Senescence in Mesenchymal Stem Cells: Functional Alterations, Molecular Mechanisms, and Rejuvenation Strategies

Liu, Jing; Ding, Yue; Liu, Zhongmin; Liang, Xiaoting

doi:10.3389/fcell.2020.00258

Cited by 161 publications

(127 citation statements)

References 127 publications

(140 reference statements)

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“…However, the regulation of SUSD2 expression was unknown until our previous study showed that SUSD2 mRNA and protein is regulated through the TGF-β/SMAD2 pathways in eMSCs [46]. Here, we showed that the culture expansion of MSCs from various sources leads to a decrease in the percentage of SUSD2-expressing cells, confirming spontaneous fibroblast differentiation upon culturing, a well-known phenomenon in the MSC field [50,51,[63][64][65]. The percentage of SUSD2 + cells from endometrial and endometrium-derived tissues increased following A83-01 treatment but not in adipose tissue and bone marrow MSCs.…”

Section: Discussionsupporting

confidence: 69%

Comparing the Effect of TGF-β Receptor Inhibition on Human Perivascular Mesenchymal Stromal Cells Derived from Endometrium, Bone Marrow and Adipose Tissues

Gurung

Dirnagl

Sturm

et al. 2020

JPM

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Rare perivascular mesenchymal stromal cells (MSCs) with therapeutic properties have been identified in many tissues. Their rarity necessitates extensive in vitro expansion, resulting in spontaneous differentiation, cellular senescence and apoptosis, producing therapeutic products with variable quality and decreased potency. We previously demonstrated that A83-01, a transforming growth factor beta (TGF-β) receptor inhibitor, maintained clonogenicity and promoted the potency of culture-expanded premenopausal endometrial MSCs using functional assays and whole-transcriptome sequencing. Here, we compared the effects of A83-01 on MSCs derived from postmenopausal endometrium, menstrual blood, placenta decidua-basalis, bone marrow and adipose tissue. Sushi-domain-containing-2 (SUSD2+) and CD34+CD31−CD45− MSCs were isolated. Expanded MSCs were cultured with or without A83-01 for 7 days and assessed for MSC properties. SUSD2 identified perivascular cells in the placental decidua-basalis, and their maternal origin was validated. A83-01 promoted MSC proliferation from all sources except bone marrow and only increased SUSD2 expression and prevented apoptosis in MSCs from endometrial-derived tissues. A83-01 only improved the cloning efficiency of postmenopausal endometrial MSCs (eMSCs), and expanded adipose tissue MSCs (adMSCs) underwent significant senescence, which was mitigated by A83-01. MSCs derived from bone marrow (bmMSCs) were highly apoptotic, but A83-01 was without effect. A83-01 maintained the function and phenotype in MSCs cultured from endometrial, but not other, tissues. Our results also demonstrated that cellular SUSD2 expression directly correlates with the functional phenotype.

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Section: Discussionsupporting

confidence: 69%

Comparing the Effect of TGF-β Receptor Inhibition on Human Perivascular Mesenchymal Stromal Cells Derived from Endometrium, Bone Marrow and Adipose Tissues

Gurung

Dirnagl

Sturm

et al. 2020

JPM

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“…Senescence, a cellular response to endogenous and exogenous stresses limiting the proliferation of damaged and dysfunctional cells, markedly affects the processes of tissue homeostasis and regeneration and contributes to both physiological aging and age-related diseases (van Deursen, 2014 ; Childs et al, 2015 ; McHugh and Gil, 2018 ). Cell senescence can be induced by harmful stimuli such as DNA damage, telomere shortening, oncogenic insults, metabolic stress, epigenetic changes, and mitochondrial dysfunction (Liu et al, 2020 ). Senescent cells accumulate with aging in different tissues, and stem cell aging and replicative exhaustion are considered as hallmarks and promoters of aging and functional attrition in organisms (van Deursen, 2014 ; Childs et al, 2015 ).…”

Section: Senescence Of Mscs Contributes To Alterations Of Tissue Regementioning

confidence: 99%

“…However, the current knowledge of senescence is primarily based on bulk cell data. Novel techniques such as single-cell RNA sequencing, extended time-lapse in vivo imaging, and genetic lineage tracing would provide a more complete understanding of MSC aging process, making it possible to slow senescence or even rejuvenate aged MSCs (Liu et al, 2020 ).…”

Section: Concluding Remarks: Reconsidering the Therapeutic Use Of Mscmentioning

confidence: 99%

Mesenchymal Stromal Cells as Critical Contributors to Tissue Regeneration

Sagaradze

Basalova

Efimenko

et al. 2020

Front. Cell Dev. Biol.

