Senescent Mesenchymal Stem Cells: Disease Mechanism and Treatment Strategy

Liu, Yajun; Chen, Qian

doi:10.1007/s40610-020-00141-0

Cited by 21 publications

(14 citation statements)

References 78 publications

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“…Aging and longevity have always been seductive topics for organisms. As a type of adult stem cells with the capacity for self-renewal, immunosuppression, differentiation, and migration, mesenchymal stem cells (MSCs) extensively reside within various tissues and organs, such as bone marrow, adipose tissue, amniotic fluid, placenta, umbilical cord, and muscle [ 1 , 2 ], and play an essential role in maintaining tissue homeostasis throughout the lifespan of an organism [ 3 , 4 ]. Accumulating evidence has revealed that biological aging and the development of many degenerative diseases can attribute to MSC senescence [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Curcumin Alleviates the Senescence of Canine Bone Marrow Mesenchymal Stem Cells during In Vitro Expansion by Activating the Autophagy Pathway

Deng

Ouyang

et al. 2021

IJMS

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Senescence in mesenchymal stem cells (MSCs) not only hinders the application of MSCs in regenerative medicine but is also closely correlated with biological aging and the development of degenerative diseases. In this study, we investigated the anti-aging effects of curcumin (Cur) on canine bone marrow-derived MSCs (cBMSCs), and further elucidated the potential mechanism of action based on the modulation of autophagy. cBMSCs were expanded in vitro with standard procedures to construct a cell model of premature senescence. Our evidence indicates that compared with the third passage of cBMSCs, many typical senescence-associated phenotypes were observed in the sixth passage of cBMSCs. Cur treatment can improve cBMSC survival and retard cBMSC senescence according to observations that Cur (1 μM) treatment can improve the colony-forming unit-fibroblasts (CFU-Fs) efficiency and upregulated the mRNA expression of pluripotent transcription factors (SOX-2 and Nanog), as well as inhibiting the senescence-associated beta-galactosidase (SA-β-gal) activities and mRNA expression of the senescence-related markers (p16 and p21) and pro-inflammatory molecules (tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)). Furthermore, Cur (0.1 μM~10 μM) was observed to increase autophagic activity, as identified by upregulation of microtubule-associated protein 1 light chain 3 (LC3), unc51-like autophagy-activating kinase-1 (ULK1), autophagy-related gene (Atg) 7 and Atg12, and the generation of type II of light chain 3 (LC3-II), thereby increasing autophagic vacuoles and acidic vesicular organelles, as well as causing a significant decrease in the p62 protein level. Moreover, the autophagy activator rapamycin (RAP) and Cur were found to partially ameliorate the senescent features of cBMSCs, while the autophagy inhibitor 3-methyladenine (3-MA) was shown to aggravate cBMSCs senescence and Cur treatment was able to restore the suppressed autophagy and counteract 3-MA-induced cBMSC senescence. Hence, our study highlights the important role of Cur-induced autophagy and its effects for ameliorating cBMSC senescence and provides new insight for delaying senescence and improving the therapeutic potential of MSCs.

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Section: Introductionmentioning

confidence: 99%

Curcumin Alleviates the Senescence of Canine Bone Marrow Mesenchymal Stem Cells during In Vitro Expansion by Activating the Autophagy Pathway

Deng

Ouyang

et al. 2021

IJMS

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“…However, for MSCs to be clinically functional, it is essential to monitor the senescence of MSC aging. Recent studies have discussed and summarized some strategies for monitoring senescence, and the molecular mechanisms involved ( Li et al, 2017 ; Liu and Chen, 2020 ). Although the topic has much clinical relevance, the current knowledge of senescence is mainly based on classical events, and sometimes, there are difficulties not previously described.…”

Section: Discussionmentioning

confidence: 99%

Senescence State in Mesenchymal Stem Cells at Low Passages: Implications in Clinical Use

Alves-Paiva

Nascimento

Oliveira

et al. 2022

Front. Cell Dev. Biol.

