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Cellular Senescence: Ex Vivo p53-Dependent Asymmetric Cell Kinetics.

Rambhatla L, Bohn SA, Stadler PB, Boyd JT, Coss RA, Sherley JL - J. Biomed. Biotechnol. (2001)

Bottom Line: Although senescence is a defining property of euploid mammalian cells, its physiologic basis remains obscure.Previously, cell kinetics properties of normal tissue cells have not been considered in models for senescence.In vivo, asymmetric cell kinetics are essential for maintenance of somatic stem cells; ex vivo, the same cell kinetics yield senescence as a simple kinetic endpoint.

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ABSTRACT
Although senescence is a defining property of euploid mammalian cells, its physiologic basis remains obscure. Previously, cell kinetics properties of normal tissue cells have not been considered in models for senescence. We now provide evidence that senescence is in fact the natural consequence of normal in vivo somatic stem cell kinetics extended in culture. This concept of senescence is based on our discovery that cells engineered to conditionally express the well-recognized tumor suppressor protein and senescence factor, p53, exhibit asymmetric cell kinetics. In vivo, asymmetric cell kinetics are essential for maintenance of somatic stem cells; ex vivo, the same cell kinetics yield senescence as a simple kinetic endpoint. This new "asymmetric cell kinetics model" for senescence suggests novel strategies for the isolation and propagation of somatic tissue stem cells in culture.

No MeSH data available.


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Asymmetric cell kinetics model for cellular senescence.Top, somatic tissue stem cell (bold-lined circles) turnover unit(TU). In vivo there are three stem cell kinetics states:highly regulated symmetric kinetics that produce two stem cells(bracketed); dormancy (stippled circle); and asymmetric cellkinetics, the most populated stem cell kinetic state in mosttissues [21, 22, 23, 24]. TDN, the number of transit cell generations before terminal arrest (closed circles), varies in different tissues from 0.0 to n. 2TDN = 0.5 × number of transit cells in the TU [24]. Bottom, theex vivo continuation of in vivo asymmetriccell kinetics results in cellular senescence. Because symmetricstem divisions are rare and possibly proapoptotic [31], asymmetric TU kinetics predominate in culture. The dilution of asymmetric stem cells by accumulating nondividing terminal cells is responsible for the observed decline in population doubling rate. Loss of p53 function in cell culture prevents senescence by allowing asymmetric stem cells to divide symmetrically; resulting in the exponential division that characterizes immortalization. In support of this model, reconstitution of normal p53 function in immortal cells restores asymmetric cell kinetics and senescence. PDL, cumulative population doublings.
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Figure 4: Asymmetric cell kinetics model for cellular senescence.Top, somatic tissue stem cell (bold-lined circles) turnover unit(TU). In vivo there are three stem cell kinetics states:highly regulated symmetric kinetics that produce two stem cells(bracketed); dormancy (stippled circle); and asymmetric cellkinetics, the most populated stem cell kinetic state in mosttissues [21, 22, 23, 24]. TDN, the number of transit cell generations before terminal arrest (closed circles), varies in different tissues from 0.0 to n. 2TDN = 0.5 × number of transit cells in the TU [24]. Bottom, theex vivo continuation of in vivo asymmetriccell kinetics results in cellular senescence. Because symmetricstem divisions are rare and possibly proapoptotic [31], asymmetric TU kinetics predominate in culture. The dilution of asymmetric stem cells by accumulating nondividing terminal cells is responsible for the observed decline in population doubling rate. Loss of p53 function in cell culture prevents senescence by allowing asymmetric stem cells to divide symmetrically; resulting in the exponential division that characterizes immortalization. In support of this model, reconstitution of normal p53 function in immortal cells restores asymmetric cell kinetics and senescence. PDL, cumulative population doublings.

Mentions: An intriguing cell kinetics feature is evident from the lineageanalyses. When symmetric divisions occur (i.e., divisions producing two dividing daughters), one of the daughterstypically undergoes a terminal division (Figure 3C and D). Target gene expression analyses indicate that p53 is active in gene regulation 2 to 5 hours after induction (Y. Liu and J. L. Sherley, submitted), well before the symmetric divisionsoccur. This pattern is also observed in the pedigrees of WI-38cells, which express wild-type p53 constitutively (Figure 4E and F). Therefore, it seems unlikely thatsub-optimal p53 expression is responsible. In addition, symmetricdivisions of this type have been observed at later times inlineages as well. These occasional symmetric divisionsin otherwise simple asymmetric lineages may indicate variabilityin transit cell maturation mechanisms. Whereas, the predominanttransit cell division number (TDN) for p53-induced “transitcells” in culture is zero (i.e., terminal arrest withoutdivision), at a low frequency, transit cells may mature to a TDNof 1 (i.e., a single division followed by terminalarrest of both daughters).


