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A High-content In Vitro Pancreatic Islet β-cell Replication Discovery Platform
Published on: July 16, 2016
Inhibition of TGF-β Signaling Promotes Human Pancreatic β-Cell Replication
Sangeeta Dhawan1, Ercument Dirice2, Rohit N Kulkarni2
1Division of Endocrinology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA.
Abstract:
Diabetes is associated with loss of functional pancreatic β-cells, and restoration of β-cells is a major goal for regenerative therapies. Endogenous regeneration of β-cells via β-cell replication has the potential to restore cellular mass; however, pharmacological agents that promote regeneration or expansion of endogenous β-cells have been elusive. The regenerative capacity of β-cells declines rapidly with age, due to accumulation of p16(INK4a), resulting in limited capacity for adult endocrine pancreas regeneration. Here, we show that transforming growth factor-β (TGF-β) signaling via Smad3 integrates with the trithorax complex to activate and maintain Ink4a expression to prevent β-cell replication. Importantly, inhibition of TGF-β signaling can result in repression of the Ink4a/Arf locus, resulting in increased β-cell replication in adult mice. Furthermore, small molecule inhibitors of the TGF-β pathway promote β-cell replication in human islets transplanted into NOD-scid IL-2Rg(null) mice. These data reveal a novel role for TGF-β signaling in the regulation of the Ink4a/Arf locus and highlight the potential of using small molecule inhibitors of TGF-β signaling to promote human β-cell replication.
Insights
Inhibiting TGF-β signaling promotes pancreatic beta cell replication by reducing p16(INK4a) expression. This finding offers a new therapeutic strategy for diabetes by enhancing beta cell regeneration.
Area of Science:
- Endocrinology
- Molecular Biology
- Regenerative Medicine
Background:
- Diabetes mellitus is characterized by the loss of functional pancreatic beta cells.
- Restoring beta cell mass is a key objective for diabetes regenerative therapies.
- Beta cell regeneration capacity diminishes with age due to p16(INK4a) accumulation, limiting endogenous repair.
Purpose of the Study:
- To investigate the role of transforming growth factor-beta (TGF-β) signaling in regulating beta cell replication.
- To identify pharmacological strategies for promoting beta cell regeneration in diabetes.
Main Methods:
- Examined the interaction of TGF-β signaling (via Smad3) with the trithorax complex in regulating Ink4a expression.
- Utilized small molecule inhibitors of TGF-β pathway in adult mice and human islet transplantation models.
- Assessed beta cell replication rates following TGF-β pathway inhibition.
Main Results:
- TGF-β signaling activates and maintains Ink4a expression, suppressing beta cell replication.
- Inhibition of TGF-β signaling represses the Ink4a/Arf locus, leading to increased beta cell replication in adult mice.
- Small molecule TGF-β inhibitors promoted beta cell replication in human islets xenografted into immunodeficient mice.
Conclusions:
- TGF-β signaling plays a critical role in suppressing the Ink4a/Arf locus, thereby limiting beta cell proliferation.
- Inhibiting TGF-β signaling represents a promising therapeutic avenue for promoting human beta cell replication and potentially treating diabetes.
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