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IFN-γ and TNF-α Pre-licensing Protects Mesenchymal Stromal Cells from the Pro-inflammatory Effects of Palmitate
Lauren Boland1, Anthony J Burand1, Alex J Brown1
1University of Iowa Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA; Department of Biomedical Engineering, University of Iowa, Iowa City, IA 52242, USA.
Abstract:
The use of mesenchymal stromal cell (MSC) therapy for the treatment of type 2 diabetes (T2D) and T2D complications is promising; however, the investigation of MSC function in the setting of T2D has not been thoroughly explored. In our current study, we investigated the phenotype and function of MSCs in a simulated in vitro T2D environment. We show that palmitate, but not glucose, exposure impairs MSC metabolic activity with moderate increases in apoptosis, while drastically affecting proliferation and morphology. In co-culture with peripheral blood mononuclear cells (PBMCs), we found that MSCs not only lose their normal suppressive ability in high levels of palmitate, but actively support and enhance inflammation, resulting in elevated PBMC proliferation and pro-inflammatory cytokine release. The pro-inflammatory effect of MSCs in palmitate was partially reversed via palmitate removal and fully reversed through pre-licensing MSCs with interferon-gamma and tumor necrosis factor alpha. Thus, palmitate, a specific metabolic factor enriched within the T2D environment, is a potent modulator of MSC immunosuppressive function, which may in part explain the depressed potency observed in MSCs isolated from T2D patients. Importantly, we have also identified a robust and durable pre-licensing regimen that protects MSC immunosuppressive function in the setting of T2D.
Insights
Palmitate, not glucose, negatively impacts mesenchymal stromal cells (MSCs) in a type 2 diabetes (T2D) environment, impairing their function. Pre-licensing MSCs with specific cytokines can restore their therapeutic potential in T2D.
Area of Science:
- Cell Biology
- Immunology
- Metabolic Diseases
Background:
- Mesenchymal stromal cell (MSC) therapy shows promise for type 2 diabetes (T2D) and its complications.
- The function of MSCs within the T2D environment requires further investigation.
Purpose of the Study:
- To investigate the phenotype and function of MSCs in a simulated in vitro T2D environment.
- To identify factors within the T2D milieu that modulate MSC function.
- To explore strategies for restoring MSC immunosuppressive function in T2D.
Main Methods:
- Exposure of MSCs to palmitate and glucose in vitro.
- Assessment of MSC metabolic activity, apoptosis, proliferation, and morphology.
- Co-culture of MSCs with peripheral blood mononuclear cells (PBMCs) to evaluate immune modulation.
- Investigation of palmitate removal and cytokine pre-licensing (interferon-gamma and tumor necrosis factor alpha) on MSC function.
Main Results:
- Palmitate exposure, but not glucose, impaired MSC metabolic activity, proliferation, and morphology, with moderate apoptosis.
- In the presence of high palmitate, MSCs lost their suppressive ability and promoted inflammation, increasing PBMC proliferation and pro-inflammatory cytokine release.
- Palmitate removal partially reversed, and cytokine pre-licensing fully reversed, the pro-inflammatory effect of MSCs.
Conclusions:
- Palmitate is a key metabolic factor in the T2D environment that significantly modulates MSC immunosuppressive function.
- This palmitate-induced modulation may explain the reduced efficacy of MSCs from T2D patients.
- A robust pre-licensing regimen using interferon-gamma and tumor necrosis factor alpha can protect MSC immunosuppressive function in a T2D setting.
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