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Moderate Exercise Mitigates the Detrimental Effects of Aging on Tendon Stem Cells.

Zhang J, Wang JH - PLoS ONE (2015)

Bottom Line: Interestingly, moderate mechanical stretching (4%) of aging TSCs in vitro significantly increased the expression of the stem cell marker, NS, but 8% stretching decreased NS expression.However, 8% stretching increased expression of the non-tenocyte-related genes, LPL, Sox-9 and Runx-2, while 4% stretching had minimal effects on the expression of these genes.In the in vivo study, moderate treadmill running (MTR) of aging mice (9 months) resulted in the increased proliferation rate of aging TSCs in culture, decreased lipid deposition, proteoglycan accumulation and calcification, and increased the expression of NS in the patellar tendons.

View Article: PubMed Central - PubMed

Affiliation: MechanoBiology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT
Aging is known to cause tendon degeneration whereas moderate exercise imparts beneficial effects on tendons. Since stem cells play a vital role in maintaining tissue integrity, in this study we aimed to define the effects of aging and moderate exercise on tendon stem/progenitor cells (TSCs) using in vitro and in vivo models. TSCs derived from aging mice (9 and 24 months) proliferated significantly slower than TSCs obtained from young mice (2.5 and 5 months). In addition, expression of the stem cell markers Oct-4, nucleostemin (NS), Sca-1 and SSEA-1 in TSCs decreased in an age-dependent manner. Interestingly, moderate mechanical stretching (4%) of aging TSCs in vitro significantly increased the expression of the stem cell marker, NS, but 8% stretching decreased NS expression. Similarly, 4% mechanical stretching increased the expression of Nanog, another stem cell marker, and the tenocyte-related genes, collagen I and tenomodulin. However, 8% stretching increased expression of the non-tenocyte-related genes, LPL, Sox-9 and Runx-2, while 4% stretching had minimal effects on the expression of these genes. In the in vivo study, moderate treadmill running (MTR) of aging mice (9 months) resulted in the increased proliferation rate of aging TSCs in culture, decreased lipid deposition, proteoglycan accumulation and calcification, and increased the expression of NS in the patellar tendons. These findings indicate that while aging impairs the proliferative ability of TSCs and reduces their stemness, moderate exercise can mitigate the deleterious effects of aging on TSCs and therefore may be responsible for decreased aging-induced tendon degeneration.

No MeSH data available.


Related in: MedlinePlus

Stem cell marker expression in TSCs from differently aged mice (2.5m–2.5 months; 5m–5 months; 9m–9 months and 24m–24 months).A–P: Immunocytochemical staining for the indicated stem cell markers was performed using stem cell marker specific antibodies. Q–T: Semi-quantitation of stem cell marker expression after immunocytochemical staining. Increase in the mouse age decreased the number of TSCs expressing Oct-4, NS, Sca-1, and SSEA-1. In 24 months old mice, except for a few NS-expressing TSCs, expression of the remaining three stem cell markers (Oct-4, Sca-1 and SSEA-1) was very low. Semi-quantitation data are expressed as mean ± SD. Student’s t-test was used to determine statistical significance (*P < 0.05) in comparison with data from the 2.5-months old mice. Bar—100 μm.
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pone.0130454.g002: Stem cell marker expression in TSCs from differently aged mice (2.5m–2.5 months; 5m–5 months; 9m–9 months and 24m–24 months).A–P: Immunocytochemical staining for the indicated stem cell markers was performed using stem cell marker specific antibodies. Q–T: Semi-quantitation of stem cell marker expression after immunocytochemical staining. Increase in the mouse age decreased the number of TSCs expressing Oct-4, NS, Sca-1, and SSEA-1. In 24 months old mice, except for a few NS-expressing TSCs, expression of the remaining three stem cell markers (Oct-4, Sca-1 and SSEA-1) was very low. Semi-quantitation data are expressed as mean ± SD. Student’s t-test was used to determine statistical significance (*P < 0.05) in comparison with data from the 2.5-months old mice. Bar—100 μm.

Mentions: To determine the effect of aging on the stemness of TSCs, the levels of four stem cell markers, Oct-4, NS, Sca-1 and SSEA-1, were analyzed by immunocytochemical staining. In previous studies these four markers were found to be expressed at high levels by TSCs in early passages [22,25] and therefore can be used to characterize the stemness of TSCs in culture. Examination of positively-stained TSCs revealed the robust presence of stem cell markers Oct-4, NS, Sca-1 and SSEA-1 in TSCs that were derived from 2.5 months old mice (Fig 2A, 2B, 2C and 2D). However, the extent of Oct-4, NS, and Sca-1 expression declined gradually from 2.5 months to 9 months old TSCs while the decrease in SSEA-1 levels was drastic and dropped significantly from 2.5 months to 5 months (Fig 2D and 2H). In 24 months old mice, only a few TSCs expressing NS could be identified (Fig 2N); the expression of other stem cell markers (Oct-4, Sca-1, and SSEA-1) were minimal (Fig 2M, 2O and 2P). Further analysis of the positively-stained cells by semi-quantification corroborated the microscopic observations and confirmed the effect of aging on stem cell marker expression in TSCs; Oct-4, NS, and Sca-1 staining decreased by ~15% in 5 months (Fig 2Q, 2R and 2S), and by ~47% (Oct-4), or ~37% (NS) in 9 months old mice (Fig 2Q and 2R). However, there was a sharp decline (~90%) in the levels of Sca-1 from 5 to 9 months and barely any staining was detected at 24 months (Fig 2S). SSEA-1 staining declined by ~70% in 5 months old mice, ~84% in 9 months and ~ 99% in 24 months old mice when compared to younger mice (2.5 months old) (Fig 2T).


