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

Felix C. Giani; Claudia Fiorini; Aoi Wakabayashi; Leif S. Ludwig; Rany M. Salem; Chintan D. Jobaliya; Stephanie N. Regan; Jacob C. Ulirsch; Ge Liang; Orna Steinberg-Shemer; Michael H. Guo; Tõnu Esko; Wei Tong; Carlo Brugnara; Joel N. Hirschhorn; Mitchell J. Weiss; Leonard I. Zon; Stella T. Chou; Deborah L. French; Kiran Musunuru; Vijay G. Sankaran

doi:10.1016/j.stem.2015.09.015

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

Felix C. Giani, Claudia Fiorini, Aoi Wakabayashi, Leif S. Ludwig, Rany M. Salem, Chintan D. Jobaliya, Stephanie N. Regan, Jacob C. Ulirsch, Ge Liang, Orna Steinberg-Shemer, Michael H. Guo, Tõnu Esko, Wei Tong, Carlo Brugnara, Joel N. Hirschhorn, Mitchell J. Weiss, Leonard I. Zon, Stella T. Chou, Deborah L. French, Kiran MusunuruVijay G. Sankaran^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

70 Scopus citations

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.

Original language	English
Pages (from-to)	73-78
Number of pages	6
Journal	Cell Stem Cell
Volume	18
Issue number	1
DOIs	https://doi.org/10.1016/j.stem.2015.09.015
State	Published - 7 Jan 2016
Externally published	Yes

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Giani, F. C., Fiorini, C., Wakabayashi, A., Ludwig, L. S., Salem, R. M., Jobaliya, C. D., Regan, S. N., Ulirsch, J. C., Liang, G., Steinberg-Shemer, O., Guo, M. H., Esko, T., Tong, W., Brugnara, C., Hirschhorn, J. N., Weiss, M. J., Zon, L. I., Chou, S. T., French, D. L., ... Sankaran, V. G. (2016). Targeted Application of Human Genetic Variation Can Improve Red Blood Cell Production from Stem Cells. Cell Stem Cell, 18(1), 73-78. https://doi.org/10.1016/j.stem.2015.09.015

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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.",

author = "Giani, {Felix C.} and Claudia Fiorini and Aoi Wakabayashi and Ludwig, {Leif S.} and Salem, {Rany M.} and Jobaliya, {Chintan D.} and Regan, {Stephanie N.} and Ulirsch, {Jacob C.} and Ge Liang and Orna Steinberg-Shemer and Guo, {Michael H.} and T{\~o}nu Esko and Wei Tong and Carlo Brugnara and Hirschhorn, {Joel N.} and Weiss, {Mitchell J.} and Zon, {Leonard I.} and Chou, {Stella T.} and French, {Deborah L.} and Kiran Musunuru and Sankaran, {Vijay G.}",

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year = "2016",

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doi = "10.1016/j.stem.2015.09.015",

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Giani, FC, Fiorini, C, Wakabayashi, A, Ludwig, LS, Salem, RM, Jobaliya, CD, Regan, SN, Ulirsch, JC, Liang, G, Steinberg-Shemer, O, Guo, MH, Esko, T, Tong, W, Brugnara, C, Hirschhorn, JN, Weiss, MJ, Zon, LI, Chou, ST, French, DL, Musunuru, K & Sankaran, VG 2016, 'Targeted Application of Human Genetic Variation Can Improve Red Blood Cell Production from Stem Cells', Cell Stem Cell, vol. 18, no. 1, pp. 73-78. https://doi.org/10.1016/j.stem.2015.09.015

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AU - Jobaliya, Chintan D.

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AU - Guo, Michael H.

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AU - Tong, Wei

AU - Brugnara, Carlo

AU - Hirschhorn, Joel N.

AU - Weiss, Mitchell J.

AU - Zon, Leonard I.

AU - Chou, Stella T.

AU - French, Deborah L.

AU - Musunuru, Kiran

AU - Sankaran, Vijay G.

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AB - 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.

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

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