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Targeted application of human genetic variation can improve red blood cell production from stem cells

Item Type:Article
Title:Targeted application of human genetic variation can improve red blood cell production from stem cells
Creators Name:Giani, F.C. and Fiorini, C. and Wakabayashi, A. and Ludwig, L.S. and Salem, R.M. and Jobaliya, C.D. and Regan, S.N. and Ulirsch, J.C. and Liang, G. and Steinberg-Shemer, O. and Guo, M.H. and Esko, T. and Tong, W. and Brugnara, C. and Hirschhorn, J.N. and Weiss, M.J. and Zon, L.I. and Chou, S.T. and French, D.L. and Musunuru, K. and Sankaran, V.G.
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.
Keywords:Cell Differentiation, CRISPR-Cas Systems, Cytokines, Embryonic Stem Cells, Erythrocytes, Fetal Blood, Genetic Techniques, Genetic Variation, Hematopoietic Stem Cells, Hemoglobins, Human Genome, Mutation, Pluripotent Stem Cells, Regenerative Medicine, Stem Cells
Source:Cell Stem Cell
Publisher:Cell Press
Page Range:73-78
Date:7 January 2016
Official Publication:https://doi.org/10.1016/j.stem.2015.09.015
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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