Insulin Promotes the Proliferation of Human Umbilical Cord Matrix-Derived Mesenchymal Stem Cells by Activating the Akt-Cyclin D1 Axis

Abstract

Background. The functions of insulin in mesenchymal stem cells (MSC) remain poorly understood. Methods. MSC from human umbilical cord matrix (UCM) cultured in serum-free media (SFM) with or without insulin were subjected to various molecular biological analyses to determine their proliferation and growth states, expression levels of Akt-cyclin D1 signaling molecules, and in vitro differentiation capacities. Results. Insulin accelerated the G1-S cell cycle progression of UCM-MSC and significantly stimulated their proliferation and growth in SFM. The pro-proliferative action of insulin was associated with augmented cyclin D1 and phosphorylated Akt expression levels. Akt inactivation remarkably abrogated insulin-induced increases in cyclin D1 expression and cell proliferation, indicating that insulin enhances the proliferation of UCM-MSC via acceleration of the G1-S transition mediated by the Akt-cyclin D1 pathway. Additionally, the UCM-MSC propagated in SFM supplemented with insulin exhibited similar specific surface antigen profiles and differentiation capacities as those generated in conventional media containing fetal bovine serum. Conclusions. These findings suggest that insulin acts solely to promote UCM-MSC proliferation without affecting their immunophenotype and differentiation potentials and thus have important implications for utilizing insulin to expand clinical-grade MSC in vitro.

Insulin immobilized PCL‐cellulose acetate micro‐nanostructured fibrous scaffolds for tendon tissue engineering

“…The data suggests, in the presence of low serum conditions, within the range of concentrations tested, insulin did not have an effect on the proliferation rate. Mitotic effects of insulin appear to be highly dependent on cell type and concentration . For instance, human lung fibroblast cells showed significant increase in proliferation after 24 hours post treatment with 2‐μg/mL insulin .…”

“…Similarly, human hepatic stellate cells treated with approximately 6‐ng/mL insulin showed significant increase in proliferation . Insulin treatment on human umbilical cord matrix derived MSCs showed no effect on proliferation at insulin concentrations below approximately 6 μg/mL but significant increase in proliferation with concentrations above 14.5 μg/mL …”

“…The concentration of insulin needed to stimulate proliferation may depend on the number of insulin receptors present on the cell membrane. A lower number of insulin receptors present in the cell may require higher doses of insulin to elicit a proliferative effect . No studies to our knowledge have been conducted on the abundance of insulin or IGF‐1 receptors on human MSCs.…”

“…No studies to our knowledge have been conducted on the abundance of insulin or IGF‐1 receptors on human MSCs. Higher microgram insulin concentrations favor not only progenitor proliferation but also chondrogenic differentiation . Therefore, only lower insulin concertation ranges were used to characterize dose responses.…”

“…Various growth factors have been shown to support tendon differentiation . Insulin‐like growth factor‐1 (IGF‐1) has been extensively researched for its ability to encourage cell proliferation, inhibition of cell apoptosis, and anabolic effects on musculoskeletal tissues . Specifically, IGF‐1 has been identified to be involved in all phases of tendon healing that include inflammatory, proliferative, and remodeling stages .…”