Collagen complexes increase the efficiency of iPS cells generated using fibroblasts from adult mice.
Different interventions are being tested for restoration of the youthfulness of adult mouse-derived fibroblasts. However, fundamental issues, such as the decline of adult mouse-derived fibroblast activity with age, remain unresolved. Therefore, in this study, we examined whether treatment with collagen complexes has beneficial effects on the rejuvenation or reprogramming of adult mouse-derived fibroblasts. Further, we investigated the mechanisms of rejuvenation of adult mouse-derived fibroblasts during treatment with total collagen complexes. We isolated total collagen complexes from the tails of young mice and cultured adult mouse-derived fibroblasts with or without the collagen complexes. When compared with fibroblasts cultured without collagen complexes, adult-derived fibroblasts cultured with collagen complexes over five consecutive passages showed a more youthful state, expanded at a higher rate, and exhibited reduced spontaneous cell death. The fibroblasts cultured in the presence of collagen complexes also showed extensive demethylation in the promoter regions of cell cycle-related genes such as PCNA, increased proliferation, and decreased senescence. In addition, the efficiency of reprogramming of fibroblasts to become induced pluripotent stem (iPS) cells was significantly higher in young- and adult-derived fibroblasts cultured with collagen complexes than in adult-derived fibroblasts cultured alone. Furthermore, mechanistic evidence shows that genes involved in anti-proliferative pathways, including Ink4a/Arf locus genes and p53, were downregulated in fibroblasts exposed to collagen complexes. Interestingly, our results suggest that the rejuvenation process was mediated via the α2β1 integrin-dependent Bmi-1 pathway. Thus, collagen complexes both stimulate proliferation and inhibit cell death and growth arrest in fibroblasts, which appears to be a promising approach for improving the efficiency of reprogramming.
Department of Cosmetology, Hanseo University, Chungnam 356-706, Republic of Korea.
Byung-Soo
BS
Chang
Yun-Jung
YJ
Choi
Jin-Hoi
JH
Kim
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D065150:Cellular Reprogramming / Q000502:physiology*; D016922:Cellular Senescence / Q000502:physiology; D003094:Collagen / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice
D003094:Collagen