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Adult stem cells that are tightly regulated by the specific microenvironment, or the stem cell niche, function to maintain tissue homeostasis and regeneration after damage. This demands the existence of specific niche components that can preserve the stem cell pool in injured tissues and restore the microenvironment for their subsequent appropriate functioning. This role may belong to mesenchymal stromal cells (MSCs) due to their resistance to damage signals and potency to be specifically activated in response to tissue injury and promote regeneration by different mechanisms. Increased amount of data indicate that activated MSCs are able to produce factors such as extracellular matrix components, growth factors, extracellular vesicles and organelles, which transiently substitute the regulatory signals from missing niche cells and restrict the injury-induced responses of them. MSCs may recruit functional cells into a niche or differentiate into missing cell components to endow a niche with ability to regulate stem cell fates. They may also promote the dedifferentiation of committed cells to reestablish a pool of functional stem cells after injury. Accumulated evidence indicates the therapeutic promise of MSCs for stimulating tissue regeneration, but the benefits of administered MSCs demonstrated in many injury models are less than expected in clinical studies. This emphasizes the importance of considering the mechanisms of endogenous MSC functioning for the development of effective approaches to their pharmacological activation or mimicking their effects. To achieve this goal, we integrate the current ideas on the contribution of MSCs in restoring the stem cell niches after damage and thereby tissue regeneration.

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“…The acquisition of SASP and permanent growth arrest lead to the stimulation of inflammation and cause tissue dysfunction [ 31 , 44 , 45 ]. For that reason, senescence is a key factor determining the quality of MSCs [ 46 ]. Studies have revealed that senescence had a harmful outcome in suppressing the proliferation and differentiation of DPSCs [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of p-Cresol on Senescence, Survival, Inflammation, and Odontoblast Differentiation in Canine Dental Pulp Stem Cells

Zayed

Iohara

2020

IJMS

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Aging, defined by a decrease in the physical and functional integrity of the tissues, leads to age-associated degenerative diseases. There is a relation between aged dental pulp and the senescence of dental pulp stem cells (DPSCs). Therefore, it is important to investigate the molecular processes underlying the senescence of DPSCs to elucidate the dental pulp aging mechanisms. p-Cresol (PC), a uremic toxin, is strongly related to cellular senescence. Here, age-related phenotypic changes including senescence, apoptosis, inflammation, and declining odontoblast differentiation in PC-treated canine DPSCs were investigated. Under the PC condition, cellular senescence was induced by decreased proliferation capacity and increased cell size, senescence-associated β-galactosidase (SA-β-gal) activity, and senescence markers p21, IL-1β, IL-8, and p53. Exposure to PC could stimulate inflammation by the increased expression of IL-6 and cause the distraction of the cell cycle by the increased level of Bax protein and decreased Bcl-2. The levels of odontoblast differentiation markers, dentin sialophosphoprotein (DSPP), dentin matrix protein 1, and osterix, were decreased. Consistent with those findings, the alizarin red staining, alkaline phosphatase, and DSPP protein level were decreased during the odontoblast differentiation process. Taken together, these findings indicate that PC could induce cellular senescence in DPSCs, which may demonstrate the changes in aging dental pulp.

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Senescence in Mesenchymal Stem Cells: Functional Alterations, Molecular Mechanisms, and Rejuvenation Strategies

Cited by 161 publications

References 127 publications

Comparing the Effect of TGF-β Receptor Inhibition on Human Perivascular Mesenchymal Stromal Cells Derived from Endometrium, Bone Marrow and Adipose Tissues

Comparing the Effect of TGF-β Receptor Inhibition on Human Perivascular Mesenchymal Stromal Cells Derived from Endometrium, Bone Marrow and Adipose Tissues

Mesenchymal Stromal Cells as Critical Contributors to Tissue Regeneration

Effects of p-Cresol on Senescence, Survival, Inflammation, and Odontoblast Differentiation in Canine Dental Pulp Stem Cells

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