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Mesenchymal stem cells protect podocytes from apoptosis induced by high glucose via secretion of epithelial growth
Introduction:
The apoptosis and subsequent injury of podocytes plays a pathogenic role in diabetic nephropathy (DN). Mesenchymal stem cells (MSCs) are promising therapeutic cells for preventing apoptosis and reducing cellular injury. Our previous study found that MSCs could protect kidneys from diabetes-induced injury without obvious engraftment. So we evaluated the effects of human adipose-derived MSCs (hAd-MSCs) on podocytic apoptosis and injury induced by high glucose (HG) and the underlying mechanisms.
Methods:
We used flow cytometry, Western blot and confocal fluorescence microscopy to study podocytic apoptosis and injury induced by HG at 24 hours, 48 hours, and 72 hours in the presence or absence of MSC-conditioned medium (CM). An antibody-based cytokine array was used to identify the mediating factor, which was verified by adding the neutralizing antibody (NtAb) to block its function or adding the recombinant cytokine to the medium to induce its function.
Results:
hAd-MSC-CM reduced podocytic apoptosis in a dose-dependent manner, decreased the expression of podocytic cleaved caspase-3, and prevented the reduced expression and maintained the normal arrangement of podocytic synaptopodin and nephrin. However, human embryonic lung cell (Wi38)-CM failed to ameliorate podocytic apoptosis or injury. Twelve cytokines with concentration ratios (MSC-CM/Wi38-CM) >10-fold were identified. Epithelial growth factor (EGF) was singled out for its known ability to prevent apoptosis. Recombinant human EGF (rhEGF) prevented podocytic apoptosis and injury similarly to hAd-MSC-CM but, upon blockade of EGF, the beneficial effect of hAd-MSC-CM decreased dramatically.
Conclusions:
hAd-MSCs prevent podocytic apoptosis and injury induced by HG, mainly through secreting soluble EG.
Insights
Human adipose-derived mesenchymal stem cells (hAd-MSCs) protect kidney podocytes from high glucose-induced injury. Their conditioned medium, rich in epithelial growth factor (EGF), prevents apoptosis and maintains podocyte structure.
Area of Science:
- Nephrology
- Stem Cell Biology
- Diabetology
Background:
- Podocyte apoptosis and injury are key in diabetic nephropathy (DN).
- Mesenchymal stem cells (MSCs) show therapeutic potential for kidney injury.
- Previous studies indicated MSCs protect kidneys without significant engraftment.
Purpose of the Study:
- To evaluate the effects of human adipose-derived MSCs (hAd-MSCs) on high glucose (HG)-induced podocyte apoptosis and injury.
- To elucidate the underlying mechanisms of hAd-MSC-mediated protection.
Main Methods:
- Podocyte apoptosis and injury induced by HG were assessed using flow cytometry, Western blot, and confocal microscopy.
- MSC-conditioned medium (CM) was used to evaluate protective effects.
- Cytokine arrays identified potential mediators, with epithelial growth factor (EGF) being further investigated using recombinant EGF and neutralizing antibodies.
Main Results:
- hAd-MSC-CM significantly reduced podocyte apoptosis and injury in a dose-dependent manner.
- hAd-MSC-CM preserved podocyte-specific proteins (synaptopodin and nephrin) and prevented cleaved caspase-3 expression.
- EGF was identified as a key mediator; recombinant EGF mimicked hAd-MSC-CM effects, and EGF blockade diminished these benefits.
Conclusions:
- hAd-MSCs effectively prevent high glucose-induced podocyte apoptosis and injury.
- The primary mechanism involves the secretion of soluble epithelial growth factor (EGF).
- hAd-MSCs represent a promising cell-based therapy for diabetic nephropathy.
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