Restoration of senescent human diploid fibroblasts by modulation of the extracellular matrix.
Human diploid fibroblasts have the capacity to complete a finite number of cell divisions before entering a state of replicative senescence characterized by growth arrest, changes in morphology, and altered gene expression. Herein, we report that interaction with extracellular matrix (ECM) from young cells is sufficient to restore aged, senescent cells to an apparently youthful state. The identity of the restored cells as having been derived from senescent cells has been confirmed by a variety of methods, including time lapse live cell imaging and DNA finger print analysis. In addition to cell morphology, phenotypic restoration was assessed by resumption of proliferative potential, growth factor responsiveness, reduction of intracellular reactive oxygen species levels, recovery of mitochondrial membrane potential, and increased telomere length. Mechanistically, we find that both Ku and SIRT1 are induced during restoration and are required for senescent cells to return to a youthful phenotype. These observations demonstrate that human cellular senescence is profoundly influenced by cues from the ECM, and that senescent cell plasticity is much greater than that was previously believed to be the case.
Department of Biochemistry and Molecular Biology, Aging and Apoptosis Research Center, Institute on Aging, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul 110-799, South Korea.
Hae Ri
HR
Choi
Kyung A
KA
Cho
Hyun Tae
HT
Kang
Jung Bin
JB
Lee
Matt
M
Kaeberlein
Yousin
Y
Suh
In Kwon
IK
Chung
Sang Chul
SC
Park
D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D002648:Child; D016172:DNA Fingerprinting; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004171:Diploidy; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007231:Infant, Newborn; D000072200:Ku Autoantigen; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D020127:Recovery of Function; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000648:ultrastructure
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D017382:Reactive Oxygen Species; C447939:SIRT1 protein, human; D056564:Sirtuin 1; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen