Improved hematopoietic differentiation of human pluripotent stem cells via estrogen receptor signaling pathway

Haengseok Song,Eun-Taek Han,Se-Ran Yang,Kwon-Soo Ha,Hye-Ryun Kim,Jong-Hee Lee,Hye-Ryeon Heo,Won Sun Park,Seok-Ho Hong

doi:10.1186/s13578-016-0111-9

Haengseok Song, Eun-Taek Han + Show 7 more

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https://doi.org/10.1186/s13578-016-0111-9

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Abstract

BackgroundAside from its importance in reproduction, estrogen (E2) is known to regulate the proliferation and differentiation of hematopoietic stem cells in rodents. However, the regulatory role of E2 in human hematopoietic system has not been investigated. The purpose of this study is to investigate the effect of E2 on hematopoietic differentiation using human pluripotent stem cells (hPSCs).ResultsE2 improved hematopoietic differentiation of hPSCs via estrogen receptor alpha (ER-α)-dependent pathway. During hematopoietic differentiation of hPSCs, ER-α is persistently maintained and hematopoietic phenotypes (CD34 and CD45) were exclusively detected in ER-α positive cells. Interestingly, continuous E2 signaling is required to promote hematopoietic output from hPSCs. Supplementation of E2 or an ER-α selective agonist significantly increased the number of hemangioblasts and hematopoietic progenitors, and subsequent erythropoiesis, whereas ER-β selective agonist did not. Furthermore, ICI 182,780 (ER antagonist) completely abrogated the E2-induced hematopoietic augmentation. Not only from hPSCs but also from human umbilical cord bloods, does E2 signaling potentiate hematopoietic development, suggesting universal function of E2 on hematopoiesis.ConclusionsOur study identifies E2 as positive regulator of human hematopoiesis and suggests that endocrine factors such as E2 influence the behavior of hematopoietic stem cells in various physiological conditions.Electronic supplementary materialThe online version of this article (doi:10.1186/s13578-016-0111-9) contains supplementary material, which is available to authorized users.

Highlights

Aside from its importance in reproduction, estrogen (E2) is known to regulate the proliferation and differentiation of hematopoietic stem cells in rodents
estrogen receptor (ER)‐alpha is persistently maintained during hematopoietic differentiation To understand potential roles of E2 during the development of human hematopoietic systems, we first examined the expression of ER in human pluripotent stem cells (hPSCs)
We demonstrated that steroid receptors, such as ER-α, ER-β, glucocorticoid receptor, and progesterone receptor, are expressed in undifferentiated hPSCs and embryoid body (EB) [6]

Summary

Introduction

Aside from its importance in reproduction, estrogen (E2) is known to regulate the proliferation and differentiation of hematopoietic stem cells in rodents. The purpose of this study is to investigate the effect of E2 on hematopoietic dif‐ ferentiation using human pluripotent stem cells (hPSCs). Aside from its importance in reproduction, a growing body of evidence indicates that E2 is involved in regulating the proliferation and differentiation of multipotent and pluripotent stem cells [5,6,7]. Consistent with the importance of Notch, Wnt and Hedgehog (Hh) signalings during early embryonic hematopoiesis, recent evidence has shown that activation of these signaling pathways is crucial for both the emergence of hemogenic cells and the subsequent hematopoietic specification from hPSCs [10, 13]. We utilized hPSCs as a robust in vitro system to investigate the function of E2 during hematopoietic cell fate decision

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