Telomeres and Telomerase in the Control of Stem Cells

Lupatov, A. Yu.; Yarygin, K N

doi:10.3390/biomedicines10102335

Cited by 15 publications

(11 citation statements)

References 212 publications

(211 reference statements)

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“…pMSCs grown in XM and LP cells grown in FM showed a higher differentiation tendency towards chondrogenic and osteogenic lineage. Interestingly, MSCs have been shown to lose their self-renewal and trilineage differentiation potential but still be able to differentiate towards the adipogenic lineage (42)(43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

WNT and VEGF/PDGF signaling regulate self-renewal in primitive mesenchymal stem cells

Mazzella

Walker

Cormier

et al. 2023

Preprint

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Background Therapeutic use of multipotent mesenchymal stem cells (MSCs) is hampered due to poor growth and limited self-renewal potential. The self-renewal potential of MSCs is also affected during propagation and changes are poorly understood. This study investigated the molecular mechanism involved in the self-renewal of primitive (p) MSCs. Methods pMSCs were cultured to low passage (LP), P3, and high passage (HP), P20, in fetal bovine serum medium (FM) and xeno-free medium (XM). The characteristics of LP and HP pMSCs were evaluated for morphology, expression of cell surface markers, doubling time (DT), colony forming efficiency (CFE), proliferation by BrdU assay, telomerase activity and trilineage differentiation. We then examined transcriptome and nucleosome occupancies using RNA-seq and MNase-seq, respectively analyses. Results pMSCs grown in FM gradually changed morphology to large elongated cells and showed a significant reduction in the expression of CD90 and CD49f, CFE, proliferation, and telomerase activity. In addition, cells had a greater propensity to differentiate into the adipogenic lineage. In contrast, pMSCs grown in XM maintained small fibroblastoid morphology, self-renewal, and differentiation potential. Transcriptomic analysis showed upregulation of genes involved in self-renewal, cell cycle, and DNA replication in XM-grown pMSCs. Whereas senescence genes were upregulated in cells in FM. MNase-seq analysis revealed less nucleosomal occupancies in self-renewal genes and senescence genes in pMSCs grown in XM and FM, respectively. The expression of selected genes associated with self-renewal, cell cycle, DNA replication, differentiation, and senescence was confirmed by qRT-PCR. These results led us to propose signaling pathways involved in the self-renewal and senescence of pMSCs. Conclusion We conclude that the self-renewal potential of pMSCs is controlled by WNT and VEGF/PDGF, but TGFβ and PI3K signaling induce senescence.

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Section: Discussionmentioning

confidence: 99%

WNT and VEGF/PDGF signaling regulate self-renewal in primitive mesenchymal stem cells

Mazzella

Walker

Cormier

et al. 2023

Preprint

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“…However, HP pMSCs in FM had a higher tendency to differentiate toward the adipogenic lineage, while pMSCs grown in XM and LP cells grown in FM showed a greater tendency to differentiate toward the chondrogenic and osteogenic lineages. While MSCs can lose their ability to self-renew and differentiate into three different cell types, they can still differentiate into the adipogenic lineage [ 51 – 54 ].…”

Section: Discussionmentioning

confidence: 99%

Regulation of self-renewal and senescence in primitive mesenchymal stem cells by Wnt and TGFβ signaling

