Study of Telomere Length Reveals Rapid Aging of Human Marrow Stromal Cells following In Vitro Expansion

Baxter, M.; Wynn, Robert F.; Jowitt, Simon N.; Wraith, J. E.; Fairbairn, Leslie J.; Bellantuono, Ilaria

doi:10.1634/stemcells.22-5-675

Cited by 701 publications

(568 citation statements)

References 37 publications

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“…To detect lipid vacuoles, cultures were stained for oil red O as described previously. (17) A well was considered positive if it contained more than 20 cells with red lipid vacuoles. The number of CFU-A was calculated following the Poisson distribution and using the formula F o ¼ e Àx , where F o is the fraction of colony-negative wells, e is a constant whose value is 2.71, and x is the number of colony-forming units per well.…”

Section: Colony-forming Unit-adipocyte (Cfu-a)mentioning

confidence: 99%

Glycogen synthase kinase-3α/β inhibition promotes in vivo amplification of endogenous mesenchymal progenitors with osteogenic and adipogenic potential and their differentiation to the osteogenic lineage

Gambardella

Nagaraju

O’Shea

et al. 2010

Journal of Bone and Mineral Research

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Small molecules are attractive therapeutics to amplify and direct differentiation of stem cells. They also can be used to understand the regulation of their fate by interfering with specific signaling pathways. Mesenchymal stem cells (MSCs) have the potential to proliferate and differentiate into several cell types, including osteoblasts. Activation of canonical Wnt signaling by inhibition of glycogen synthase kinase 3 (GSK-3) has been shown to enhance bone mass, possibly by involving a number of mechanisms ranging from amplification of the mesenchymal stem cell pool to the commitment and differentiation of osteoblasts. Here we have used a highly specific novel inhibitor of GSK-3, AR28, capable of inducing b-catenin nuclear translocation and enhanced bone mass after 14 days of treatment in BALB/c mice. We have shown a temporally regulated increase in the number of colony-forming units-osteoblast (CFU-O) and -adipocyte (CFU-A) but not colony-forming units-fibroblast (CFU-F) in mice treated for 3 days. However, the number of CFU-O and CFU-A returned to normal levels after 14 days of treatment, and the number of CFU-F was decreased significantly. In contrast, the number of osteoblasts increased significantly only after 14 days of treatment, and this was seen together with a significant decrease in bone marrow adiposity. These data suggest that the increased bone mass is the result of an early temporal wave of amplification of a subpopulation of MSCs with both osteogenic and adipogenic potential, which is driven to osteoblast differentiation at the expense of adipogenesis. ß

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Section: Colony-forming Unit-adipocyte (Cfu-a)mentioning

confidence: 99%

Glycogen synthase kinase-3α/β inhibition promotes in vivo amplification of endogenous mesenchymal progenitors with osteogenic and adipogenic potential and their differentiation to the osteogenic lineage

Gambardella

Nagaraju

O’Shea

et al. 2010

Journal of Bone and Mineral Research

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“…Bone marrow‐derived mesenchymal stem cells (BMMSCs) decline in number with aging and show degenerative properties including reduced osteogenic differentiation capacity, increased adipogenic differentiation capacity and reduced proliferative ability; these are partially caused by bone aging (Wilson et al., 2010; Zhou et al., 2008). Different mechanisms of MSC senescence have been demonstrated including telomere shortening (Baxter et al., 2004), increased reactive oxygen species (ROS) (Stolzing & Scutt, 2006) and transcriptional control (Li et al., 2017). However, the complex molecular network is still largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Autophagy controls mesenchymal stem cell properties and senescence during bone aging

et al. 2017

Aging Cell

270

194

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SummaryBone marrow‐derived mesenchymal stem cells (BMMSCs) exhibit degenerative changes, including imbalanced differentiation and reduced proliferation during aging, that contribute to age‐related bone loss. We demonstrate here that autophagy is significantly reduced in aged BMMSCs compared with young BMMSCs. The autophagy inhibitor 3‐methyladenine (3‐MA) could turn young BMMSCs into a relatively aged state by reducing their osteogenic differentiation and proliferation capacity and enhancing their adipogenic differentiation capacity. Accordingly, the autophagy activator rapamycin could restore the biological properties of aged BMMSCs by increasing osteogenic differentiation and proliferation capacity and decreasing adipogenic differentiation capacity. Possible underlying mechanisms were explored, and the analysis revealed that autophagy could affect reactive oxygen species and p53 levels, thus regulating biological properties of BMMSCs. In an in vivo study, we found that activation of autophagy restored bone loss in aged mice. In conclusion, our results suggest that autophagy plays a pivotal role in the aging of BMMSCs, and activation of autophagy could partially reverse this aging and may represent a potential therapeutic avenue to clinically treat age‐related bone loss.

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“…The differences in expandability may be explained by telomere length and telomerase activity (20)(21)(22), although some studies have indicated that telomerase activity does not occur in MSCs during expansion (23).…”

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confidence: 99%

Comparison of human stem cells derived from various mesenchymal tissues: Superiority of synovium as a cell source

Sakaguchi¹,

Sekiya²,

Yagishita³

et al. 2005

Arthritis & Rheumatism

1,375

1,171

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Objective. To compare the properties of human mesenchymal stem cells (MSCs) isolated from bone marrow, synovium, periosteum, skeletal muscle, and adipose tissue.Methods. Human mesenchymal tissues were obtained from 8 donors during knee surgery for ligament injury. After collagenase digestion or gradient-density separation, nucleated cells were plated at an appropriate density for expansion at the maximum rate without colony-to-colony contact. Yield, expandability, differentiation potential, and epitope profile were compared among MSCs from the 5 different tissue sources.Results. Colony number per 10 3 nucleated cells was lower, and cell number per colony was higher, in bone marrow than in other mesenchymal tissues. When the cells were replated at low density every 14 days, bone marrow-, synovium-, and periosteum-derived cells retained their proliferation ability even at passage 10. In chondrogenesis studies in which the cells were pelleted and cultured in vitro, pellets from bone marrow-, synovium-, and periosteum-derived cells were shown to be larger and stained more extensively for cartilage matrix. Synovium-derived cells, in particular, had the greatest ability for chondrogenesis. In adipogenesis experiments, the frequency of oil red O-positive colonies was highest in synovium-and adipose tissue-derived cells. In studies of osteogenesis, the rate of alizarin red-positive colonies was highest in bone marrow-, synovium-, and periosteum-derived cells. For epitope profiling, 15 surface antigens were measured. Most appeared to have similar epitope profiles irrespective of cell source.Conclusion. Our findings indicate that there are significant differences in MSC properties according to tissue source, beyond donor and experimental variation. Superiority of synovium as a potential source of MSCs for clinical applications was demonstrated.

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Study of Telomere Length Reveals Rapid Aging of Human Marrow Stromal Cells following In Vitro Expansion

Cited by 701 publications

References 37 publications

Glycogen synthase kinase-3α/β inhibition promotes in vivo amplification of endogenous mesenchymal progenitors with osteogenic and adipogenic potential and their differentiation to the osteogenic lineage

Glycogen synthase kinase-3α/β inhibition promotes in vivo amplification of endogenous mesenchymal progenitors with osteogenic and adipogenic potential and their differentiation to the osteogenic lineage

Autophagy controls mesenchymal stem cell properties and senescence during bone aging

Comparison of human stem cells derived from various mesenchymal tissues: Superiority of synovium as a cell source

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