Open AccessMaintenance of Pluripotency in Human Embryonic Stem Cells Is STAT3 Independent
Author(s) -
Humphrey Rohan K.,
Beattie Gillian M.,
Lopez Ana D.,
Bucay Nathan,
King Charles C.,
Firpo Meri T.,
RoseJohn Stefan,
Hayek Alberto
Publication year - 2004
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1634/stemcells.22-4-522
Subject(s) - leukemia inhibitory factor , biology , glycoprotein 130 , microbiology and biotechnology , homeobox protein nanog , stem cell , embryonic stem cell , stat3 , signal transduction , leukemia inhibitory factor receptor , stem cell factor , cytokine , cancer research , induced pluripotent stem cell , immunology , progenitor cell , interleukin 6 , biochemistry , gene
The preservation of “stemness” in mouse embryonic stem (mES) cells is maintained through a signal transduction pathway that requires the gp130 receptor, the interleukin‐6 (IL‐6) family of cytokines, and the Janus Kinase‐signal transducer and activator (JAK/STAT) pathway. The factors and signaling pathways that regulate “stemness” in human embryonic stem (hES) cells remain to be elucidated. Here we report that STAT3 activation is not sufficient to block hES cell differentiation when the cells are grown on mouse feeder cells or when they are treated with conditioned media from feedercells. Human ES cells differentiate in the presence of members of the IL‐6 family of cytokines including leukemia inhibitory factor (LIF) and IL‐6 or in the presence of the designer cytokine hyper‐IL‐6, which is a complex of soluble interleukin‐6 receptor (IL‐6R) and IL‐6 with greatly enhanced bio‐activity. Human ES cells express LIF, IL‐6, and gp130 receptors, as well as the downstream signaling molecules. Stimulation of human and mouse ES cells with gp130 cytokines resulted in a robust phosphorylation of downstream ERK1, ERK2, and Akt kinases, as well as the STAT3 transcription factor. Loss of the pluripotency markers Nanog, Oct‐4, and TRA‐1‐60 was observed in hES cells during gp130‐dependent signaling, indicating that signaling through this pathway is insufficient to prevent the onset of differentiation. These data underscore a fundamental difference in requirements of murine versus hES cells. Furthermore, the data demonstrate the existence of an as‐yet‐unidentified factor in the conditioned media of mouse feeder layer cells that acts to maintain hES cell renewal in a STAT3‐independent manner.