Cellular Senescence: Ex Vivo p53-Dependent Asymmetric Cell Kinetics.

Rambhatla L, Bohn SA, Stadler PB, Boyd JT, Coss RA, Sherley JL - J. Biomed. Biotechnol. (2001)

Asymmetric cell kinetics model for cellular senescence.Top, somatic tissue stem cell (bold-lined circles) turnover unit(TU). In vivo there are three stem cell kinetics states:highly regulated symmetric kinetics that produce two stem cells(bracketed); dormancy (stippled circle); and asymmetric cellkinetics, the most populated stem cell kinetic state in mosttissues [21, 22, 23, 24]. TDN, the number of transit cell generations before terminal arrest (closed circles), varies in different tissues from 0.0 to n. 2TDN = 0.5 × number of transit cells in the TU [24]. Bottom, theex vivo continuation of in vivo asymmetriccell kinetics results in cellular senescence. Because symmetricstem divisions are rare and possibly proapoptotic [31], asymmetric TU kinetics predominate in culture. The dilution of asymmetric stem cells by accumulating nondividing terminal cells is responsible for the observed decline in population doubling rate. Loss of p53 function in cell culture prevents senescence by allowing asymmetric stem cells to divide symmetrically; resulting in the exponential division that characterizes immortalization. In support of this model, reconstitution of normal p53 function in immortal cells restores asymmetric cell kinetics and senescence. PDL, cumulative population doublings.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC79675&req=5

Figure 4: Asymmetric cell kinetics model for cellular senescence.Top, somatic tissue stem cell (bold-lined circles) turnover unit(TU). In vivo there are three stem cell kinetics states:highly regulated symmetric kinetics that produce two stem cells(bracketed); dormancy (stippled circle); and asymmetric cellkinetics, the most populated stem cell kinetic state in mosttissues [21, 22, 23, 24]. TDN, the number of transit cell generations before terminal arrest (closed circles), varies in different tissues from 0.0 to n. 2TDN = 0.5 × number of transit cells in the TU [24]. Bottom, theex vivo continuation of in vivo asymmetriccell kinetics results in cellular senescence. Because symmetricstem divisions are rare and possibly proapoptotic [31], asymmetric TU kinetics predominate in culture. The dilution of asymmetric stem cells by accumulating nondividing terminal cells is responsible for the observed decline in population doubling rate. Loss of p53 function in cell culture prevents senescence by allowing asymmetric stem cells to divide symmetrically; resulting in the exponential division that characterizes immortalization. In support of this model, reconstitution of normal p53 function in immortal cells restores asymmetric cell kinetics and senescence. PDL, cumulative population doublings.
Mentions: An intriguing cell kinetics feature is evident from the lineageanalyses. When symmetric divisions occur (i.e., divisions producing two dividing daughters), one of the daughterstypically undergoes a terminal division (Figure 3C and D). Target gene expression analyses indicate that p53 is active in gene regulation 2 to 5 hours after induction (Y. Liu and J. L. Sherley, submitted), well before the symmetric divisionsoccur. This pattern is also observed in the pedigrees of WI-38cells, which express wild-type p53 constitutively (Figure 4E and F). Therefore, it seems unlikely thatsub-optimal p53 expression is responsible. In addition, symmetricdivisions of this type have been observed at later times inlineages as well. These occasional symmetric divisionsin otherwise simple asymmetric lineages may indicate variabilityin transit cell maturation mechanisms. Whereas, the predominanttransit cell division number (TDN) for p53-induced “transitcells” in culture is zero (i.e., terminal arrest withoutdivision), at a low frequency, transit cells may mature to a TDNof 1 (i.e., a single division followed by terminalarrest of both daughters).

Bottom Line: Although senescence is a defining property of euploid mammalian cells, its physiologic basis remains obscure.Previously, cell kinetics properties of normal tissue cells have not been considered in models for senescence.In vivo, asymmetric cell kinetics are essential for maintenance of somatic stem cells; ex vivo, the same cell kinetics yield senescence as a simple kinetic endpoint.

View Article: PubMed Central - HTML - PubMed

ABSTRACT
Although senescence is a defining property of euploid mammalian cells, its physiologic basis remains obscure. Previously, cell kinetics properties of normal tissue cells have not been considered in models for senescence. We now provide evidence that senescence is in fact the natural consequence of normal in vivo somatic stem cell kinetics extended in culture. This concept of senescence is based on our discovery that cells engineered to conditionally express the well-recognized tumor suppressor protein and senescence factor, p53, exhibit asymmetric cell kinetics. In vivo, asymmetric cell kinetics are essential for maintenance of somatic stem cells; ex vivo, the same cell kinetics yield senescence as a simple kinetic endpoint. This new "asymmetric cell kinetics model" for senescence suggests novel strategies for the isolation and propagation of somatic tissue stem cells in culture.

No MeSH data available.


Related in: MedlinePlus