Erythropoiesis from human embryonic stem cells through erythropoietin- independent AKT signaling

William S. Kim, Yuhua Zhu, Qiming Deng, Chee Jia Chin, Chong Bin He, Amanda J. Grieco, Gautam G. Dravid, Chintan Parekh, Roger P. Hollis, Timothy F. Lane, Eric E. Bouhassira, Donald B. Kohn, Gay M. Crooks

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Unlimited self renewal capacity and differentiation potential make human pluripotent stem cells (PSC) a promising source for the ex vivo manufacture of red blood cells (RBCs) for safe transfusion. Current methods to induce erythropoiesis from PSC suffer from low yields of RBCs, most of which are immature and contain embryonic and fetal rather than adult hemoglobins. We have previously shown that homodimerization of the intracellular component of MPL (ic-MPL) induces erythropoiesis from human cord blood progenitors. The goal of this study was to investigate the potential of ic-MPL dimerization to induce erythropoiesis from human embryonic stem cells (hESCs) and to identify the signaling pathways activated by this strategy. We present here the evidence that ic-MPL dimerization induces erythropoietin (EPO)-independent erythroid differentiation from hESC by inducing the generation of erythroid progenitors and by promoting more efficient erythroid maturation with increased RBC enucleation as well as increased gamma:epsilon globin ratio and production of beta-globin protein. ic-MPL dimerization is significantly more potent than EPO in inducing erythropoiesis, and its effect is additive to EPO. Signaling studies show that dimerization of ic-MPL, unlike stimulation of the wild type MPL receptor, activates AKT in the absence of JAK2/STAT5 signaling. AKT activation upregulates GATA-1 and FOXO3 transcriptional pathways with resulting inhibition of apoptosis, modulation of cell cycle, and enhanced maturation of erythroid cells. These findings open up potential new targets for the generation of therapeutically relevant RBC products from hPSC. Stem Cells 2014;32:1503-1514

Original languageEnglish (US)
Pages (from-to)1503-1514
Number of pages12
JournalStem Cells
Volume32
Issue number6
DOIs
StatePublished - 2014

Fingerprint

Erythropoiesis
Dimerization
Erythropoietin
Pluripotent Stem Cells
Erythrocytes
epsilon-Globins
gamma-Globins
Erythrocyte Transfusion
Erythroid Cells
beta-Globins
Fetal Blood
Cell Cycle
Hemoglobins
Up-Regulation
Stem Cells
Apoptosis
Human Embryonic Stem Cells
Proteins

Keywords

  • AKT
  • Erythropoiesis
  • Erythropoietin
  • GATA-1
  • Human embryonic stem cells
  • MPL

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

Cite this

Kim, W. S., Zhu, Y., Deng, Q., Chin, C. J., He, C. B., Grieco, A. J., ... Crooks, G. M. (2014). Erythropoiesis from human embryonic stem cells through erythropoietin- independent AKT signaling. Stem Cells, 32(6), 1503-1514. https://doi.org/10.1002/stem.1677

Erythropoiesis from human embryonic stem cells through erythropoietin- independent AKT signaling. / Kim, William S.; Zhu, Yuhua; Deng, Qiming; Chin, Chee Jia; He, Chong Bin; Grieco, Amanda J.; Dravid, Gautam G.; Parekh, Chintan; Hollis, Roger P.; Lane, Timothy F.; Bouhassira, Eric E.; Kohn, Donald B.; Crooks, Gay M.

In: Stem Cells, Vol. 32, No. 6, 2014, p. 1503-1514.

Research output: Contribution to journalArticle

Kim, WS, Zhu, Y, Deng, Q, Chin, CJ, He, CB, Grieco, AJ, Dravid, GG, Parekh, C, Hollis, RP, Lane, TF, Bouhassira, EE, Kohn, DB & Crooks, GM 2014, 'Erythropoiesis from human embryonic stem cells through erythropoietin- independent AKT signaling', Stem Cells, vol. 32, no. 6, pp. 1503-1514. https://doi.org/10.1002/stem.1677
Kim, William S. ; Zhu, Yuhua ; Deng, Qiming ; Chin, Chee Jia ; He, Chong Bin ; Grieco, Amanda J. ; Dravid, Gautam G. ; Parekh, Chintan ; Hollis, Roger P. ; Lane, Timothy F. ; Bouhassira, Eric E. ; Kohn, Donald B. ; Crooks, Gay M. / Erythropoiesis from human embryonic stem cells through erythropoietin- independent AKT signaling. In: Stem Cells. 2014 ; Vol. 32, No. 6. pp. 1503-1514.
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abstract = "Unlimited self renewal capacity and differentiation potential make human pluripotent stem cells (PSC) a promising source for the ex vivo manufacture of red blood cells (RBCs) for safe transfusion. Current methods to induce erythropoiesis from PSC suffer from low yields of RBCs, most of which are immature and contain embryonic and fetal rather than adult hemoglobins. We have previously shown that homodimerization of the intracellular component of MPL (ic-MPL) induces erythropoiesis from human cord blood progenitors. The goal of this study was to investigate the potential of ic-MPL dimerization to induce erythropoiesis from human embryonic stem cells (hESCs) and to identify the signaling pathways activated by this strategy. We present here the evidence that ic-MPL dimerization induces erythropoietin (EPO)-independent erythroid differentiation from hESC by inducing the generation of erythroid progenitors and by promoting more efficient erythroid maturation with increased RBC enucleation as well as increased gamma:epsilon globin ratio and production of beta-globin protein. ic-MPL dimerization is significantly more potent than EPO in inducing erythropoiesis, and its effect is additive to EPO. Signaling studies show that dimerization of ic-MPL, unlike stimulation of the wild type MPL receptor, activates AKT in the absence of JAK2/STAT5 signaling. AKT activation upregulates GATA-1 and FOXO3 transcriptional pathways with resulting inhibition of apoptosis, modulation of cell cycle, and enhanced maturation of erythroid cells. These findings open up potential new targets for the generation of therapeutically relevant RBC products from hPSC. Stem Cells 2014;32:1503-1514",
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