Figure 6
Figure 6. Mice undergoing long-term induction of TRF1 deletion undergo replicative senescence and exhaustion because of telomere shortening. (A) β-galactosidase staining of TRF1flox/floxMx1-wt and TRF1flox/floxMx1-Cre mice after 4 weeks of long-term Cre induction and 5 days of pause before measurement to exclude any interferon related effects. Images were captured with ×10 magnification, small window represents a magnified (×20) section of the image showing representative β-galactosidase–positive (indicated by black arrows) and –negative cells. (B) Quantification of β-galactosidase staining of panel A. Two-sided t test was used for statistical comparison. (C) Macroscopic view of CFA assays of TRF1flox/floxMx1-wt and TRF1flox/floxMx1-Cre mice after 12 days. (D) Quantification of CFU assay of TRF1flox/floxMx1-wt and TRF1flox/floxMx1-Cre mice after 4 weeks of long-term Cre induction and 5 days of pause before culturing. Two-sided t test was used for statistical comparison. (E) Representative IHC staining for p21 of TRF1flox/floxMx1-wt and TRF1flox/floxMx1-Cre mice being bone marrow donor for serial transplantation. Mice underwent 8 weeks of long-term Cre induction and 5 days of pause before being euthanized for serial transplantation. Image was captured with ×20 magnification (blue bar represents 100 μm), small image shows ×80 magnification. (F) Quantification of the percentage of p21-positive area calculated to the area of all cells is shown on the right. Two-sided t test was used for statistical comparison. (G) Overall survival of mice undergoing serial transplantation. TRF1flox/floxMx1-wt and TRF1flox/floxMx1-Cre bone marrow donor mice underwent 8 weeks of long-term Cre induction and had 5 days of pause before being killed as donors for serial transplantation. Both groups were compared with animals not receiving bone marrow transplantation. Log-rank test was used for comparison between TRF1flox/floxMx1-wt and TRF1flox/floxMx1-Cre mice (P = < .0005) and TRF1flox/floxMx1-Cre mice were compared with mice without bone marrow transplantation (P = .14). (H) Proposed model of the consequences of reduced TRF1 levels in patients with TIN2 mutations.

Mice undergoing long-term induction of TRF1 deletion undergo replicative senescence and exhaustion because of telomere shortening. (A) β-galactosidase staining of TRF1flox/floxMx1-wt and TRF1flox/floxMx1-Cre mice after 4 weeks of long-term Cre induction and 5 days of pause before measurement to exclude any interferon related effects. Images were captured with ×10 magnification, small window represents a magnified (×20) section of the image showing representative β-galactosidase–positive (indicated by black arrows) and –negative cells. (B) Quantification of β-galactosidase staining of panel A. Two-sided t test was used for statistical comparison. (C) Macroscopic view of CFA assays of TRF1flox/floxMx1-wt and TRF1flox/floxMx1-Cre mice after 12 days. (D) Quantification of CFU assay of TRF1flox/floxMx1-wt and TRF1flox/floxMx1-Cre mice after 4 weeks of long-term Cre induction and 5 days of pause before culturing. Two-sided t test was used for statistical comparison. (E) Representative IHC staining for p21 of TRF1flox/floxMx1-wt and TRF1flox/floxMx1-Cre mice being bone marrow donor for serial transplantation. Mice underwent 8 weeks of long-term Cre induction and 5 days of pause before being euthanized for serial transplantation. Image was captured with ×20 magnification (blue bar represents 100 μm), small image shows ×80 magnification. (F) Quantification of the percentage of p21-positive area calculated to the area of all cells is shown on the right. Two-sided t test was used for statistical comparison. (G) Overall survival of mice undergoing serial transplantation. TRF1flox/floxMx1-wt and TRF1flox/floxMx1-Cre bone marrow donor mice underwent 8 weeks of long-term Cre induction and had 5 days of pause before being killed as donors for serial transplantation. Both groups were compared with animals not receiving bone marrow transplantation. Log-rank test was used for comparison between TRF1flox/floxMx1-wt and TRF1flox/floxMx1-Cre mice (P = < .0005) and TRF1flox/floxMx1-Cre mice were compared with mice without bone marrow transplantation (P = .14). (H) Proposed model of the consequences of reduced TRF1 levels in patients with TIN2 mutations.

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