Type

Journal Article

Authors

Michael F Gallagher
John J O'Leary
Luke O'Neill
Sharon O'Toole
Desmond G. Higgins
Paul N. Moynagh
Eric L Campbell
Mathia Yc Lee
Charles d'Adhemar
Mark Bates
and 16 others

Subjects

Biochemistry

Topics
cancer treatment stem cell human cells ground state toll like receptor carcinoma cells protein array analysis regenerative medicine

MyD88 is an essential component of retinoic acid-induced differentiation in human pluripotent embryonal carcinoma cells. (2017)

Abstract We have previously reported that myeloid differentiation primary response gene 88 (MyD88) is downregulated during all-trans retinoic acid (RA)-induced differentiation of pluripotent NTera2 human embryonal carcinoma cells (hECCs), whereas its maintained expression is associated with RA differentiation resistance in nullipotent 2102Ep hECCs. MyD88 is the main adapter for toll-like receptor (TLR) signalling, where it determines the secretion of chemokines and cytokines in response to pathogens. In this study, we report that loss of MyD88 is essential for RA-facilitated differentiation of hECCs. Functional analysis using a specific MyD88 peptide inhibitor (PepInh) demonstrated that high MyD88 expression in the self-renewal state inhibits the expression of a specific set of HOX genes. In NTera2 cells, MyD88 is downregulated during RA-induced differentiation, a mechanism that could be broadly replicated by MyD88 PepInh treatment of 2102Ep cells. Notably, MyD88 inhibition transitioned 2102Ep cells into a stable, self-renewing state that appears to be primed for differentiation upon addition of RA. At a molecular level, MyD88 inhibition combined with RA treatment upregulated HOX, RA signalling and TLR signalling genes. These events permit differentiation through a standard downregulation of Oct4-Sox2-Nanog mechanism. In line with its role in regulating secretion of specific proteins, conditioned media experiments demonstrated that differentiated (MyD88 low) NTera2 cell media was sufficient to differentiate NTera2 cells. Protein array analysis indicated that this was owing to secretion of factors known to regulate angiogenesis, neurogenesis and all three branches of TGF-β Superfamily signalling. Collectively, these data offer new insights into RA controlled differentiation of pluripotent cells, with notable parallels to the ground state model of embryonic stem cell self-renewal. These data may provide insights to facilitate improved differentiation protocols for regenerative medicine and differentiation-therapies in cancer treatment.
Collections Ireland -> Maynooth University -> Academic Unit = Faculty of Science and Engineering: Biology
Ireland -> Maynooth University -> Type = Article
Ireland -> Maynooth University -> Academic Unit = Faculty of Science and Engineering
Ireland -> Maynooth University -> Status = Published
Ireland -> Maynooth University -> Open Access DRIVERset
Ireland -> Maynooth University -> PubMed

Full list of authors on original publication

Michael F Gallagher, John J O'Leary, Luke O'Neill, Sharon O'Toole, Desmond G. Higgins, Paul N. Moynagh, Eric L Campbell, Mathia Yc Lee, Charles d'Adhemar, Mark Bates and 16 others

Experts in our system

1
Michael Gallagher
Trinity College Dublin
Total Publications: 21
 
2
John O'Leary
Trinity College Dublin
Total Publications: 93
 
3
Luke Anthony John O'Neill
Trinity College Dublin
Total Publications: 262
 
4
Sharon O'Toole
Trinity College Dublin
Total Publications: 29
 
5
Desmond G Higgins
University College Dublin
Total Publications: 76
 
6
Paul N. Moynagh
Maynooth University
Total Publications: 91
 
7
Eric L Campbell
Maynooth University
Total Publications: 10
 
8
Mark Bates
Trinity College Dublin
Total Publications: 5