leads to failure of erythroblast nuclear extrusion","volume":"281","author":"Soni","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/nm.3057","article-title":"CD169(+) macrophages provide a niche promoting erythropoiesis under homeostasis and stress","volume":"19","author":"Chow","year":"2013","journal-title":"Nat. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fphys.2014.00003","article-title":"Primitive and definitive erythropoiesis in mammals","volume":"5","author":"Palis","year":"2014","journal-title":"Front. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/bs.ircmb.2015.01.006","article-title":"New insights into the mechanisms of mammalian erythroid chromatin condensation and enucleation","volume":"316","author":"Ji","year":"2015","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1200\/JCO.2010.31.1175","article-title":"Unraveling the molecular pathophysiology of myelodysplastic syndromes","volume":"29","author":"Bejar","year":"2011","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1172\/JCI89741","article-title":"Intravascular hemolysis and the pathophysiology of sickle cell disease","volume":"127","author":"Kato","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0140-6736(17)31822-6","article-title":"Thalassaemia","volume":"391","author":"Taher","year":"2018","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Gaudio, A., Xourafa, A., Rapisarda, R., Zanoli, L., Signorelli, S.S., and Castellino, P. (2020). Hematological Diseases and Osteoporosis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103538"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1182\/blood-2001-12-0188","article-title":"Involvement and functional impairment of the CD34(+)CD38(-)Thy-1(+) hematopoietic stem cell pool in myelodysplastic syndromes with trisomy 8","volume":"100","author":"Nilsson","year":"2002","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Jiang, H., Yang, L., Guo, L., Cui, N., Zhang, G., Liu, C., Xing, L., Shao, Z., and Wang, H. (2018). Impaired Mitophagy of Nucleated Erythroid Cells Leads to Anemia in Patients with Myelodysplastic Syndromes. Oxid. Med. Cell. Longev., 2018.","DOI":"10.1155\/2018\/6328051"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1182\/blood-2018-06-818187","article-title":"How I manage medical complications of beta-thalassemia in adults","volume":"132","author":"Taher","year":"2018","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.cr.2018.10.001","article-title":"Research advances in erythrocyte regeneration sources and methods in vitro","volume":"7","author":"Sun","year":"2018","journal-title":"Cell Regen."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1182\/blood.V73.1.100.100","article-title":"Proliferation and maturation of human erythroid progenitors in liquid culture","volume":"73","author":"Fibach","year":"1989","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1006\/bcmd.2002.0502","article-title":"In vitro mass production of human erythroid cells from the blood of normal donors and of thalassemic patients","volume":"28","author":"Migliaccio","year":"2002","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1016\/S0301-472X(02)00818-4","article-title":"Human stem-progenitor cells from neonatal cord blood have greater hematopoietic expansion capacity than those from mobilized adult blood","volume":"30","author":"Tanavde","year":"2002","journal-title":"Exp. Hematol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/nbt1047","article-title":"Ex vivo generation of fully mature human red blood cells from hematopoietic stem cells","volume":"23","author":"Giarratana","year":"2005","journal-title":"Nat. Biotechnol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1074\/mcp.M115.057315","article-title":"Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation","volume":"15","author":"Wilson","year":"2016","journal-title":"Mol. Cell. Proteom."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3337","DOI":"10.1182\/bloodadvances.2019000689","article-title":"Large-scale in vitro production of red blood cells from human peripheral blood mononuclear cells","volume":"3","author":"Heshusius","year":"2019","journal-title":"Blood Adv."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"453","DOI":"10.3727\/096368909X485049","article-title":"Humanized culture medium for clinical expansion of human erythroblasts","volume":"19","author":"Migliaccio","year":"2010","journal-title":"Cell Transplant."