Abstract
Human bone marrow-mesenchymal stromal cells (hBM-MSCs) undergo cellular senescence during in vitro culture. In this study, we defined this replicative senescence as impaired proliferation, deterioration in representative cell characteristics, accumulated DNA damage, and decreased telomere length and telomerase activity with or without genomic abnormalities. The UBC gene expression gradually decreased during passaging along with the reduction in series of molecules including hub genes; CDK1, CCNA2, MCM10, E2F1, BRCA1, HIST1H1A and HIST1H3B. UBC knockdown in hBM-MSCs induced impaired proliferation in dose-dependent manner and showed replicative senescence-like phenomenon. Gene expression changes after UBC knockdown were similar to late passage hBM-MSCs. Additionally, UBC overexpession improved the proliferation activity of hBM-MSCs accompanied by increased expression of the hub genes. Consequently, UBC worked in higher-order through regulation of the hub genes controlling cell cycle and proliferation. These results indicate that the decrement of UBC expression plays a pivotal role in replicative senescence of hBM-MSCs.
Highlights
Mesenchymal stromal cells (MSCs) are the major cellular component of a niche and reside in virtually all postnatal organs and tissues[1]
Average population doubling time (PDT) at less than P3 was 34.5 ± 5.9 h, which was gradually increased after P4 and P5 (46.1 ± 8.4 h) and markedly increased after P6 (63.4 ± 9.4 h)
One of the principal characteristics of senescence, was coupled with gain of SA-β-gal-positive and large-sized type II MSCs as expected. hBM-MSC barely maintained the general characteristics, such as surface markers and multipotency, but the representative capacities clearly weakened during long-term in vitro culture
Summary
Mesenchymal stromal cells (MSCs) are the major cellular component of a niche and reside in virtually all postnatal organs and tissues[1]. They possess a self-renewal capacity and can differentiate into a variety of cell types. Taking advantage of these characteristics, MSCs have been considered as one of the important sources of regenerative medicine. Unlike embryonic stem cells or induced pluripotent stem cells (iPSCs), MSCs lose their proliferation activity and original characteristics after repetitive subculture, they are considered to have a stemness nature[2]. Human bone marrow MSCs (hBM-MSCs) are the most investigated source of adult stem cells. For efficient and effective application of hBM-MSCs in regenerative therapy, more evidence and understanding of the replicative senescence of hBM-MSCs are crucial
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