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Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling
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Coordinating Tissue Regeneration Through Transforming Growth Factor-β Activated Kinase 1 Inactivation and

Hsiao Hsin Sung Hsieh1,2,3, Shailesh Agarwal1, David J Cholok1

  • 1Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.

Stem Cells (Dayton, Ohio)
|February 21, 2019
PubMed

Insights

Aberrant wound healing can be improved by controlling transforming growth factor-β activated kinase 1 (TAK1) signaling. A new mouse model demonstrates that coordinated TAK1 inactivation and reactivation promotes tissue regeneration.

Area of Science:

  • Regenerative Medicine
  • Molecular Biology
  • Tissue Engineering

Background:

  • Aberrant wound healing involves improper tissue formation, either excessive or insufficient.
  • Transforming growth factor-β activated kinase 1 (TAK1) signaling influences cellular differentiation and tissue development.
  • Current regenerative medicine strategies primarily focus on drug administration, neglecting the impact of drug withdrawal.

Purpose of the Study:

  • To investigate the role of TAK1 signaling in tissue regeneration.
  • To develop a model for studying the dynamic effects of drug treatment and withdrawal in regenerative therapy.
  • To explore a coordinated approach of TAK1 inactivation and reactivation for enhanced tissue repair.

Main Methods:

  • Utilized a dual-inducible COmbinational Sequential Inversion ENgineering (COSIEN) mouse model for temporal control of gene function.
  • Genetically inactivated and reactivated Tak1 signaling in a calvarial defect model.
  • Assessed tissue formation, cellular differentiation, and proliferation in response to TAK1 modulation.

Main Results:

  • Loss of TAK1 signaling reduced heterotopic ossification (inappropriate tissue formation) by decreasing cellular differentiation.
  • Loss of TAK1 signaling increased cellular proliferation.
  • Coordinated inactivation and reactivation of TAK1 promoted tissue regeneration in a calvarial defect model.

Conclusions:

  • TAK1 signaling plays a critical role in regulating tissue formation during wound healing.
  • A regenerative strategy involving sequential inactivation and reactivation of TAK1 can enhance tissue repair.
  • The COSIEN mouse model provides a valuable platform for studying "drug on" and "drug off" dynamics in targeted therapies.
Keywords:
Cellular proliferationDifferentiationProgenitor cellsProliferationStem/progenitor cellTissue regeneration

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