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1002\/stem.1342","article-title":"Concise Review: Early Embryonic Erythropoiesis: Not so Primitive After All","volume":"31","author":"Baron","year":"2013","journal-title":"Stem Cells"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1002\/stem.1677","article-title":"Erythropoiesis from human embryonic stem cells through erythropoietin-independent AKT signaling","volume":"32","author":"Kim","year":"2014","journal-title":"Stem Cells"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.cell.2006.07.024","article-title":"Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors","volume":"126","author":"Takahashi","year":"2006","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.3324\/haematol.2010.023556","article-title":"Red blood cell generation from human induced pluripotent stem cells: Perspectives for transfusion medicine","volume":"95","author":"Lapillonne","year":"2010","journal-title":"Haematologica"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.3324\/haematol.2011.055566","article-title":"Human induced pluripotent stem cells can reach complete terminal maturation: In vivo and in vitro evidence in the erythropoietic differentiation model","volume":"97","author":"Kobari","year":"2012","journal-title":"Haematologica"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/mt.2013.201","article-title":"Extensive ex vivo expansion of functional human erythroid precursors established from umbilical cord blood cells by defined factors","volume":"22","author":"Huang","year":"2014","journal-title":"Mol. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Wang, L.B., Sommer, A.G., Leung, A., Park, S., Chui, D.H.K., Steinberg, M.H., Mostoslavsky, G., and Murphy, G.J. (2014). Multisystem, Induced Pluripotent Stem Cell (iPSC) Modeling Reveals a Role for Growth Differentiation Factors (GDFs) in the Etiology of \u03b2 Thalassemia and Ineffective Erythropoiesis. Blood, 124.","DOI":"10.1182\/blood.V124.21.4039.4039"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.scr.2018.04.016","article-title":"E ffi cient production of erythroid, megakaryocytic and myeloid cells, using single cell-derived iPSC colony di ff erentiation","volume":"29","author":"Hansen","year":"2018","journal-title":"Stem Cell Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1002\/stem.2335","article-title":"\u03b2-Globin-Expressing Definitive Erythroid Progenitor Cells Generated from Embryonic and Induced Pluripotent Stem Cell-Derived Sacs","volume":"34","author":"Fujita","year":"2016","journal-title":"Stem Cells"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1002\/stem.2517","article-title":"Efficient Generation of beta-Globin-Expressing Erythroid Cells Using Stromal Cell-Derived Induced Pluripotent Stem Cells from Patients with Sickle Cell Disease","volume":"35","author":"Uchida","year":"2017","journal-title":"Stem Cells"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1002\/stem.2562","article-title":"Activation of KLF1 Enhances the Differentiation and Maturation of Red Blood Cells from Human Pluripotent Stem Cells","volume":"35","author":"Yang","year":"2017","journal-title":"Stem Cells"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Barbarani, G., Fugazza, C., Strouboulis, J., and Ronchi, A.E. (2019). The Pleiotropic Effects of GATA1 and KLF1 in Physiological Erythropoiesis and in Dyserythropoietic Disorders. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.00091"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4103","DOI":"10.1073\/pnas.1401598111","article-title":"Transcriptional divergence and conservation of human and mouse erythropoiesis","volume":"111","author":"Pishesha","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1097\/MOH.0000000000000134","article-title":"Human and murine erythropoiesis","volume":"22","author":"An","year":"2015","journal-title":"Curr. Opin. Hematol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/nbt0502-467","article-title":"Human erythroid cells produced ex vivo at large scale differentiate into red blood cells in vivo","volume":"20","author":"Wajcman","year":"2002","journal-title":"Nat. Biotechnol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5938","DOI":"10.1182\/blood-2010-11-321414","article-title":"Macrophages prevent human red blood cell reconstitution in immunodeficient mice","volume":"118","author":"Hu","year":"2011","journal-title":"Blood"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.stemcr.2016.08.005","article-title":"Improved Human Erythropoiesis and Platelet Formation in Humanized NSGW41 Mice","volume":"7","author":"Rahmig","year":"2016","journal-title":"Stem Cell Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.exphem.2006.10.001","article-title":"Heterozygous kit mutants with little or no apparent anemia exhibit large defects in overall hematopoietic stem cell function","volume":"35","author":"Sharma","year":"2007","journal-title":"Exp. Hematol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.stem.2014.06.001","article-title":"Kit regulates HSC engraftment across the human-mouse species barrier","volume":"15","author":"Cosgun","year":"2014","journal-title":"Cell Stem Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"E513","DOI":"10.1002\/ajh.24805","article-title":"Developmentally-faithful and effective human erythropoiesis in immunodeficient and Kit mutant mice","volume":"92","author":"Fiorini","year":"2017","journal-title":"Am. J. Hematol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.omtm.2019.10.017","article-title":"Low-Dose Busulfan Reduces Human CD34 + Cell Doses Required for Engraftment in c-kit Mutant Immunodeficient Mice","volume":"15","author":"Leonard","year":"2019","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_43","first-page":"573","article-title":"Adult haematopoietic stem cell niches","volume":"17","author":"Crane","year":"2017","journal-title":"Nat. Publ. Gr."