Abstract
BackgroundAnemia is a hematologic disorder with decreased number of erythrocytes. Erythropoiesis, the process by which red blood cells differentiate, are conserved in humans, mice and zebrafish. The only known agents available to treat pathological anemia are erythropoietin and its biologic derivatives. However, erythropoietin therapy elicits unwanted side-effects, high cost and intravenous or subcutaneous injection, warranting the development of a more cost effective and non-peptide alternative. Ginger (Zingiber officinale) has been widely used in traditional medicine; however, to date there is no scientific research documenting the potential of ginger to stimulate hematopoiesis.Methodology/Principal FindingsHere, we utilized gata1:dsRed transgenic zebrafish embryos to investigate the effect of ginger extract on hematopoiesis in vivo and we identified its bioactive component, 10-gingerol. We confirmed that ginger and 10-gingerol promote the expression of gata1 in erythroid cells and increase the expression of hematopoietic progenitor markers cmyb and scl. We also demonstrated that ginger and 10-gingerol can promote the hematopoietic recovery from acute hemolytic anemia in zebrafish, by quantifying the number of circulating erythroid cells in the dorsal aorta using video microscopy. We found that ginger and 10-gingerol treatment during gastrulation results in an increase of bmp2b and bmp7a expression, and their downstream effectors, gata2 and eve1. At later stages ginger and 10-gingerol can induce bmp2b/7a, cmyb, scl and lmo2 expression in the caudal hematopoietic tissue area. We further confirmed that Bmp/Smad pathway mediates this hematopoiesis promoting effect of ginger by using the Bmp-activated Bmp type I receptor kinase inhibitors dorsomorphin, LND193189 and DMH1.Conclusions/SignificanceOur study provides a strong foundation to further evaluate the molecular mechanism of ginger and its bioactive components during hematopoiesis and to investigate their effects in adults. Our results will provide the basis for future research into the effect of ginger during mammalian hematopoiesis to develop novel erythropoiesis promoting agents.
Highlights
The bone morphogenetic protein (Bmp) signaling pathway plays a critical role in hematopoeisis during the induction and maintenance of Hematopoietic Stem Cells (HSCs) in the ‘‘AortaGonad-Mesonephros’’ (AGM) axis [1,2]
Erythrocytes can be visualized in vivo in Tg(gata1:dsRed) transgenic zebrafish embryos by fluorescence microscopy as they exhibit an erythrocyte-specific red fluorescence under the control of the gata1 promoter [33]
Our results demonstrate that ginger extract and its purified component 10-G potentially stimulate both the primitive and definitive waves of hematopoiesis in zebrafish embryos
Summary
The bone morphogenetic protein (Bmp) signaling pathway plays a critical role in hematopoeisis during the induction and maintenance of Hematopoietic Stem Cells (HSCs) in the ‘‘AortaGonad-Mesonephros’’ (AGM) axis [1,2]. Bmp’s are members of the TGF-b superfamily of secreted factors, which regulate the development of multiple organ systems, such as bone, neural and renal tissue In addition to their function in dorsal-ventral specification, Bmp’s regulate the development of human HSCs [3] and embryonic hematopoiesis (blood cell formation) during early vertebrate development, but this function is independent of their mesoderm inductive activity [4]. In the vertebrate zebrafish, blood cells form in different sites during early embryonic development starting from the mesoderm near the aorta (ICM or Intermediate Cell Mass) and at the posterior blood island (PBI) in the tail These sites are of special interest because they contain hematopoietic progenitors which give rise to the blood cells and can be used as a model to study the molecular mechanism of hematopoeisis and erythropoiesis in vivo [12,13]. Ginger (Zingiber officinale) has been widely used in traditional medicine; to date there is no scientific research documenting the potential of ginger to stimulate hematopoiesis
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