PubMed · 15926483
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Yuki Takei, Tetsuya Tabata. 2005. [Morphogens].. https://pubmed.ncbi.nlm.nih.gov/15926483/
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Follicular helper T cells (TFH cells) are CD4(+) T cells specialized in helping B cells and are associated both with protective antibody responses and autoimmune diseases. The promise of targeting TFH cells therapeutically has been limited by fragmentary understanding of extrinsic signals that regulate the differentiation of human TFH cells. A screen of a human protein library identified activin A as a potent regulator of TFH cell differentiation. Activin A orchestrated the expression of multiple genes associated with the TFH program, independently or in concert with additional signals. TFH cell programming by activin A was antagonized by the cytokine IL-2. Activin A's ability to drive TFH cell differentiation in vitro was conserved in non-human primates but not in mice. Finally, activin-A-induced TFH programming was dependent on signaling via SMAD2 and SMAD3 and was blocked by pharmacological inhibitors.
Embryonic stem (ES) cells are self-renewing cells that maintain pluripotency to differentiate into all types of cells. Because of their potential to provide a variety of tissues for use in regenerative medicine, there is great interest in the identification of growth factors that govern these unique properties of ES cells. However, the signaling pathways controlling ES cell proliferation remain largely unknown. Since transforming growth factor beta (TGFbeta) superfamily members have been implicated in the processes of early embryogenesis, we investigated their roles in ES cell self-renewal. Inhibition of activin-Nodal-TGFbeta signaling by Smad7 or SB-431542 dramatically decreased ES cell proliferation without decreasing ES pluripotency. By contrast, inhibition of bone morphogenetic protein (BMP) signaling by Smad6 did not exhibit such effects, suggesting that activin-Nodal-TGFbeta signaling, but not BMP signaling, is indispensable for ES cell propagation. In serum-free culture, supplementation of recombinant activin or Nodal, but not TGFbeta or BMP, significantly enhanced ES cell propagation without affecting pluripotency. We also found that activin-Nodal signaling was constitutively activated in an autocrine fashion in serum-free cultured ES cells, and that inhibition of such endogenous signaling by SB-431542 decreased ES cell propagation in serum-free conditions. These findings suggest that endogenously activated autocrine loops of activin-Nodal signaling promote ES cell self-renewal.
Human ESCs (hESCs) respond to signals that determine their pluripotency, proliferation, survival, and differentiation status. In this report, we demonstrate that phosphatidylinositol 3-kinase (PI3K) antagonizes the ability of hESCs to differentiate in response to transforming growth factor beta family members such as Activin A and Nodal. Inhibition of PI3K signaling efficiently promotes differentiation of hESCs into mesendoderm and then definitive endoderm (DE) by allowing them to be specified by Activin/Nodal signals present in hESC cultures. Under conditions where hESCs are grown in mouse embryo fibroblast-conditioned medium under feeder-free conditions, approximately 70%-80% are converted into DE following 5 days of treatment with inhibitors of the PI3K pathway, such as LY 294002 and AKT1-II. Microarray and quantitative polymerase chain reaction-based gene expression profiling demonstrates that definitive endoderm formation under these conditions closely parallels that following specification with elevated Activin A and low fetal calf serum (FCS)/knockout serum replacement (KSR). Reduced insulin/insulin-like growth factor (IGF) signaling was found to be critical for cell fate commitment into DE. Levels of insulin/IGF present in FCS/KSR, normally used to promote self-renewal of hESCs, antagonized differentiation. In summary, we show that generation of hESC-DE requires two conditions: signaling by Activin/Nodal family members and release from inhibitory signals generated by PI3K through insulin/IGF. These findings have important implications for our understanding of hESC self-renewal and early cell fate decisions.