title: Targeted Application of Human Genetic Variation Can Improve Red Blood Cell Production from Stem Cells.
abstract: Multipotent and pluripotent stem cells are potential sources for cell and tissue replacement therapies. For example, stem cell-derived red blood cells (RBCs) are a potential alternative to donated blood, but yield and quality remain a challenge. Here, we show that application of insight from human population genetic studies can enhance RBC production from stem cells. The SH2B3 gene encodes a negative regulator of cytokine signaling and naturally occurring loss-of-function variants in this gene increase RBC counts in vivo. Targeted suppression of SH2B3 in primary human hematopoietic stem and progenitor cells enhanced the maturation and overall yield of in-vitro-derived RBCs. Moreover, inactivation of SH2B3 by CRISPR/Cas9 genome editing in human pluripotent stem cells allowed enhanced erythroid cell expansion with preserved differentiation. Our findings therefore highlight the potential for combining human genome variation studies with genome editing approaches to improve cell and tissue production for regenerative medicine.
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.|Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Department of Neonatology, Charité-Universitätsmedizin Berlin, Berlin 10117, Germany.
authors.forename: Felix C
authors.initials: FC
authors.lastname: Giani
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.|Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Fiorini
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.|Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Aoi
authors.initials: A
authors.lastname: Wakabayashi
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.|Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Department of Neonatology, Charité-Universitätsmedizin Berlin, Berlin 10117, Germany.|Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin 14195, Germany.
authors.forename: Leif S
authors.initials: LS
authors.lastname: Ludwig
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rany M
authors.initials: RM
authors.lastname: Salem
authors.affiliation: Departments of Pathology and Laboratory Medicine and Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Chintan D
authors.initials: CD
authors.lastname: Jobaliya
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Stephanie N
authors.initials: SN
authors.lastname: Regan
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.|Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Jacob C
authors.initials: JC
authors.lastname: Ulirsch
authors.affiliation: Departments of Pathology and Laboratory Medicine and Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ge
authors.initials: G
authors.lastname: Liang
authors.affiliation: Departments of Pathology and Laboratory Medicine and Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Orna
authors.initials: O
authors.lastname: Steinberg-Shemer
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Guo
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Tõnu
authors.initials: T
authors.lastname: Esko
authors.affiliation: Departments of Pathology and Laboratory Medicine and Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Tong
authors.affiliation: Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Carlo
authors.initials: C
authors.lastname: Brugnara
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.affiliation: Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Weiss
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.|Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
authors.affiliation: Departments of Pathology and Laboratory Medicine and Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Stella T
authors.initials: ST
authors.lastname: Chou
authors.affiliation: Departments of Pathology and Laboratory Medicine and Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: French
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Kiran
authors.initials: K
authors.lastname: Musunuru
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.|Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Vijay G
authors.initials: VG
authors.lastname: Sankaran
mesh_terms: D064113:CRISPR-Cas Systems; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology; D004912:Erythrocytes / Q000166:cytology*; D005312:Fetal Blood / Q000166:cytology; D005821:Genetic Techniques; D014644:Genetic Variation; D015894:Genome, Human; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D009154:Mutation; D039904:Pluripotent Stem Cells / Q000166:cytology; D044968:Regenerative Medicine / Q000379:methods; D013234:Stem Cells / Q000166:cytology*
chemical_list: D016207:Cytokines; D006454:Hemoglobins