Survival of irradiated recipient mice after transplantation of bone marrow from young, old and "early aging" mice

Abstract

Bone marrow transplantation is used to examine survival, hematopoietic stem cell function and pathology in recipients of young and old wild type bone marrow derived stem cells (BMDSCs) as well as cells from p53-based models of premature aging. There is no difference in the long term survival of recipients of 8 week-old p53+/m donor cells compared to recipients of 8 week-old wild-type (WT) donor cells (70 weeks) or of recipients of 16-18 weeks-old donor cells from either p53+/m or WT mice. There is shorter survival in recipients of older versus younger WT donor bone marrow, but the difference is only significant when comparing 8 and 18 week-old donors. In the p44-based model, short term survival/engraftment is significantly reduced in recipients of 11 month-old p44 donor cells compared to 4 week-old p44 or wild type donor cells of either age; mid-life survival at 40 weeks is also significantly less in recipients of p44 cells. BMDSCs are readily detectable within recipient bone marrow, lymph node, intestinal villi and liver sinusoids, but not in epithelial derived cells. These results indicate that recipients of young BMDSCs may survive longer than recipients of old bone marrow, but the difference is marginal at best.

Keywords: aging; bone marrow transplantation; p44; p53.

Figure 1. Long-term survival of C57Bl/6 recipients

(A) Four-week old female C57Bl/6 mice were lethally irradiated and transplanted with 2 × 10⁶ BMCs from 8-week old +/m or wild-type donors (n=20/group). (B) Four-week old female C57Bl/6 mice were lethally irradiated and transplanted with 2 × 10⁶ BMCs from 18-week old +/m (n=13) or wild-type donors (n=17). No differences were detected between the two groups of recipients suggesting that lifespan was not reduced by transplantation of +/m BMCs.

Figure 2. Survival proportions of irradiated C57Bl/6 female recipients

Four week-old female recipients were lethally irradiated with (1050 rads) and transplanted with 2 × 10⁶ BM from 8 week-old (squares, n = 20) or 18 week-old (triangles, n = 17) male C57Bl/6 donors. Recipients of older (18 week-old) BM exhibited reduced longevity compared to recipients of younger (8 week) BM (p<0.001).

Figure 3. Survival analysis of C57BL/6 female mice receiving BM from young (7 week-old) and old (27 month-old) male donors

Figure 4. Comparison of phenotypes of p53+/m as originally reported in Tyner et al (2002) and those maintained by the Sell group

(A) Top: Representative 20-month-old skinned p53^+/+ female mouse (top) and age- and sex-matched p53^+/m mouse (bottom). Pronounced lordokyphosis, loss of body mass, muscle atrophy and loss of adipose tissue is evident in the p53^+/m mouse (B and C). Representative of a skinned 20 month-old (B) and 8 month-old male (C) mouse. Both mice possess excessive amounts of adipose tissue and do not exhibit lordokyphosis.

Figure 5. Mean and maximum lifespans of “Sell” and “Tyner et al” mice p53+/m and wildtype mice

Mean and maximum lifespans of Sell and Tyner mice are nearly identical.

Figure 6. Survival 4-weeks post-irradiation and transplantation

Numbers indicate the number of animals initially irradiated and transplanted. *indicates p<0.01 compared to recipients who had received BMCs from 4-week old ICR male donors as determined by chi-square test.

Figure 7. Total CFU decrease as mice age

BM was isolated from at least 3 male ICR or p44 mice a 10, 16, or 20–24 months and 2 × 10⁴ cells were plated on MethoCult (StemCell Technologies). Colonies, defined as a cluster of at least 30 cells, were counted on Day 7. Results are mean ± SE (n≥3).

Figure 8. Long-term survival of ICR recipients

Figure 9. Mean and maximal life spans of ICR recipients

Long term survival was similar across all transplanted groups of mice. Mean and maximum survival rates across all transplanted groups were approximately 50 and 70 weeks, respectively.

Figure 10. Survival analysis of BM transplant recipients at 40 weeks

Recipients that received BM from 4-week old or 11-month old p44 donors exhibited a significant (p<0.05) reduction in mid-life survival as compared to un-transplanted controls or recipients of old or young wild-type BM.