Suppression of TGF-β and ERK Signaling Pathways as a New Strategy to Provide Rodent and Non-Rodent Pluripotent Stem Cells

Abstract

Stem cells are unspecialized cells and excellent model in developmental biology and a promising approach to the treatment of disease and injury. In the last 30 years, pluripotent embryonic stem (ES) cells were established from murine and primate sources, and display indefinite replicative potential and the ability to differentiate to all three embryonic germ layers. Despite large efforts in many aspects of rodent and non-rodent pluripotent stem cell culture, a number of diverse challenges remain. Natural and synthetic small molecules (SMs) strategy has the potential to overcome these hurdles. Small molecules are typically fast and reversible that target specific signaling pathways, epigenetic processes and other cellular processes. Inhibition of the transforming growth factor-β (TGF-β/Smad) and fibroblast growth factor 4 (FGF4)/ERK signaling pathways by SB431542 and PD0325901 small molecules, respectively, known as R2i, enhances the efficiency of mouse, rat, and chicken pluripotent stem cells passaging from different genetic backgrounds. Therefore, the application of SM inhibitors of TGF-β and ERK1/2 with leukemia inhibitory factor (LIF) allows the cultivation of pluripotent stem cells in a chemically defined condition. In this review, we discuss recently emerging evidence that dual inhibition of TGF-β and FGF signaling pathways plays an important role in regulating pluripotency in both rodent and non-rodent pluripotent stem cells.

The Remarkable Plasticity of Macrophages: A Chance to Fight Cancer

“…Therefore, this molecule appeared to be a central mediator in the TAM/CAF/TIL axis. In the literature on erythropoiesis or on fibrotic diseases, one can find that an anti-TGFβ treatment could be done, in principle, by reducing the concentration of circulating TGFβ with anti-TGFβ antibodies or with TGFβ ligand traps (44), or with pharmacological blockers of TGFβ signaling, such as SB431542 (45). Importantly for the activity of anti-tumor T cells, the combination of TGFβ blockade and anti-PDL1 has been shown to decrease the activity of fibroblasts and the density of ECM relieving the exclusion of T cells from malignant cells (46, 47).…”

Differentiation of human induced pluripotent stem cells into erythroid cells

“…In contrast, human iPSCs have less ethical and social issues compared to human ESCs [24,25]. Human iPSCs are produced by the manipulation of differentiated somatic cells [26][27][28][29]. Reprogramming of human somatic cells through the ectopic expression of transcription factors has provided a new avenue for disease modeling and regenerative medicine [16,30].…”

Reprogramming of fish somatic cells for nuclear transfer is primed by Xenopus egg extract

“…The TGFβ signaling inhibition observed in our treated cells, including that of the non-canonical MAPK / ERK pathway, would be one preliminary step in this reprogramming process. Indeed, experimental inhibition of TGFβ signaling was shown to cooperate in the reprogramming of murine fibroblasts into iPSCs [46,49,64] . Furthermore, ERK inhibition was also shown to be an early molecular signature of somatic cell reprogramming in this model species [65] , and inhibition of both TGFbeta receptors and ERK [48] also improved fibroblast reprogramming [66] .…”