{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:18:27Z","timestamp":1790705907399,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,9,24]],"date-time":"2020-09-24T00:00:00Z","timestamp":1600905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Doris Duke Foundation","award":["2017087"],"award-info":[{"award-number":["2017087"]}]},{"DOI":"10.13039\/100012636","name":"New York State Stem Cell Science","doi-asserted-by":"publisher","award":["C030135, C029154"],"award-info":[{"award-number":["C030135, C029154"]}],"id":[{"id":"10.13039\/100012636","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL130764"],"award-info":[{"award-number":["HL130764"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The consequences of sickle cell disease (SCD) include ongoing hematopoietic stress, hemolysis, vascular damage, and effect of chronic therapies, such as blood transfusions and hydroxyurea, on hematopoietic stem and progenitor cell (HSPC) have been poorly characterized. We have quantified the frequencies of nine HSPC populations by flow cytometry in the peripheral blood of pediatric and adult patients, stratified by treatment and control cohorts. We observed broad differences between SCD patients and healthy controls. SCD is associated with 10 to 20-fold increase in CD34dim cells, a two to five-fold increase in CD34bright cells, a depletion in Megakaryocyte-Erythroid Progenitors, and an increase in hematopoietic stem cells, when compared to controls. SCD is also associated with abnormal expression of CD235a as well as high levels CD49f antigen expression. These findings were present to varying degrees in all patients with SCD, including those on chronic therapy and those who were therapy naive. HU treatment appeared to normalize many of these parameters. Chronic stress erythropoiesis and inflammation incited by SCD and HU therapy have long been suspected of causing premature aging of the hematopoietic system, and potentially increasing the risk of hematological malignancies. An important finding of this study was that the observed concentration of CD34bright cells and of all the HSPCs decreased logarithmically with time of treatment with HU. This correlation was independent of age and specific to HU treatment. Although the number of circulating HSPCs is influenced by many parameters, our findings suggest that HU treatment may decrease premature aging and hematologic malignancy risk compared to the other therapeutic modalities in SCD.<\/jats:p>","DOI":"10.3390\/cells9102159","type":"journal-article","created":{"date-parts":[[2020,9,24]],"date-time":"2020-09-24T08:33:03Z","timestamp":1600936383000},"page":"2159","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Characterization of Hematopoiesis in Sickle Cell Disease by Prospective Isolation of Stem and Progenitor Cells"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2235-4902","authenticated-orcid":false,"given":"Seda S.","family":"Tolu","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Hematology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shouping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3036-1005","authenticated-orcid":false,"given":"Karl","family":"Roberts","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew S.","family":"Crouch","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gracy","family":"Sebastian","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8809-9919","authenticated-orcid":false,"given":"Mark","family":"Chaitowitz","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric D.","family":"Fornari","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Montefiore Medical Center, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan M.","family":"Schwechter","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Montefiore Medical Center, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan","family":"Uehlinger","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Transfusion Medicine, Montefiore Health System, Bronx, NY 10467, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepa","family":"Manwani","sequence":"additional","affiliation":[{"name":"Pediatric Hematology\/Oncology\/Marrow and Blood Cell Transplantation, Montefiore Health System, Bronx, NY 10467, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina P.","family":"Minniti","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric E.","family":"Bouhassira","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"},{"name":"Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1111\/bjh.15902","article-title":"Bone marrow characterization in sickle cell disease: Inflammation and stress erythropoiesis lead to suboptimal CD34 recovery","volume":"186","author":"Leonard","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1111\/j.1365-2141.1975.tb00844.x","article-title":"Ultrastructural studies of the bone marrow in sickle cell anaemia. I. The structure of sickled erythrocytes and reticulocytes and their phagocytic destruction","volume":"31","author":"Grasso","year":"1975","journal-title":"Br. J. Haematol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1111\/j.1365-2141.1975.tb00869.x","article-title":"Ultrastructural studies of the bone marrow in sickle cell anaemia. II. The morphology of erythropoietic cells and their response to deoxygenation in vitro","volume":"31","author":"Grasso","year":"1975","journal-title":"Br. J. Haematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3639","DOI":"10.1182\/blood-2005-04-1376","article-title":"Evidence for ineffective erythropoiesis in severe sickle cell disease","volume":"106","author":"Wu","year":"2005","journal-title":"Blood"},{"key":"ref_5","first-page":"141","article-title":"Erythropoietic precursors in mice under erythropoietic