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Fibroblast growth factor (FGF), transforming growth factor (TGF)/Nodal, and Insulin/insulin‐like growth factor (IGF) signaling pathways are sufficient to maintain human embryonic stem cells (ESCs) and induced pluripotent stem cells in a proliferative, undifferentiated state. Here, we show that only a few FGF family members (FGF2, FGF4, FGF6, and FGF9) are able to sustain strong extracellular‐signal‐regulated kinase (ERK) phosphorylation and  NANOG  expression levels in human ESCs. Surprisingly, FGF1, which is reported to target the same set of receptors as FGF2, fails to sustain ERK phosphorylation and  NANOG  expression under standard culture conditions. We find that the failure of FGF1 to sustain ES is due to thermal instability of the wild‐type protein, not receptor specificity, and that a mutated thermal‐stable FGF1 sustains human ESCs and supports both differentiation and reprogramming protocols. S TEM  C ELLS   2012; 30:623–630

stem cells

Thermal Stability of Fibroblast Growth Factor Protein Is a Determinant Factor in Regulating Self‐Renewal, Differentiation, and Reprogramming in Human Pluripotent Stem Cells