Mazzella,

Walker,

Cormier

et al. 2023

Stem Cell Res Ther

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Background The therapeutic application of multipotent mesenchymal stem cells (MSCs) encounters significant challenges, primarily stemming from their inadequate growth and limited self-renewal capabilities. Additionally, as MSCs are propagated, their ability to self-renew declines, and the exact cellular and molecular changes responsible for this are poorly understood. This study aims to uncover the complex molecular mechanisms that govern the self-renewal of primitive (p) MSCs. Methods We grew pMSCs using two types of medium, fetal bovine serum (FM) and xeno-free (XM), at both low passage (LP, P3) and high passage (HP, P20). To evaluate LP and HP pMSCs, we examined their physical characteristics, cell surface markers, growth rate, colony-forming ability, BrdU assays for proliferation, telomerase activity, and potential to differentiate into three lineages. Moreover, we conducted RNA-seq to analyze their transcriptome and MNase-seq analysis to investigate nucleosome occupancies. Results When grown in FM, pMSCs underwent changes in their cellular morphology, becoming larger and elongated. This was accompanied by a decrease in the expression of CD90 and CD49f, as well as a reduction in CFE, proliferation rate, and telomerase activity. In addition, these cells showed an increased tendency to differentiate into the adipogenic lineage. However, when grown in XM, pMSCs maintained their self-renewal capacity and ability to differentiate into multiple lineages while preserving their fibroblastoid morphology. Transcriptomic analysis showed an upregulation of genes associated with self-renewal, cell cycle regulation, and DNA replication in XM-cultured pMSCs, while senescence-related genes were upregulated in FM-cultured cells. Further analysis demonstrated differential nucleosomal occupancies in self-renewal and senescence-related genes for pMSCs grown in XM and FM, respectively. These findings were confirmed by qRT-PCR analysis, which revealed alterations in the expression of genes related to self-renewal, cell cycle regulation, DNA replication, differentiation, and senescence. To understand the underlying mechanisms, we investigated the involvement of Wnt and TGFβ signaling pathways by modulating them with agonists and antagonists. This experimental manipulation led to the upregulation and downregulation of self-renewal genes in pMSCs, providing further insights into the signaling pathways governing the self-renewal and senescence of pMSCs. Conclusion Our study shows that the self-renewal potential of pMSCs is associated with the Wnt pathway, while senescence is linked to TGFβ.

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“…This is achieved by adding specific DNA repeat sequences to the chromosome termini. Notably, telomerase exhibits activity in specific cell types, such as stem cells and germ cells, while remaining inactive in most other cell types [124].…”

Section: Telomere Length Regulation In Malaria Parasitementioning

confidence: 99%

Telomeres and Telomerase as Promising Targets for Malaria Therapy: A Comprehensive Review

Wakai,

Anzaku,

Afolabi

2024

Preprint

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Infection with the malaria parasite Plasmodium, remains a major cause of illness and death world-wide. The development of evasion strategies by the parasite from host immunity and its adaptability to antimalarial drugs has raised the urgency for developing new strategies to combat this disease. One promising avenue is targeting telomeres – sequences found at chromosome termini– and telomerase – the enzyme that catalysis synthesis of telomeres using an intrinsic RNA template. As telomeres shorten critically, cells undergo replicative senescence or apoptosis. Plasmodium, lacking telomerase activity in its human stages, exploits alternative mechanisms, accelerating telomere shortening, aging, and immune evasion. Chemical telomerase inhibitors show promise as antimalarials. In this review, we examine the potential of targeting this system in malaria therapy, with telomerase inhibitors offering a novel approach. A systematic search on PubMed using Boolean techniques identified 246 relevant articles from 1985 to March 31, 2024. After filtering, 43 articles met inclusion criteria, supplemented by snowball sampling. The telomerase inhibitor drug strategy is widely applicable against cancer. However, given the drugability of telomerase and the absolute requirement for active telomere maintenance in the vast majority of parasites including plasmodium, telomerase and telomere maintenance could well represent the Achilles heel of the parasite

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Telomeres and Telomerase in the Control of Stem Cells

Cited by 15 publications

References 212 publications

WNT and VEGF/PDGF signaling regulate self-renewal in primitive mesenchymal stem cells

WNT and VEGF/PDGF signaling regulate self-renewal in primitive mesenchymal stem cells

Regulation of self-renewal and senescence in primitive mesenchymal stem cells by Wnt and TGFβ signaling

Telomeres and Telomerase as Promising Targets for Malaria Therapy: A Comprehensive Review

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