stimulation and suppression","volume":"5","author":"Hara","year":"1977","journal-title":"Exp. Hematol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1182\/blood.V75.4.1006.1006","article-title":"Heterogeneity in the properties of burst-forming units of erythroid lineage in sickle cell anemia: DNA synthesis and burst-promoting activity production is related to peripheral hemoglobin F levels","volume":"75","author":"Croizat","year":"1990","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1111\/j.1365-2141.2000.02342.x","article-title":"Primitive haematopoietic progenitors in the blood of patients with sickle cell disease appear to be endogenously mobilized","volume":"111","author":"Croizat","year":"2000","journal-title":"Br. J. Haematol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1172\/JCI15956","article-title":"Spontaneous circulation of myeloid-lymphoid-initiating cells and SCID-repopulating cells in sickle cell crisis","volume":"111","author":"Lamming","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1089\/humc.2017.029","article-title":"Bone Marrow as a Hematopoietic Stem Cell Source for Gene Therapy in Sickle Cell Disease: Evidence from Rhesus and SCD Patients","volume":"28","author":"Uchida","year":"2017","journal-title":"Hum. Gene Ther. Clin. Dev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5300","DOI":"10.1182\/blood-2009-04-146852","article-title":"How I use hydroxyurea to treat young patients with sickle cell anemia","volume":"115","author":"Ware","year":"2010","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.cell.2008.01.025","article-title":"Hematopoiesis: An evolving paradigm for stem cell biology","volume":"132","author":"Orkin","year":"2008","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1146\/annurev.immunol.25.022106.141538","article-title":"Ontogeny of the hematopoietic system","volume":"25","author":"Cumano","year":"2007","journal-title":"Annu. Rev. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.stem.2007.10.001","article-title":"Identification of a Hierarchy of Multipotent Hematopoietic Progenitors in Human Cord Blood","volume":"1","author":"Majeti","year":"2007","journal-title":"Cell Stem Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1126\/science.1201219","article-title":"Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment","volume":"333","author":"Notta","year":"2011","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2580","DOI":"10.1016\/j.celrep.2019.02.021","article-title":"Ultra-High-Frequency Reprogramming of Individual Long-Term Hematopoietic Stem Cells Yields Low Somatic Variant Induced Pluripotent Stem Cells","volume":"26","author":"Wang","year":"2019","journal-title":"Cell Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1182\/blood-2015-07-660670","article-title":"Human hematopoietic stem cells from mobilized peripheral blood can be purified based on CD49f integrin expression","volume":"126","author":"Huntsman","year":"2015","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Wang, K., Yan, Z., Zhang, S., Bartholdy, B., Eaves, C.J., and Bouhassira, E.E. (2019). Clonal Origin in Normal Adults of All Blood Lineages and Circulating Hematopoietic Stem Cells. SSRN Electron. J., Online ahe.","DOI":"10.2139\/ssrn.3469828"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.coi.2012.08.002","article-title":"The road to purified hematopoietic stem cell transplants is paved with antibodies","volume":"24","author":"Logan","year":"2012","journal-title":"Curr. Opin. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1097\/MOH.0b013e32834521c8","article-title":"Stress erythropoiesis: New signals and new stress progenitor cells","volume":"18","author":"Paulson","year":"2011","journal-title":"Curr. Opin. Hematol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4507","DOI":"10.1172\/JCI41291","article-title":"Murine erythroid short-term radioprotection requires a BMP4-dependent, self-renewing population of stress erythroid progenitors","volume":"120","author":"Harandi","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.coi.2011.05.006","article-title":"Aging of hematopoietic stem cells: Intrinsic changes or micro-environmental effects?","volume":"23","author":"Woolthuis","year":"2011","journal-title":"Curr. Opin. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Notta, F., Zandi, S., Takayama, N., Dobson, S., Gan, O.I., Wilson, G., Kaufmann, K.B., McLeod, J., Laurenti, E., and Dunant, C.F. (2015). Distinct routes of lineage development reshape the human blood hierarchy across ontogeny. Science, 351.","DOI":"10.1126\/science.aab2116"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"11872","DOI":"10.1073\/pnas.172384399","article-title":"Prospective isolation of human clonogenic common myeloid progenitors","volume":"99","author":"Manz","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.exphem.2006.01.017","article-title":"Isolation and characterization of human myeloid progenitor populations--TpoR as discriminator between common myeloid and megakaryocyte\/erythroid progenitors","volume":"34","author":"Edvardsson","year":"2006","journal-title":"Exp. Hematol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.ccr.2010.12.012","article-title":"Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia","volume":"19","author":"Goardon","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"eaau7148","DOI":"10.1126\/sciimmunol.aau7148","article-title":"Identification of two distinct pathways of human myelopoiesis","volume":"4","author":"Drissen","year":"2019","journal-title":"Sci. