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Cell Cycle. 2015;14(19):3016-29. doi: 10.1080/15384101.2015.1078031.

The crucial role of Activin A on the formation of primordial germ cell-like cells from skin-derived stem cells in vitro.

Sun R1, Sun YC2,3, Ge W2,3, Tan H2,3, Cheng SF2,3, Yin S2,3, Sun XF2,3, Li L2,3, Dyce P4, Li J4, Yang X5, Shi QH1,6, Shen W2,3.

Author information

a Molecular and Cell Genetics Laboratory; The CAS Key Laboratory of Innate Immunity and Chronic Disease; Hefei National Laboratory for Physical Sciences at Microscale; School of Life Sciences; University of Science and Technology of China ; Hefei , Anhui , China.
b Institute of Reproductive Sciences; Qingdao Agricultural University , Qingdao ; Shandong , China.
c Key Laboratory of Animal Reproduction and Germplasm Enhancement in Universities of Shandong; College of Animal Science and Technology; Qingdao Agricultural University , Qingdao ; Shandong , China.
d Department of Animal and Poultry Science ; University of Guelph ; Guelph ; Ontario , Canada.
e Genetic Laboratory of Development and Diseases; Beijing Institute of Biotechnology ; Beijing , China.
f Collaborative Innovation Center of Genetics and Development; Fudan University ; Shanghai , China.


Primordial germ cells (PGCs) are founder cells of the germ cell lineage, and can be differentiated from stem cells in an induced system in vitro. However, the induction conditions need to be optimized in order to improve the differentiation efficiency. Activin A (ActA) is a member of the TGF-β super family and plays an important role in oogenesis and folliculogenesis. In the present study, we found that ActA promoted PGC-like cells (PGCLCs) formation from mouse skin-derived stem cells (SDSCs) in both embryoid body-like structure (EBLS) differentiation and the co-culture stage in a dose dependent manner. ActA treatment (100 ng/ml) during EBLS differentiation stage and further co-cultured for 6 days without ActA significantly increased PGCLCs from 53.2% to 82.8%, and as well as EBLS differentiation without ActA followed by co-cultured with 100 ng/ml ActA for 4 to 12 days with the percentage of PGCLCs increasing markedly in vitro. Moreover, mice treated with ActA at 100 ng/kg body weight from embryonic day (E) 5.5-12.5 led to more PGCs formation. However, the stimulating effects of ActA were interrupted by Smad3 RNAi, and in an in vitro cultured Smad3(-/-) mouse skin cells scenario. SMAD3 is thus likely a key effecter molecule in the ActA signaling pathway. In addition, we found that the expression of some epiblast cell markers, Fgf5, Dnmt3a, Dnmt3b and Wnt3, was increased in EBLSs cultured for 4 days or PGCLCs co-cultured for 12 days with ActA treatment. Interestingly, at 16 days of differentiation, the percentage of PGCLCs was decreased in the presence of ActA, but the expression of meiosis-relative genes, such as Stra8, Dmc1, Sycp3 and Sycp1, was increased. In conclusion, our data here demonstrated that ActA can promote PGCLC formation from SDSCs in vitro, at early stages of differentiation, and affect meiotic initiation of PGCLCs in later stages.


activin A; differentiation; primordial germ cells; skin-derived stem cells; smad3

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