Dataset Information

Proteomic and biological analysis of metformin senomorphics effects on the mesenchymal stromal cells

ABSTRACT: Senotherapeutics are new drugs, which can modulate senescence phenomena within tissues and reduces the onset of age-related pathologies. Senotherapeutics are divided in senolytics and senomorphics. The senolytics kill selectively senescent cells, while the senomorphics may delay or block the onset of senescence. Metformin is used for treatment of diabetes since several decades. Recently, it has been evidenced that metformin may have anti-aging properties by preventing DNA damage and inflammation. We evaluated the senomorphics effect of metformin on the biology human adipose mesenchymal stromal cells (MSCs) treated for six weeks with therapeutic doses of metformin. The study was combined with proteome analysis of changes occurring in MSCs intracellular and secretome protein composition, this to identify molecular pathways associated with the observed biological phenomena. The metformin reduced the replicative senescence and cell death phenomena, which are associated with prolonged in vitro cultivation. The continuous metformin supplementation delayed/reduced the impairment of MSC functions as evidenced by the presence of specific pathways in metformin treated samples: i) the alpha-adrenergic signaling, which contributes to regulation of MSCs physiological secretory activity; the signaling pathway associated with MSCs detoxification activity; the aspartate degradation pathway for optimal energy production. The senomorphics function of metformin seemed related to its reactive oxygen species (ROS) scavenging activity. In metformin treated samples, the CEBPA, TP53 and USF1 transcription factors appeared implicated in the regulation of several factors (SOD1, SOD2, CAT, GLRX, GSTP1) involved in blocking ROS.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Stem Cell

SUBMITTER: Servet ÖZCAN

LAB HEAD: Servet Özcan

PROVIDER: PXD028349 | Pride | 2022-02-15

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	200102_D35_Cont_Metfor_WC_F_SET11.wiff	Wiff
	200102_D35_Cont_Metfor_WC_F_SET11.wiff.scan	Wiff
	200102_D35_Cont_Metfor_WC_F_SET11_1_.group	Other
	200102_D35_Cont_Metfor_WC_F_SET12.wiff	Wiff
	200102_D35_Cont_Metfor_WC_F_SET12.wiff.scan	Wiff

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Publications

Proteomic and Biological Analysis of the Effects of Metformin Senomorphics on the Mesenchymal Stromal Cells.

Acar Mustafa Burak MB Ayaz-Güner Şerife Ş Gunaydin Zeynep Z Karakukcu Musa M Peluso Gianfranco G Di Bernardo Giovanni G Özcan Servet S Galderisi Umberto U

Frontiers in bioengineering and biotechnology 20211005

Senotherapeutics are new drugs that can modulate senescence phenomena within tissues and reduce the onset of age-related pathologies. Senotherapeutics are divided into senolytics and senomorphics. The senolytics selectively kill senescent cells, while the senomorphics delay or block the onset of senescence. Metformin has been used to treat diabetes for several decades. Recently, it has been proposed that metformin may have anti-aging properties as it prevents DNA damage and inflammation. We eval ...[more]

PMID: 34676202

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Project description:Obesity is a health problem characterized by large expansion of adipose tissue. During this expansion, genotoxic stressors can be accumulated and negatively affect the Mesenchymal Stem Cells (MSCs) of adipose tissue. Due to the oxidative stress generated by these genotoxic stressors, senescence phenotype might be observed in adipose tissue MSCs. Senescent MSCs lose their proliferations and differentiation properties and secrete senescence-associated molecules to their niche thus triggering senescence for the rest of the tissue. Accumulation of senescent cells in adipose tissue results in decreased tissue regeneration and functional impairment not only in the close vicinity but also in the other tissues. Here we hypothesized that declined tissue regeneration might be associated with loss of stemness in MSCs population. We analyzed the expression of several stemness genes in adipose tissue MSCs of high-fat diet and normal diet mice models. Since the MSCs population covers a small percentage of the pluripotent stem cells, a role in proliferation and tissue regeneration, we measured the percentage of these cells via TRA-1-60 surface antigen. Additionally, by conducting a shotgun proteomic approach using LC-MS/MS, whole cell proteome of the adipose tissue MSCs of high-fat diet and normal diet mice were analyzed and identified proteins were evaluated via Gene Ontology and PPI network analysis. MSCs of obese mice showed senescent phenotype and altered cell cycle distribution due to a hostile environment with oxidative stress in adipose tissue where they reside. Additionally, the number of pluripotent markers expressing cells declined in the MSC population of the high-fat diet mice. Gene expression analysis evidenced the loss of stemness with a decrease in the expression of stemness-associated genes. Of the proteomic comparison of the normal and the high-fat diet group, MSCs revealed that stemness-associated molecules were decreased while inflammation and senescence-associated phenotypes emerged in obese mice MSCs. Our results showed us that the MSCs of adipose tissue may lose their stemness properties due to obesity-associated stress conditions.