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.ymeth.2015.09.016","article-title":"Mesenchymal stem cells: Identification, phenotypic characterization, biological properties and potential for regenerative medicine through biomaterial micro-engineering of their niche","volume":"99","author":"Kobolak","year":"2016","journal-title":"Methods"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.exphem.2015.11.007","article-title":"Hematopoietic niches, erythropoiesis and anemia of chronic infection","volume":"44","author":"Gomes","year":"2016","journal-title":"Exp. Hematol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/j.cell.2005.05.026","article-title":"SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells","volume":"121","author":"Kiel","year":"2005","journal-title":"Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/ncb2730","article-title":"Quantitative imaging of haematopoietic stem and progenitor cell localization and hypoxic status in the bone marrow microenvironment","volume":"15","author":"Pivarnik","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/nature17624","article-title":"Distinct bone marrow blood vessels differentially regulate haematopoiesis","volume":"532","author":"Itkin","year":"2016","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1038\/nature12612","article-title":"Arteriolar niches maintain haematopoietic stem cell quiescence","volume":"502","author":"Kunisaki","year":"2013","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1016\/j.cell.2011.09.053","article-title":"Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche","volume":"147","author":"Yamazaki","year":"2011","journal-title":"Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1038\/nature09262","article-title":"Mesenchymal and haematopoietic stem cells form a unique bone marrow niche","volume":"466","author":"Michurina","year":"2010","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nature10783","article-title":"Endothelial and perivascular cells maintain haematopoietic stem cells","volume":"481","author":"Ding","year":"2012","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/nature11926","article-title":"CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance","volume":"495","author":"Greenbaum","year":"2013","journal-title":"Nature"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nature11885","article-title":"Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches","volume":"495","author":"Ding","year":"2013","journal-title":"Nature"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/ncb3475","article-title":"Differential cytokine contributions of perivascular haematopoietic stem cell niches","volume":"19","author":"Asada","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"542","DOI":"10.3324\/haematol.2009.010736","article-title":"Hematopoietic stem cells in co-culture with mesenchymal stromal cells--modeling the niche compartments in vitro","volume":"95","author":"Jing","year":"2010","journal-title":"Haematologica"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"10716","DOI":"10.1073\/pnas.191362598","article-title":"Hematopoietic colony-forming cells derived from human embryonic stem cells","volume":"98","author":"Kaufman","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1182\/blood-2004-04-1649","article-title":"Human embryonic stem cell-derived CD34+ cells: Efficient production in the coculture with OP9 stromal cells and analysis of lymphohematopoietic potential","volume":"105","author":"Vodyanik","year":"2005","journal-title":"Blood"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"13087","DOI":"10.1073\/pnas.0802220105","article-title":"Generation of functional erythrocytes from human embryonic stem cell-derived definitive hematopoiesis","volume":"105","author":"Ma","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/j.1423-0410.2010.01453.x","article-title":"The influence of extracellular matrix proteins and mesenchymal stem cells on erythropoietic cell maturation","volume":"101","author":"Dorn","year":"2011","journal-title":"Vox Sang."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Chen, T.-L., Chiang, Y.-W., Lin, G.-L., Chang, H.-H., Lien, T.-S., Sheh, M.-H., and Sun, D.