Targeted Application of Human Genetic Variation Can Improve Red Blood Cell Production from Stem Cells

被引：70

作者：

Giani, Felix C. ^{[1
,2
,3
,11
]}

Fiorini, Claudia ^{[1
,2
,3
]}

Wakabayashi, Aoi ^{[1
,2
,3
]}

Ludwig, Leif S. ^{[1
,2
,3
,11
,12
]}

Salem, Rany M. ^{[3
,7
,8
]}

Jobaliya, Chintan D. ^{[4
,5
]}

Regan, Stephanie N. ^{[3
,6
]}

Ulirsch, Jacob C. ^{[1
,2
,3
]}

Liang, Ge ^{[4
,5
]}

Steinberg-Shemer, Orna ^{[4
,5
]}

Guo, Michael H. ^{[3
,7
,8
]}

Esko, Tonu ^{[3
,7
,8
]}

Tong, Wei ^{[4
,5
]}

Brugnara, Carlo ^{[10
]}

Hirschhorn, Joel N. ^{[3
,7
,8
]}

Weiss, Mitchell J. ^{[9
]}

Zon, Leonard I. ^{[1
,2
,3
,6
]}

Chou, Stella T. ^{[4
,5
]}

French, Deborah L. ^{[4
,5
]}

Musunuru, Kiran ^{[3
,6
]}

Sankaran, Vijay G. ^{[1
,2
,3
]}

机构：

[1] Harvard Univ, Sch Med, Div Hematol Oncol, Boston Childrens Hosp, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA

[3] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[4] Univ Penn, Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[5] Univ Penn, Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA

[6] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[7] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA

[8] Harvard Univ, Sch Med, Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA

[9] St Jude Childrens Res Hosp, Dept Hematol, Memphis, TN 38105 USA

[10] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Lab Med, Boston, MA 02115 USA

[11] Charite, Dept Neonatol, D-10117 Berlin, Germany

[12] Free Univ Berlin, Inst Chem & Biochem, D-14195 Berlin, Germany

来源：

CELL STEM CELL | 2016年 / 18卷 / 01期

基金：

美国国家卫生研究院;

关键词：

LNK; DIFFERENTIATION; MUTATIONS; SPECIFICATION; PROGENITORS; CHALLENGES; PROTEIN; VIVO;

D O I：

10.1016/j.stem.2015.09.015

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

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.

引用

页码：73 / 78

页数：6

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