The metabolic syndrome alters the miRNA signature of porcine adipose tissue‐derived mesenchymal stem cells

Abstract

Background Autologous transplantation of mesenchymal stem cells (MSCs) may be a viable option for the treatment of several diseases. Evidence indicates that MSCs release extracellular vesicles (EVs) that shuttle miRNAs to damaged parenchymal cells, activating an endogenous repair program. However, whether comorbidities, such as metabolic syndrome (MetS) interfere with the packaging of cargo of MSC-derived EVs has never been explored. We hypothesized that MetS modulates the miRNA content packed within MSC-derived EVs. Methods MSCs were collected from swine abdominal adipose tissue after 16 weeks of Lean or Obese diet (n=7 each). Next-generation miRNA sequencing (miRNA-seq) was performed to identify miRNAs enriched in MSC-derived EVs, and their predicted target genes. Functional pathway analysis of the top 50 target genes of the top 4 miRNAs enriched in each group was performed using FunRich. Results Fourteen and 8 miRNAs were enriched in Lean- and MetS- EVs, respectively. Target genes of miRNAs enriched in MetS-EVs were implicated in the development of MetS and its complications, including diabetes-related pathways, validated transcriptional targets of AP1 family members Fra1 and Fra2, Class A/1 (Rhodopsin-like receptors), and Peptide ligand-binding receptors. Contrarily, miRNAs enriched in Lean EVs target primarily EphrinA-EPHA and the Rho family of GTPases. Conclusions MetS alters the miRNA content of EVs derived from porcine adipose tissue MSCs. These alterations could impair the efficacy of autologous MSCs and limit its therapeutic use in subjects with MetS. Our findings may assist in developing adequate regenerative strategies to preserve the reparative potency of MSCs in individuals with MetS.

Impaired Bone Regenerative Effect of Exosomes Derived from Bone Marrow Mesenchymal Stem Cells in Type 1 Diabetes

“…Exosomes, originating from the endosomes of parental cells, are highly stable in terms of cargo storage and therefore faithfully reflect the genomic characteristics of their parent cell . Consistent with the findings in BMSCs , in the present study, we demonstrate that the pro‐osteogenic and proangiogenic effects of BMSC‐exos are also impaired by T1DM.…”

“…Diabetes mellitus and metabolic syndrome lead to the formation of important microenvironments that may affect the function of various types of cells . In particular, as a promising seed cell in tissue engineering, BMSCs are negatively affected by diabetes mellitus.…”

“…Thus, the components present in BMSC‐exos may have changed in T1DM condition. In a previous study, Meng et al indicated that metabolic syndrome altered the miRNA content of extracellular vesicles (EVs) secreted by adipose tissue‐derived MSCs . They found that metabolic syndrome‐ and lean‐EVs were enriched with 8 and 14 distinct miRNAs, respectively.…”

Metabolic Syndrome Interferes with Packaging of Proteins within Porcine Mesenchymal Stem Cell-Derived Extracellular Vesicles

“…Cell‐free supernatants were then subjected to a second ultra‐centrifugation at 100,000 g for 1 hour at 4°C, washed in serum‐free medium containing HEPES 25 mM, and submitted to a third step of ultra‐centrifugation. Lean‐ and MetS‐EVs exhibited typical size distribution by nanoparticle tracking analysis, and expressed common MSC and EV (e.g., CD9, CD29, CD81, and CD63) markers by Western blotting and fluorescence‐activated cell sorting, as previously shown .…”

“…We have recently shown that MetS alters mRNA expression related to insulin signaling in porcine adipose tissue‐derived MSCs , and interferes with the microRNA cargo of their EVs, favoring modulation of pathways involved in the development of MetS and its complications . Notably, delivery of genetic material to recipient cells may constitute a different mode of regulation compared with protein delivery.…”