-S. (2018). Different effects of granulocyte colony-stimulating factor and erythropoietin on erythropoiesis. Stem Cell Res. Ther., 9.","DOI":"10.1186\/s13287-018-0877-2"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1089\/scd.2011.0078","article-title":"Generation of red blood cells from human induced pluripotent stem cells","volume":"20","author":"Dias","year":"2011","journal-title":"Stem Cells Dev."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1111\/bjh.12910","article-title":"Human induced pluripotent stem cell derived erythroblasts can undergo definitive erythropoiesis and co-express gamma and beta globins","volume":"166","author":"Yang","year":"2014","journal-title":"Br. J. Haematol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.immuni.2010.08.017","article-title":"Article The Essential Functions of Adipo-osteogenic Progenitors as the Hematopoietic Stem and Progenitor Cell Niche","volume":"33","author":"Omatsu","year":"2010","journal-title":"Immunity"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Zhou, X., von der Mark, K., Henry, S., Norton, W., Adams, H., and de Crombrugghe, B. (2014). Chondrocytes transdifferentiate into osteoblasts in endochondral bone during development, postnatal growth and fracture healing in mice. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004820"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1038\/nature07547","article-title":"Endochondral ossification is required for haematopoietic stem-cell niche formation","volume":"457","author":"Chan","year":"2009","journal-title":"Nature"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1101\/gad.311068.117","article-title":"Stem cell niche-specific Ebf3 maintains the bone marrow cavity","volume":"32","author":"Seike","year":"2018","journal-title":"Genes Dev."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.3892\/ijmm.2016.2712","article-title":"Three-dimensional co-culture of mesenchymal stromal cells and differentiated osteoblasts on human bio-derived bone scaffolds supports active multi-lineage hematopoiesis in vitro: Functional implication of the biomimetic HSC niche","volume":"38","author":"Huang","year":"2016","journal-title":"Int. J. Mol. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.cell.2004.07.004","article-title":"Tie2\/Angiopoietin-1 Signaling Regulates Hematopoietic Stem Cell Quiescence in the Bone Marrow Niche","volume":"118","author":"Arai","year":"2004","journal-title":"Cell"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.trsl.2006.12.007","article-title":"Expression of angiopoietin-1 in osteoblasts and its inhibition by tumor necrosis factor-alpha and interferon-gamma","volume":"149","author":"Kasama","year":"2007","journal-title":"Transl. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/j.stem.2007.10.008","article-title":"Critical Role of Thrombopoietin in Maintaining Adult Quiescent Hematopoietic Stem Cells","volume":"1","author":"Qian","year":"2007","journal-title":"Cell Stem Cell"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.stem.2007.10.020","article-title":"Thrombopoietin\/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche","volume":"1","author":"Yoshihara","year":"2007","journal-title":"Cell Stem Cell"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3258","DOI":"10.1182\/blood-2003-11-4011","article-title":"Hematopoiesis is severely altered in mice with an induced osteoblast deficiency","volume":"103","author":"Visnjic","year":"2004","journal-title":"Blood"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"16976","DOI":"10.1073\/pnas.0802898105","article-title":"Osteoblastic regulation of B lymphopoiesis is mediated by Gs{alpha}-dependent signaling pathways","volume":"105","author":"Wu","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.cell.2012.01.051","article-title":"The HIF Signaling Pathway in Osteoblasts Directly Modulates Erythropoiesis through the Production of EPO","volume":"149","author":"Rankin","year":"2012","journal-title":"Cell"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Salati, S., Lisignoli, G., Manferdini, C., Pennucci, V., Zini, R., Bianchi, E., Norfo, R., Facchini, A., Ferrari, S., and Manfredini, R. (2013). Co-culture of hematopoietic stem\/progenitor cells with human osteblasts favours mono\/macrophage differentiation at the expense of the erythroid lineage. