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Published on: June 30, 2017
Activation of the PDGFRα-Nrf2 pathway mediates impaired adipocyte differentiation in bone marrow mesenchymal stem
1Division of Experimental Medicine, Department of Medicine, McGill University and The Research Institute of McGill University Health Centre, Montreal, QC, H4A 3J1, Canada.
Background:
The limited options to treat obesity and its complications result from an incomplete understanding of the underlying molecular mechanisms regulating white adipose tissue development, including adipocyte hypertrophy (increase in size) and hyperplasia (increase in number through adipogenesis). We recently demonstrated that lack of the adaptor protein Nck1 in mice is associated with reduced adiposity and impaired adipocyte differentiation. In agreement, Nck1 depletion in 3 T3-L1 cells also attenuates adipocyte differentiation by enhancing PDGFRα activation and signaling. This is accompanied by higher expression of PDGF-A, a specific PDGFRα ligand, that may contribute to enhanced activation of PDGFRα signaling in the absence of Nck1 in white adipose tissue. However, whether Nck1 deficiency also impairs adipogenic differentiation in bone marrow still remains to be determined.
Methods:
To address this point, Nck1-deficient derived bone marrow mesenchymal stem/stromal cells (BM-MSCs) and C3H10T1/2 mesenchymal stem cells were differentiated into adipocytes in vitro. Genes and proteins expression in these cellular models were determined using qPCR and western blotting respectively. Pharmacological approaches were used to assess a role for Nrf2 in mediating Nck1 deficiency effect on mesenchymal stem cells adipocyte differentiation.
Results:
Nck1 deficiency in both BM-MSCs and C3H10T1/2 results in impaired adipocyte differentiation, accompanied by increased activation of the transcription factor Nrf2, as shown by increased mRNA levels of Nrf2 target genes, including PDGF-A. Using pharmacological activator and inhibitor of Nrf2, we further provide evidence that Nrf2 is an important player in PDGFRα signaling that mediates expression of PDGF-A and impaired adipogenesis in Nck1-deficient BM-MSCs and C3H10T1/2 cells.
Conclusion:
This study demonstrates that Nck1 deficiency in mesenchymal stem cells impairs adipogenesis through activation of the PDGFRα-Nrf2 anti-adipogenic signaling pathway. Video Abstract.
Insights
Nck1 deficiency impairs adipogenesis in mesenchymal stem cells by activating the PDGFRα-Nrf2 pathway. This finding offers new insights into obesity treatments by targeting this signaling cascade for therapeutic intervention.
Area of Science:
- Cell Biology
- Molecular Biology
- Obesity Research
Background:
- Limited treatment options for obesity stem from incomplete understanding of white adipose tissue development.
- Nck1 deficiency in mice and 3T3-L1 cells reduces adiposity and impairs adipocyte differentiation.
- Nck1 depletion enhances PDGFRα signaling and PDGF-A expression, contributing to impaired adipogenesis.
Purpose of the Study:
- To investigate the role of Nck1 deficiency in adipogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs).
- To elucidate the molecular mechanisms underlying Nck1's effect on adipogenesis in mesenchymal stem cells.
Main Methods:
- In vitro differentiation of Nck1-deficient BM-MSCs and C3H10T1/2 cells into adipocytes.
- Gene and protein expression analysis using qPCR and western blotting.
- Pharmacological assessment of Nrf2's role in Nck1 deficiency-mediated adipogenesis.
Main Results:
- Nck1 deficiency impaired adipocyte differentiation in both BM-MSCs and C3H10T1/2 cells.
- Increased activation of the transcription factor Nrf2 was observed in Nck1-deficient cells.
- Nrf2 mediates PDGFRα signaling, leading to PDGF-A expression and impaired adipogenesis.
Conclusions:
- Nck1 deficiency impairs mesenchymal stem cell adipogenesis via the PDGFRα-Nrf2 anti-adipogenic signaling pathway.
- This study identifies a novel molecular mechanism linking Nck1, PDGFRα, and Nrf2 in adipogenesis regulation.
