Interplay between growth factor signaling and epigenetic landscapes in stem cell stemness

Growth factors and cytokines are fundamental regulators of stem cell fate, controlling both self-renewal and differentiation across the embryonic hierarchy. ESCs that originate from the ICM of the blastocyst can self-renew indefinitely and remain pluripotent in response to cytokine-driven signaling cues. In contrast, ASCs, such as HSCs and MSCs, rely on niche-derived growth factors and cytokines for limited self-renewal and lineage commitment. Major extrinsic inputs are key regulators such as LIF, Wnt ligands, FGF2, BMP4, TGF-β family members, and Notch signaling molecules, but their effects are finally controlled by downstream epigenetic pathways. In this review, we highlight that growth factor signals are not understood in isolation but are transduced to stable transcriptional outputs by means of chromatin remodeling, DNA methylation, histone changes, and interactions with transcriptional regulatory networks. These pathways maintain ESC identity, regulate lineage priming, and orchestrate the development of the three germ layers during gastrulation and later tissue-specific differentiation. The same pathways work in specific niches of adult stem cells to balance asymmetric division, quiescence, self-renewal, and differentiation. We also highlight the context-dependent signaling outputs, which are regulated by epigenetic and chromatin changes, in determining stemness, lineage commitment, and tissue regeneration. Insights into the link between extracellular signaling and epigenetic regulation provide a groundwork for tailored techniques in stem cell engineering and regenerative medicine.