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0053496"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1007\/s11914-014-0236-x","article-title":"Osteoblasts: A novel source of erythropoietin","volume":"12","author":"Wu","year":"2014","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1038\/nbt.1687","article-title":"Substrate elasticity provides mechanical signals for the expansion of hemopoietic stem and progenitor cells","volume":"28","author":"Holst","year":"2010","journal-title":"Nat. Biotechnol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.biomaterials.2015.09.014","article-title":"Extracellular matrix deposition of bone marrow stroma enhanced by macromolecular crowding","volume":"73","author":"Prewitz","year":"2015","journal-title":"Biomaterials"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"25419","DOI":"10.1074\/jbc.M112.376699","article-title":"Hyaluronan expressed by the hematopoietic microenvironment is required for bone marrow hematopoiesis","volume":"287","author":"Goncharova","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_81","first-page":"8","article-title":"Erythroblastic island, functional unity of bone marrow","volume":"13","author":"Bessis","year":"1958","journal-title":"Rev. Hematol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1182\/blood.V51.4.633.633","article-title":"Three-dimensional model of bone marrow","volume":"51","author":"Mohandas","year":"1978","journal-title":"Blood"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1292\/jvms.65.449","article-title":"Migration of erythroblastic islands toward the sinusoid as erythroid maturation proceeds in rat bone marrow","volume":"65","author":"Yokoyama","year":"2003","journal-title":"J. Vet. Med. Sci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1084\/jem.20101688","article-title":"Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche","volume":"208","author":"Chow","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.exphem.2014.03.009","article-title":"Mobilization with granulocyte colony-stimulating factor blocks medullar erythroid island macrophages in the mouse","volume":"42","author":"Jacobsen","year":"2014","journal-title":"Exp. Hematol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"4815","DOI":"10.1182\/blood-2009-11-253534","article-title":"Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs","volume":"116","author":"Winkler","year":"2010","journal-title":"Blood"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1182\/blood.2019000430","article-title":"Identification and transcriptome analysis of erythroblastic island macrophages","volume":"134","author":"Li","year":"2019","journal-title":"Blood"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Seu, K.G., Papoin, J., Fessler, R., Hom, J., Huang, G., Mohandas, N., Blanc, L., and Kalfa, T.A. (2017). Unraveling Macrophage Heterogeneity in Erythroblastic Islands. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.01140"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1016\/j.imbio.2016.11.007","article-title":"Van Den Immunobiology Digesting the role of bone marrow macrophages on hematopoiesis","volume":"222","author":"Heideveld","year":"2017","journal-title":"Immunobiology"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"3494","DOI":"10.1182\/blood.V84.10.3494.3494","article-title":"The association of erythroblasts with macrophages promotes erythroid proliferation and maturation: A 30-kD heparin-binding protein is involved in this contact","volume":"84","author":"Hanspal","year":"1994","journal-title":"Blood"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1111\/j.1365-2141.2006.06279.x","article-title":"A detailed study of time-dependent changes in human red blood cells: From reticulocyte maturation to erythrocyte senescence","volume":"135","author":"Gifford","year":"2006","journal-title":"Br. J. Haematol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1084\/jem.181.1.411","article-title":"Very late activation antigen 4-vascular cell adhesion molecule 1 interaction is involved in the formation of erythroblastic islands","volume":"181","author":"Sadahira","year":"1995","journal-title":"J. Exp. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1182\/blood-2006-03-006759","article-title":"Targeted gene deletion demonstrates that the cell adhesion molecule ICAM-4 is critical for erythroblastic island formation","volume":"108","author":"Lee","year":"2006","journal-title":"Blood"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"3963","DOI":"10.1182\/blood-2014-01-547976","article-title":"MerTK-mediated engulfment of pyrenocytes by central macrophages in erythroblastic islands","volume":"123","author":"Toda","year":"2014","journal-title":"Blood"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1097\/MOH.0000000000000131","article-title":"Macrophages and regulation of erythropoiesis","volume":"22","author":"Jacobsen","year":"2015","journal-title":"Curr. Opin. Hematol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.bcmd.2016.06.004","article-title":"Blood Cells, Molecules and Diseases Novel interactions between erythroblast macrophage protein and cell migration","volume":"60","author":"Javan","year":"2016","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/ejh.12983","article-title":"Erythroblast macrophage protein (Emp): Past, present, and future","volume":"100","author":"Javan","year":"2018","journal-title":"Eur. J. Haematol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"914","DOI":"10.3324\/haematol.2018.215160","article-title":"Ephrin\/Eph