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Production and Administration of Therapeutic Mesenchymal Stem/Stromal Cell (MSC) Spheroids Primed in 3-D Cultures Under Xeno-free Conditions
Published on: March 18, 2017
SIRT1 is required for long-term growth of human mesenchymal stem cells
Hong-Feng Yuan1, Chao Zhai, Xin-Long Yan
1Stem Cell and Regeneration Medicine Lab, Beijing Institute of Transfusion Medicine, 27 Taiping Road, Beijing, China.
Abstract:
Human mesenchymal stem cells (MSCs) have therapeutic potential because of their ability to self-renew and differentiate into multiple tissues. However, senescence often occurs in MSCs when they are cultured in vitro and the molecular mechanisms underlying this effect remain unclear. In this study, we found that NAD-dependent protein deacetylase SIRT1 is differentially expressed in both human bone marrow-derived MSCs (B-MSCs) and adipose tissue-derived MSCs after increasing passages of cell culture. Using lentiviral shRNA we demonstrated that selective knockdown of SIRT1 in human MSCs at early passage slows down cell growth and accelerates cellular senescence. Conversely, overexpression of SIRT1 delays senescence in B-MSCs that have undergone prolonged in vitro culturing and the cells do not lose adipogenic and osteogenic potential. In addition, we found that the delayed accumulation of the protein p16 is involved in the effect of SIRT1. However, resveratrol, which has been used as an activator of SIRT1 deacetylase activity, only transiently promotes proliferation of B-MSCs. Our findings will help us understand the role of SIRT1 in the aging of normal diploid cells and may contribute to the prevention of human MSCs senescence thus benefiting MSCs-based tissue engineering and therapies.
Insights
SIRT1 protein influences human mesenchymal stem cell (MSC) aging. Lowering SIRT1 accelerates senescence, while increasing it delays aging, preserving MSC therapeutic potential for tissue engineering.
Area of Science:
- Cell Biology
- Regenerative Medicine
- Biochemistry
Background:
- Human mesenchymal stem cells (MSCs) possess therapeutic potential due to self-renewal and differentiation capabilities.
- In vitro cell culture often induces senescence in MSCs, with underlying molecular mechanisms needing clarification.
- SIRT1, an NAD-dependent protein deacetylase, shows differential expression during MSC culture passage.
Purpose of the Study:
- To investigate the role of SIRT1 in the senescence of human mesenchymal stem cells (MSCs).
- To determine if modulating SIRT1 levels can prevent or delay MSC senescence.
- To explore the therapeutic implications of controlling MSC aging for tissue engineering.
Main Methods:
- Differential expression analysis of SIRT1 in human bone marrow-derived MSCs (B-MSCs) and adipose-derived MSCs.
- Lentiviral shRNA to selectively knockdown SIRT1 expression in early-passage MSCs.
- Overexpression of SIRT1 in prolonged cultured B-MSCs.
- Assessment of cell growth, senescence markers (e.g., p16 accumulation), and differentiation potential (adipogenic, osteogenic).
Main Results:
- Selective knockdown of SIRT1 accelerated cellular senescence and slowed growth in early-passage MSCs.
- Overexpression of SIRT1 delayed senescence in prolonged cultured B-MSCs without compromising differentiation potential.
- Delayed accumulation of the protein p16 was identified as a mechanism involved in SIRT1's effect.
- Resveratrol, a SIRT1 activator, only transiently promoted B-MSC proliferation.
Conclusions:
- SIRT1 plays a crucial role in regulating the aging process of human MSCs.
- Modulating SIRT1 activity offers a potential strategy to prevent or delay MSC senescence.
- These findings support the use of MSCs in tissue engineering and therapies by maintaining their functional lifespan.
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