CLINICAL RESEARCH · TYPE 2 DIABETES
Decitabine Assists Umbilical Cord-Derived Mesenchymal Stem Cells in Improving Glucose Homeostasis
By Modulating Macrophage Polarization in Type 2 Diabetic Mice
Abstract
Background & Methods
Background: MSCs have emerged as a promising therapy for type 2 diabetes (T2D). The anti-diabetic effect of MSCs is partially mediated by eliciting macrophages into an anti-inflammatory phenotype, thus alleviating insulin resistance. However, single MSC infusion is insufficient to ameliorate sustained hyperglycemia or normalize blood glucose levels.
This study used decitabine (DAC), which is involved in the regulation of macrophage polarization, to test whether MSCs combined with decitabine can prolong and enhance the anti-diabetic effect in T2D mice.
Methods: High-fat diet (HFD) and streptozocin (STZ) were used to induce T2D mouse models. T2D mice were randomly divided into four groups: T2D group, MSC group, DAC group, and MSC+DAC group. Blood glucose was monitored, and glucose tolerance and insulin sensitivity were evaluated throughout the analysis period.
Results & Conclusions
Results: MSC infusion effectively improved insulin sensitivity and glucose homeostasis in T2D mice within 1 week. Combination therapy of MSCs+DAC extended the anti-diabetic effects from 1 to 4 weeks (the end of the observation). More M2 macrophages in adipose tissue were observed in the combination therapy group over the entire study period.
In vitro, MSCs combined with decitabine more effectively polarized M1 macrophages to M2 macrophages. The effect was largely abrogated by the PPARγ antagonist GW9662.
Conclusions: MSCs combined with decitabine can more effectively alleviate insulin resistance and prolong the anti-diabetic effect in T2D mice — in part by prompting M2 polarization in a PPARγ-dependent manner. Decitabine may be an applicable addition to MSCs for diabetes therapy.
Extended Anti-Diabetic Effect
MSC+DAC combination extended benefits from 1 week to 4 weeks vs MSC alone — a 4× extension in sustained glucose homeostasis improvement.
M2 Macrophage Polarization
More anti-inflammatory M2 macrophages observed in adipose tissue in the combination group — the mechanism behind improved insulin sensitivity.
PPARγ-Dependent Mechanism
The effect of MSC+DAC on macrophage polarization was abrogated by PPARγ antagonist GW9662 — confirming the specific mechanism of action.
