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Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling
Published on: August 3, 2018
Transient inhibition of transforming growth factor-beta1 in human diabetic CD34+ cells enhances vascular reparative
Ashay D Bhatwadekar1, E P Guerin, Yagna P R Jarajapu
1Pharmacology and Therapeutics, University of Florida, Gainesville, Florida, USA.
Objective:
Peripheral blood CD34(+) cells from diabetic patients demonstrate reduced vascular reparative function due to decreased proliferation and diminished migratory prowess, largely resulting from decreased nitric oxide (NO) bioavailability. The level of TGF-beta, a key factor that modulates stem cell quiescence, is increased in the serum of type 2 diabetic patients. We asked whether transient TGF-beta1 inhibition in CD34(+) cells would improve their reparative ability.
Research Design And Methods:
To inhibit TGF-beta1 protein expression, CD34(+) cells were treated ex vivo with antisense phosphorodiamidate morpholino oligomers (TGF-beta1-PMOs) and analyzed for cell surface CXCR4 expression, cell survival in the absence of added growth factors, SDF-1-induced migration, NO release, and in vivo retinal vascular reparative ability.
Results:
TGF-beta1-PMO treatment of diabetic CD34(+) cells resulted in increased expression of CXCR4, enhanced survival in the absence of growth factors, and increased migration and NO release as compared with cells treated with control PMO. Using a retinal ischemia reperfusion injury model in mice, we observed that recruitment of diabetic CD34(+) cells to injured acellular retinal capillaries was greater after TGF-beta1-PMO treatment compared with control PMO-treated cells.
Conclusions:
Transient inhibition of TGF-beta1 may represent a promising therapeutic strategy for restoring the reparative capacity of dysfunctional diabetic CD34(+) cells.
Insights
Transiently inhibiting transforming growth factor-beta1 (TGF-beta1) in diabetic CD34(+) cells improved their vascular repair functions. This approach enhanced cell migration, nitric oxide release, and in vivo retinal repair capabilities.
Area of Science:
- Stem cell biology
- Diabetic vascular complications
- Regenerative medicine
Background:
- Diabetic CD34(+) cells exhibit impaired vascular repair due to reduced nitric oxide (NO) bioavailability and migration.
- Increased transforming growth factor-beta1 (TGF-beta1) in type 2 diabetes mellitus (T2DM) serum may contribute to stem cell dysfunction.
Purpose of the Study:
- To investigate if transient inhibition of TGF-beta1 in CD34(+) cells can restore their vascular reparative function.
- To assess the impact of TGF-beta1 inhibition on diabetic CD34(+) cell migration, survival, and NO release.
Main Methods:
- Ex vivo treatment of diabetic CD34(+) cells with TGF-beta1 antisense phosphorodiamidate morpholino oligomers (TGF-beta1-PMOs).
- Analysis of cell surface CXCR4 expression, cell survival, SDF-1-induced migration, and NO release.
- Evaluation of in vivo retinal vascular reparative ability using a mouse ischemia-reperfusion injury model.
Main Results:
- TGF-beta1-PMO treatment increased CXCR4 expression, cell survival, migration, and NO release in diabetic CD34(+) cells compared to controls.
- Diabetic CD34(+) cells treated with TGF-beta1-PMOs showed enhanced recruitment to injured retinal capillaries in vivo.
Conclusions:
- Transient TGF-beta1 inhibition effectively restores the reparative capacity of dysfunctional diabetic CD34(+) cells.
- This strategy holds promise for therapeutic interventions in diabetic vascular complications.
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