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Mesenchymal stem cells (MSCs) are multipotent cells found in various tissues and are easily cultivated. For use in clinical protocols, MSCs must be expanded to obtain an adequate number of cells, but a senescence state may be instituted after some passages, reducing their replicative potential. In this study, we report a case where MSC derived from an elderly donor acquired a senescence state after three passages. The bone marrow was aspirated from a female patient submitted to a cell therapy for the incontinency urinary protocol; MSCs were cultivated with DMEM low glucose, supplemented with 10% autologous serum (AS) plus 1% L-glutamine and 1% antibiotic/antimycotic. Senescence analysis was performed by β-galactosidase staining after 24 and 48 h. Controls were established using BM-MSC from healthy donors and used for senescence and gene expression assays. Gene expression was performed using RT-PCR for pluripotency genes, such as SOX2, POU5F1, NANOG, and KLF4. MSC telomere length was measured by the Southern blotting technique, and MSCs were also analyzed for their capacity to differentiate into adipocytes, chondrocytes, and osteocytes. The patient’s MSC expansion using AS displayed an early senescence state. In order to understand the role of AS in senescence, MSCs were then submitted to two different culture conditions: 1) with AS or 2) with FBS supplementation. Senescence state was assessed after 24 h, and no statistical differences were observed between the two conditions. However, patients’ cells cultured with AS displayed a higher number of senescence cells than FBS medium after 48 h (p = 0.0018). Gene expression was performed in both conditions; increased expression of KLF4 was observed in the patient’s cells in comparison to healthy controls (p = 0.0016); reduced gene expression was observed for NANOG (p = 0.0016) and SOX2 (p = 0.0014) genes. Telomere length of the patient’s cells was shorter than that of a healthy donor and that of a patient of similar age. Osteocyte differentiation seemed to be more diffuse than that of the healthy donor and that of the patient of similar age. MSCs could enter a senescence state during expansion in early passages and can impact MSC quality for clinical applications, reducing their efficacy when administered.

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“…They are still inherently MSCs due to the expression of MSC surface markers, such as CD90, CD73 and CD105 [ 64 , 65 ]. But they no longer retain the self-renewal and differentiation potentials of normal MSCs [ 66 ]. SnMSCs have unique features different to normal MSCs, such as an enlarged and more granular morphology, condensed heterochromatin structure in the nuclei, changes in epigenetic regulation, shortened telomeres, and changes in differentiation potentials [ 66 , 67 , 68 , 69 ].…”

Section: Sactai In Adult Tissuesmentioning

confidence: 99%

“…But they no longer retain the self-renewal and differentiation potentials of normal MSCs [ 66 ]. SnMSCs have unique features different to normal MSCs, such as an enlarged and more granular morphology, condensed heterochromatin structure in the nuclei, changes in epigenetic regulation, shortened telomeres, and changes in differentiation potentials [ 66 , 67 , 68 , 69 ]. Characteristics of cellular senescence also apply to SnMSCs, such as increased expressions of senescence markers SA-β-gal, p16 INK4A and p53 [ 70 ].…”

Section: Sactai In Adult Tissuesmentioning

confidence: 99%

Senescence-Associated Cell Transition and Interaction (SACTAI): A Proposed Mechanism for Tissue Aging, Repair, and Degeneration

Liu

Schwam

Chen

2022

Cells

Self Cite

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Aging is a broad process that occurs as a time-dependent functional decline and tissue degeneration in living organisms. On a smaller scale, aging also exists within organs, tissues, and cells. As the smallest functional unit in living organisms, cells “age” by reaching senescence where proliferation stops. Such cellular senescence is achieved through replicative stress, telomere erosion and stem cell exhaustion. It has been shown that cellular senescence is key to tissue degradation and cell death in aging-related diseases (ARD). However, senescent cells constitute only a small percentage of total cells in the body, and they are resistant to death during aging. This suggests that ARD may involve interaction of senescent cells with non-senescent cells, resulting in senescence-triggered death of non-senescent somatic cells and tissue degeneration in aging organs. Here, based on recent research evidence from our laboratory and others, we propose a mechanism—Senescence-Associated Cell Transition and Interaction (SACTAI)—to explain how cell heterogeneity arises during aging and how the interaction between somatic cells and senescent cells, some of which are derived from aging somatic cells, results in cell death and tissue degeneration.

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Senescent Mesenchymal Stem Cells: Disease Mechanism and Treatment Strategy

Cited by 21 publications

References 78 publications

Curcumin Alleviates the Senescence of Canine Bone Marrow Mesenchymal Stem Cells during In Vitro Expansion by Activating the Autophagy Pathway

Curcumin Alleviates the Senescence of Canine Bone Marrow Mesenchymal Stem Cells during In Vitro Expansion by Activating the Autophagy Pathway

Senescence State in Mesenchymal Stem Cells at Low Passages: Implications in Clinical Use

Senescence-Associated Cell Transition and Interaction (SACTAI): A Proposed Mechanism for Tissue Aging, Repair, and Degeneration

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