|Ghrelin induces cardiac lineage differentiation of human embryonic stem cells through ERK1/2 pathway|
|Gao, Meijuan1,3; Yang, Jin1,3; Wei, Rui1,3; Liu, Guoqiang1,3; Zhang, Lin1,3; Wang, Haining1,3; Wang, Guang1,3; Gao, Hongwei1,3; Chen, Guian2,3; Hong, Tianpei1,3|
|关键词||Human embryonic stem cells Ghrelin Differentiation Cardiomyocytes|
|刊名||INTERNATIONAL JOURNAL OF CARDIOLOGY|
|WOS标题词||Science & Technology|
|类目[WOS]||Cardiac & Cardiovascular Systems|
|研究领域[WOS]||Cardiovascular System & Cardiology|
|关键词[WOS]||CARDIOMYOCYTE DIFFERENTIATION ; HEART-FAILURE ; BLASTOCYSTS ; SOX9 ; CARDIOMYOGENESIS ; TRANSCRIPTION ; PROGENITORS ; DYSFUNCTION ; POPULATION ; INHIBITOR|
Background: Ghrelin, an endogenous ligand for growth hormone secretagogue receptor (GHS-R), shows cardioprotective activity and regulates the differentiation of several mesoderm-derived cells, including myocytes, adipocytes and osteoblasts. The effect of ghrelin on cardiogenesis and its underlying mechanism, however, have not been studied in detail.
Methods: The effects of ghrelin on cardiomyocyte differentiation were tested both in human embryonic stem cells (hESCs) cultured in embryoid body (EB)-based differentiation protocol, and in hESCs transplanted into rat hearts. The signaling mechanisms of ghrelin were further investigated under the EB-based culture condition.
Results: The generation of beating EBs and the expression of cardiac-specific markers including cardiac troponin I (cTnI) and alpha-myosin heavy chain (alpha-MHC) were 2 to 3-fold upregulated by ghrelin. Although GHS-R1 alpha protein was expressed in differentiated EBs, the effects of exogenous ghrelin were unchanged by D-[lys(3)]-GHRP-6, a specific GHS-R1 alpha antagonist. Moreover, des-acyl ghrelin, which does not bind to GHS-R1 alpha, displayed similar effects with ghrelin. Importantly, activation of ERK1/2, but not Akt, was induced by ghrelin in the newly-formed EBs, and the ghrelin-induced effects of cardiomyocyte differentiation were abolished by adding specific ERK1/2 inhibitor PD98059, but not specific PI3K inhibitor Wortmannin. In addition, ghrelin promoted the differentiation of grafted hESCs into Sox9- and Flk1-positive mesodermal/cardiac progenitor cells in rat hearts.
Conclusions: These results suggest that ghrelin induces cardiomyocyte differentiation from hESCs via the activation of the ERK1/2 signaling pathway. Our study, therefore, indicates that using ghrelin may be an effective strategy to promote the differentiation of hESCs into cardiomyocytes. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
|项目编号||30771032 ; 30700879 ; 81070701 ; 81000315 ; 2006AA02A112 ; 2012CB517502 ; 20100001110083|
|资助机构||National Natural Science Foundations of China ; Chinese National 863 Program ; Chinese National 973 Program ; Specialized Research Fund for the Doctoral Program of Higher Education|
|作者单位||1.Peking Univ, Hosp 3, Dept Endocrinol & Metab, Beijing 100191, Peoples R China|
2.Peking Univ, Hosp 3, Reprod Med Ctr, Beijing 100191, Peoples R China
3.Peking Univ, Hosp 3, Clin Stem Cell Res Ctr, Beijing 100191, Peoples R China
|Gao, Meijuan,Yang, Jin,Wei, Rui,et al. Ghrelin induces cardiac lineage differentiation of human embryonic stem cells through ERK1/2 pathway[J]. INTERNATIONAL JOURNAL OF CARDIOLOGY,2013,167(6):2724-2733.|
|APA||Gao, Meijuan.,Yang, Jin.,Wei, Rui.,Liu, Guoqiang.,Zhang, Lin.,...&Hong, Tianpei.(2013).Ghrelin induces cardiac lineage differentiation of human embryonic stem cells through ERK1/2 pathway.INTERNATIONAL JOURNAL OF CARDIOLOGY,167(6),2724-2733.|
|MLA||Gao, Meijuan,et al."Ghrelin induces cardiac lineage differentiation of human embryonic stem cells through ERK1/2 pathway".INTERNATIONAL JOURNAL OF CARDIOLOGY 167.6(2013):2724-2733.|