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.exphem.2004.02.003","article-title":"Human CD34+ and CD34+CD38\u2212 hematopoietic progenitors in sickle cell disease differ phenotypically and functionally from normal and suggest distinct subpopulations that generate F cells","volume":"32","author":"Luck","year":"2004","journal-title":"Exp. Hematol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1182\/blood-2011-12-399683","article-title":"Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations","volume":"120","author":"Will","year":"2012","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2924","DOI":"10.1182\/blood-2002-09-2782","article-title":"SCID-repopulating cell activity of human cord blood-derived CD34- cells assured by intra-bone marrow injection","volume":"101","author":"Wang","year":"2003","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2202","DOI":"10.1038\/s41467-018-04441-z","article-title":"A revised road map for the commitment of human cord blood CD34-negative hematopoietic stem cells","volume":"9","author":"Sumide","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Carden, M.A., Fasano, R.M., and Meier, E.R. (2019). Not all red cells sickle the same: Contributions of the reticulocyte to disease pathology in sickle cell anemia. Blood Rev., 100637.","DOI":"10.1016\/j.blre.2019.100637"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1111\/j.1537-2995.2012.03822.x","article-title":"Low-shear red blood cell oxygen transport effectiveness is adversely affected by transfusion and further worsened by deoxygenation in sickle cell disease patients on chronic transfusion therapy","volume":"53","author":"Detterich","year":"2013","journal-title":"Transfusion"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1111\/j.1537-2995.2012.03961.x","article-title":"Patients with sickle cell anemia on simple chronic transfusion protocol show sex differences for hemodynamic and hematologic responses to transfusion","volume":"53","author":"Detterich","year":"2013","journal-title":"Transfusion"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1182\/blood-2006-02-003327","article-title":"Leukosialin (CD43) defines hematopoietic progenitors in human embryonic stem cell differentiation cultures","volume":"108","author":"Vodyanik","year":"2006","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Olivier, E.N., Zhang, S., Yan, Z., Suzuka, S., Roberts, K., Wang, K., and Bouhassira, E.E. (2019). PSC-RED and MNC-RED: Albumin-free and low-transferrin robust erythroid differentiation protocols to produce human enucleated red blood cells. Exp. Hematol.","DOI":"10.1016\/j.exphem.2019.05.006"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1089\/scd.2016.0319","article-title":"The Role of Integrin \u03b16 (CD49f) in Stem Cells: More than a Conserved Biomarker","volume":"26","author":"Krebsbach","year":"2017","journal-title":"Stem Cells Dev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1126\/science.1256337","article-title":"Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal","volume":"345","author":"Fares","year":"2014","journal-title":"Science (80-.)"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1182\/blood.2019002301","article-title":"Single-cell analysis of bone marrow-derived CD34+ cells from children with sickle cell disease and thalassemia","volume":"134","author":"Hua","year":"2019","journal-title":"Blood"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1002\/ajh.2830210212","article-title":"Hematologic malignancy in sickle cell disease: Report of four cases and review of the literature","volume":"21","author":"Stricker","year":"1986","journal-title":"Am. J. Hematol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1182\/blood-2017-05-783233","article-title":"Increased risk of leukemia among sickle cell disease patients in California","volume":"130","author":"Brunson","year":"2017","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Rundberg Nilsson, A., Soneji, S., Adolfsson, S., Bryder, D., and Pronk, C.J. (2016). Human and Murine Hematopoietic Stem Cell Aging Is Associated with Functional Impairments and Intrinsic Megakaryocytic\/Erythroid Bias. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0158369"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1053\/j.seminhematol.2016.10.004","article-title":"Age-associated changes in human hematopoietic stem cells","volume":"54","author":"Pang","year":"2017","journal-title":"Semin. Hematol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.stem.2012.05.013","article-title":"Bone Marrow Failure in Fanconi Anemia Is Triggered by an Exacerbated p53\/p21 DNA Damage Response that Impairs Hematopoietic Stem and Progenitor Cells","volume":"11","author":"Ceccaldi","year":"2012","journal-title":"Cell Stem Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3026","DOI":"10.1182\/blood-2008-06-158386","article-title":"French INSERM and the European EUMNET Networks on Myelofibrosis Does primary myelofibrosis involve a defective stem cell niche? From concept to evidence","volume":"112","author":"Lataillade","year":"2008","journal-title":"Blood"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1182\/blood-2017-03-776070","article-title":"SF3B1-initiating mutations in MDS-RSs target lymphomyeloid hematopoietic stem cells","volume":"130","author":"Dimitriou","year":"2017","journal-title":"Blood"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/10\/2159\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:13:10Z","timestamp":1760177590000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/10\/2159"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,24]]},"references-count":46,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["cells9102159"],"URL":"https:\/\/doi.org\/10.3390\/cells9102159","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints202008.0403.v1","asserted-by":"object"}]},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,24]]}}}