Moderate Exercise Mitigates the Detrimental Effects of Aging on Tendon Stem Cells.

Zhang J, Wang JH - PLoS ONE (2015)

Stem cell marker expression in TSCs from differently aged mice (2.5m–2.5 months; 5m–5 months; 9m–9 months and 24m–24 months).A–P: Immunocytochemical staining for the indicated stem cell markers was performed using stem cell marker specific antibodies. Q–T: Semi-quantitation of stem cell marker expression after immunocytochemical staining. Increase in the mouse age decreased the number of TSCs expressing Oct-4, NS, Sca-1, and SSEA-1. In 24 months old mice, except for a few NS-expressing TSCs, expression of the remaining three stem cell markers (Oct-4, Sca-1 and SSEA-1) was very low. Semi-quantitation data are expressed as mean ± SD. Student’s t-test was used to determine statistical significance (*P < 0.05) in comparison with data from the 2.5-months old mice. Bar—100 μm.
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pone.0130454.g002: Stem cell marker expression in TSCs from differently aged mice (2.5m–2.5 months; 5m–5 months; 9m–9 months and 24m–24 months).A–P: Immunocytochemical staining for the indicated stem cell markers was performed using stem cell marker specific antibodies. Q–T: Semi-quantitation of stem cell marker expression after immunocytochemical staining. Increase in the mouse age decreased the number of TSCs expressing Oct-4, NS, Sca-1, and SSEA-1. In 24 months old mice, except for a few NS-expressing TSCs, expression of the remaining three stem cell markers (Oct-4, Sca-1 and SSEA-1) was very low. Semi-quantitation data are expressed as mean ± SD. Student’s t-test was used to determine statistical significance (*P < 0.05) in comparison with data from the 2.5-months old mice. Bar—100 μm.
Mentions: To determine the effect of aging on the stemness of TSCs, the levels of four stem cell markers, Oct-4, NS, Sca-1 and SSEA-1, were analyzed by immunocytochemical staining. In previous studies these four markers were found to be expressed at high levels by TSCs in early passages [22,25] and therefore can be used to characterize the stemness of TSCs in culture. Examination of positively-stained TSCs revealed the robust presence of stem cell markers Oct-4, NS, Sca-1 and SSEA-1 in TSCs that were derived from 2.5 months old mice (Fig 2A, 2B, 2C and 2D). However, the extent of Oct-4, NS, and Sca-1 expression declined gradually from 2.5 months to 9 months old TSCs while the decrease in SSEA-1 levels was drastic and dropped significantly from 2.5 months to 5 months (Fig 2D and 2H). In 24 months old mice, only a few TSCs expressing NS could be identified (Fig 2N); the expression of other stem cell markers (Oct-4, Sca-1, and SSEA-1) were minimal (Fig 2M, 2O and 2P). Further analysis of the positively-stained cells by semi-quantification corroborated the microscopic observations and confirmed the effect of aging on stem cell marker expression in TSCs; Oct-4, NS, and Sca-1 staining decreased by ~15% in 5 months (Fig 2Q, 2R and 2S), and by ~47% (Oct-4), or ~37% (NS) in 9 months old mice (Fig 2Q and 2R). However, there was a sharp decline (~90%) in the levels of Sca-1 from 5 to 9 months and barely any staining was detected at 24 months (Fig 2S). SSEA-1 staining declined by ~70% in 5 months old mice, ~84% in 9 months and ~ 99% in 24 months old mice when compared to younger mice (2.5 months old) (Fig 2T).

Bottom Line: Interestingly, moderate mechanical stretching (4%) of aging TSCs in vitro significantly increased the expression of the stem cell marker, NS, but 8% stretching decreased NS expression.However, 8% stretching increased expression of the non-tenocyte-related genes, LPL, Sox-9 and Runx-2, while 4% stretching had minimal effects on the expression of these genes.In the in vivo study, moderate treadmill running (MTR) of aging mice (9 months) resulted in the increased proliferation rate of aging TSCs in culture, decreased lipid deposition, proteoglycan accumulation and calcification, and increased the expression of NS in the patellar tendons.

View Article: PubMed Central - PubMed

Affiliation: MechanoBiology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT
Aging is known to cause tendon degeneration whereas moderate exercise imparts beneficial effects on tendons. Since stem cells play a vital role in maintaining tissue integrity, in this study we aimed to define the effects of aging and moderate exercise on tendon stem/progenitor cells (TSCs) using in vitro and in vivo models. TSCs derived from aging mice (9 and 24 months) proliferated significantly slower than TSCs obtained from young mice (2.5 and 5 months). In addition, expression of the stem cell markers Oct-4, nucleostemin (NS), Sca-1 and SSEA-1 in TSCs decreased in an age-dependent manner. Interestingly, moderate mechanical stretching (4%) of aging TSCs in vitro significantly increased the expression of the stem cell marker, NS, but 8% stretching decreased NS expression. Similarly, 4% mechanical stretching increased the expression of Nanog, another stem cell marker, and the tenocyte-related genes, collagen I and tenomodulin. However, 8% stretching increased expression of the non-tenocyte-related genes, LPL, Sox-9 and Runx-2, while 4% stretching had minimal effects on the expression of these genes. In the in vivo study, moderate treadmill running (MTR) of aging mice (9 months) resulted in the increased proliferation rate of aging TSCs in culture, decreased lipid deposition, proteoglycan accumulation and calcification, and increased the expression of NS in the patellar tendons. These findings indicate that while aging impairs the proliferative ability of TSCs and reduces their stemness, moderate exercise can mitigate the deleterious effects of aging on TSCs and therefore may be responsible for decreased aging-induced tendon degeneration.

No MeSH data available.


Related in: MedlinePlus