receptor interaction facilitates macrophage recognition of differentiating human erythroblasts","volume":"105","author":"Severn","year":"2020","journal-title":"Haematologica"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.1182\/blood-2007-06-098178","article-title":"Adherence to macrophages in erythroblastic islands enhances erythroblast proliferation and increases erythrocyte production by a different mechanism than erythropoietin","volume":"111","author":"Rhodes","year":"2008","journal-title":"Blood"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"178","DOI":"10.3324\/haematol.2014.114405","article-title":"Dexamethasone targeted directly to macrophages induces macrophage niches that promote erythroid expansion","volume":"100","author":"Falchi","year":"2015","journal-title":"Haematologica"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/nm.3126","article-title":"Macrophages support pathological erythropoiesis in polycythemia vera and \u03b2-thalassemia","volume":"19","author":"Ramos","year":"2013","journal-title":"Nat. Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1182\/blood-2008-03-077883","article-title":"Erythroblastic islands: Niches for erythropoiesis","volume":"112","author":"Chasis","year":"2008","journal-title":"Blood"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S0070-2153(07)00002-6","article-title":"The erythroblastic island","volume":"82","author":"Manwani","year":"2008","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s10577-008-9005-y","article-title":"Chromatin condensation in terminally differentiating mouse erythroblasts does not involve special architectural proteins but depends on histone deacetylation","volume":"17","author":"Popova","year":"2009","journal-title":"Chromosome Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.3324\/haematol.2010.029827","article-title":"Histone deacetylase 2 is required for chromatin condensation and subsequent enucleation of cultured mouse fetal erythroblasts","volume":"95","author":"Ji","year":"2010","journal-title":"Haematologica"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1038\/nature03964","article-title":"Phosphatidylserine-dependent engulfment by macrophages of nuclei from erythroid precursor cells","volume":"437","author":"Yoshida","year":"2005","journal-title":"Nature"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1083\/jcb.6.2.231","article-title":"Various aspects of iron in the organism. I. Ferritin and ferruginous micelles","volume":"6","author":"Bessis","year":"1959","journal-title":"J. Biophys. Biochem. Cytol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.bbagen.2018.10.019","article-title":"The iron islands: Erythroblastic islands and iron metabolism","volume":"1863","author":"Yeo","year":"2019","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.3324\/haematol.2015.125492","article-title":"CD14+ cells from peripheral blood positively regulate hematopoietic stem and progenitor cell survival resulting in increased erythroid yield","volume":"100","author":"Heideveld","year":"2015","journal-title":"Haematologica"},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Belay, E., Hayes, B.J., Blau, C.A., and Torok-Storb, B. (2017). Human Cord Blood and Bone Marrow CD34+ Cells Generate Macrophages That Support Erythroid Islands. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0171096"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/S0145-2126(96)00132-4","article-title":"The human bladder carcinoma cell line 5637 constitutively secretes functional cytokines","volume":"21","author":"Quentmeier","year":"1997","journal-title":"Leuk. Res."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"33","DOI":"10.2144\/000114435","article-title":"A phased strategy to differentiate human CD14+monocytes into classically and alternatively activated macrophages and dendritic cells","volume":"61","author":"Zarif","year":"2016","journal-title":"Biotechniques"},{"key":"ref_113","first-page":"1","article-title":"Genetic programming of macrophages generates an in vitro model for the human erythroid island niche","volume":"10","author":"Yang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/s41375-019-0532-7","article-title":"A three-dimensional in vitro model of erythropoiesis recapitulates erythroid failure in myelodysplastic syndromes","volume":"34","author":"Dimitriou","year":"2020","journal-title":"Leukemia"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/15\/5263\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:51:31Z","timestamp":1760176291000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/15\/5263"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,24]]},"references-count":114,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["ijms21155263"],"URL":"https:\/\/doi.org\/10.3390\/ijms21155263","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,24]]}}}