Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells,
☆ Part of these results has been presented in an abstract form at the 8th Workshop on Cell Biology of Bone and Cartilage in Health and Disease, Davos, Switzerland, April 2000.
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Fig. 1
Representative long-term growth curve of MSC from a young donor showing percentage life span completed as a function of time in culture: (1) early-passage cells with <50% life span completed, (2) middle-passage cells with between 50 and 80% life span completed, (3) late-passage cells with >80% life span completed.
Fig. 2
Long-term growth curves of human MSC showing cumulative PD as a function of time in culture: Young donors (♦, n = 6) and old donors (○, n = 5). (A) Long-term growth curves each obtained from an individual donor. (B) Mean values of young and old donors. Each point represents mean ± SD. *P < 0.05.
Fig. 3
Growth characteristics of human MSC in long-term culture. (A) Maximum life span (the Hayflick limit) of human MSC cultured in vitro measured as the maximum number of PD reached after long-term culture. (B) PD rate of human MSC cultured in vitro measured as maximal number of PD reached per number of days in culture. Young donors (□, n = 5) and old donors (■, n = 5). Results are represented as means ± SD. *P < 0.01.
Fig. 4
Senescence-associated β-galactosidase (SA β-gal) staining expressed as the number of positive cells per total cells. Young (n = 5) and old (n = 5) MSC in early passage (□) and late passage (■).
Fig. 5
In vivo bone formation of MSC from young (n = 3) and old (n = 1) donors in early and late passages. (white bar) Percentage bone volume per total volume (BV/TV), (striped bar) percentage hydroxyapatite/tricalcium phosphate (HA/TCP) per total volume, (black bar) percentage adipose tissue per total volume (AT/TV). On the right is shown a nondecalcified plastic-embedded implant, sectioned and stained with Goldner's Trichrome stain (original magnification, ×80). Human MSC formed trabecular bone (b) within the HA/TCP granules (ha). Fibrous tissue (ft) was surrounding bone and HA/TCP granules. Newly formed osteoid (o) and fat cells (f) were seen in the nondecalcified section.
Abstract
Age-related decrease in bone formation is well described. However, the cellular causes are not known. Thus, we have established cultures of bone marrow stromal cells (MSC) from young (aged 18–29 years, n = 6) and old (aged 68–81 years, n = 5) donors. MSC were serially passaged until reaching maximal life span. Cell growth, markers of cellular senescence, and osteogenic and adipogenic potential were determined in early-passage and late-passage cells established from young and old donors. MSC from old donors exhibited a decreased maximal life span compared with cells from young donors (24 ± 11 population doublings [PD] vs 41 ± 10 PD, P < 0.05) and mean PD rate was lower in old donor cells (0.05 ± 0.02 PD/day) compared with young donor cells (0.09 ± 0.02 PD/day) (P < 0.05). No differences were detected in number of senescence-associated β-galactosidase positive (SA β-gal+) cells and mean telomere length in early-passage cells obtained from young and old donors. However, MSC from old donors exhibited accelerated senescence evidenced by increased number of SA β-gal+ cells per PD as compared with young (4% per PD vs 0.4% per PD, respectively). MSC from young and old donors were able to form similar amounts of mineralized matrix in vitro and of normal lamellar bone in vivo. In adipogenic medium similar numbers of adipocytes formed in cultures of young and old donors. In conclusion, aging is associated with decreased proliferative capacity of osteoprogenitor cells, suggesting that decreased osteoblastic cell number, and not function, leads to age-related decrease in bone formation.
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☆☆ This work was supported by grants from Danish Medical Research Council, Novo Nordisk Foundation, Danish Center for Stem Cell Research, Karen Elise Jensen's Foundation, and Albani Foundation.☆,☆☆
