Researchers have identified a stromal cell-derived inducing activity (SDIA) that promotes neural differentiation of mouse embryonic stem (ES) cells. SDIA, which accumulates on the surface of PA6 stromal cells, induces efficient neuronal differentiation of ES cells in serum-free conditions without the use of retinoic acid or embryoid bodies. BMP4, a known antineuralizing morphogen in Xenopus, suppresses SDIA-induced neuralization and promotes epidermal differentiation. SDIA-treated ES cells produce a high proportion of tyrosine hydroxylase-positive neurons that generate dopamine. When transplanted, these neurons integrate into the mouse striatum and remain positive for tyrosine hydroxylase expression. This method provides a new powerful tool for both basic neuroscience research and therapeutic applications. The study introduces an efficient system for in vitro neural differentiation of mouse ES cells in a serum-free condition that requires neither embryoid bodies nor retinoic acid treatment. This method efficiently produces dopaminergic neurons, which have potential for therapeutic applications. The SDIA activity is present in various stromal cells and is not solely due to artifacts from PFA fixation. SDIA is likely composed of multiple factors, including a cell surface-anchored factor and a soluble factor, or secreted factors that are secondarily tethered to the cell surface. SDIA-induced neurons contain a high proportion of dopaminergic neurons, as evidenced by tyrosine hydroxylase (TH) positivity. These neurons produce dopamine and express markers of mesencephalic dopaminergic neurons. When transplanted into the mouse striatum, SDIA-induced neurons integrate into the host tissue and maintain TH expression. This suggests that SDIA-induced neurons could be used for cell replacement therapy in Parkinson's disease. The study also shows that SDIA-induced neurons can be integrated into the mouse brain after implantation, restoring TH-positive areas in the striatum. The method provides a convenient experimental system for neuroscience research, including neural development, cell biology, neuropharmacology, and electrophysiology. The SDIA activity may play a role in early neural development, as its time course of neural marker induction resembles that observed in the developing central nervous system. The SDIA activity may also suppress the mesodermalizing effects of BMP4 on ES cells, promoting epidermogenesis instead of mesodermal differentiation. The study highlights the potential of SDIA-induced neurons for cell replacement therapy in Parkinson's disease. However, further research is needed to fully understand the molecular nature of SDIA and its role in neural development. The method offers a noninvasive alternative to embryonal brain tissues and neural stem cells for neuronal replacement therapy. The study also emphasizes the importance of further research to determine the safety and efficacy of SDIA-induced neurons in long-term implantation studies.Researchers have identified a stromal cell-derived inducing activity (SDIA) that promotes neural differentiation of mouse embryonic stem (ES) cells. SDIA, which accumulates on the surface of PA6 stromal cells, induces efficient neuronal differentiation of ES cells in serum-free conditions without the use of retinoic acid or embryoid bodies. BMP4, a known antineuralizing morphogen in Xenopus, suppresses SDIA-induced neuralization and promotes epidermal differentiation. SDIA-treated ES cells produce a high proportion of tyrosine hydroxylase-positive neurons that generate dopamine. When transplanted, these neurons integrate into the mouse striatum and remain positive for tyrosine hydroxylase expression. This method provides a new powerful tool for both basic neuroscience research and therapeutic applications. The study introduces an efficient system for in vitro neural differentiation of mouse ES cells in a serum-free condition that requires neither embryoid bodies nor retinoic acid treatment. This method efficiently produces dopaminergic neurons, which have potential for therapeutic applications. The SDIA activity is present in various stromal cells and is not solely due to artifacts from PFA fixation. SDIA is likely composed of multiple factors, including a cell surface-anchored factor and a soluble factor, or secreted factors that are secondarily tethered to the cell surface. SDIA-induced neurons contain a high proportion of dopaminergic neurons, as evidenced by tyrosine hydroxylase (TH) positivity. These neurons produce dopamine and express markers of mesencephalic dopaminergic neurons. When transplanted into the mouse striatum, SDIA-induced neurons integrate into the host tissue and maintain TH expression. This suggests that SDIA-induced neurons could be used for cell replacement therapy in Parkinson's disease. The study also shows that SDIA-induced neurons can be integrated into the mouse brain after implantation, restoring TH-positive areas in the striatum. The method provides a convenient experimental system for neuroscience research, including neural development, cell biology, neuropharmacology, and electrophysiology. The SDIA activity may play a role in early neural development, as its time course of neural marker induction resembles that observed in the developing central nervous system. The SDIA activity may also suppress the mesodermalizing effects of BMP4 on ES cells, promoting epidermogenesis instead of mesodermal differentiation. The study highlights the potential of SDIA-induced neurons for cell replacement therapy in Parkinson's disease. However, further research is needed to fully understand the molecular nature of SDIA and its role in neural development. The method offers a noninvasive alternative to embryonal brain tissues and neural stem cells for neuronal replacement therapy. The study also emphasizes the importance of further research to determine the safety and efficacy of SDIA-induced neurons in long-term implantation studies.