title: Efficient Generation of β-Globin-Expressing Erythroid Cells Using Stromal Cell-Derived Induced Pluripotent Stem Cells from Patients with Sickle Cell Disease.
abstract: Human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells represent an ideal source for in vitro modeling of erythropoiesis and a potential alternative source for red blood cell transfusions. However, iPS cell-derived erythroid cells predominantly produce ε- and γ-globin without β-globin production. We recently demonstrated that ES cell-derived sacs (ES sacs), known to express hemangioblast markers, allow for efficient erythroid cell generation with β-globin production. In this study, we generated several iPS cell lines derived from bone marrow stromal cells (MSCs) and peripheral blood erythroid progenitors (EPs) from sickle cell disease patients, and evaluated hematopoietic stem/progenitor cell (HSPC) generation after iPS sac induction as well as subsequent erythroid differentiation. MSC-derived iPS sacs yielded greater amounts of immature hematopoietic progenitors (VEGFR2 + GPA-), definitive HSPCs (CD34 + CD45+), and megakaryoerythroid progenitors (GPA + CD41a+), as compared to EP-derived iPS sacs. Erythroid differentiation from MSC-derived iPS sacs resulted in greater amounts of erythroid cells (GPA+) and higher β-globin (and βS-globin) expression, comparable to ES sac-derived cells. These data demonstrate that human MSC-derived iPS sacs allow for more efficient erythroid cell generation with higher β-globin production, likely due to heightened emergence of immature progenitors. Our findings should be important for iPS cell-derived erythroid cell generation. Stem Cells 2017;35:586-596.
authors.affiliation: Molecular and Clinical Hematology Branch, National Heart Lung and Blood Institutes (NHLBI)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Naoya
authors.initials: N
authors.lastname: Uchida
authors.affiliation: Molecular and Clinical Hematology Branch, National Heart Lung and Blood Institutes (NHLBI)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Haro-Mora
authors.affiliation: Molecular and Clinical Hematology Branch, National Heart Lung and Blood Institutes (NHLBI)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fujita
authors.affiliation: Biochemistry Core, NHLBI, NIH, Bethesda, Maryland, USA.
authors.forename: Duck-Yeon
authors.initials: DY
authors.lastname: Lee
authors.affiliation: Hematology Branch, NHLBI, NIH, Bethesda, Maryland, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Winkler
authors.affiliation: Molecular and Clinical Hematology Branch, National Heart Lung and Blood Institutes (NHLBI)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Hsieh
authors.affiliation: Molecular and Clinical Hematology Branch, National Heart Lung and Blood Institutes (NHLBI)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Tisdale
mesh_terms: D000755:Anemia, Sickle Cell / Q000473:pathology*; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D041905:Erythroid Cells / Q000378:metabolism*; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D051379:Mice; D017154:Stromal Cells / Q000378:metabolism; D055544:beta-Globins / Q000378:metabolism*
chemical_list: D055544:beta-Globins
keywords: Erythroid differentiation; Hemogenic endothelium; Pluripotent stem cells; Primitive and definitive hematopoiesis