Coordinating Tissue Regeneration Through Transforming Growth Factor-β Activated Kinase 1 Inactivation and Reactivation

Hsiao Hsin Sung Hsieh, Shailesh Agarwal, David J. Cholok, Shawn J. Loder, Kieko Kaneko, Amanda Huber, Michael T. Chung, Kavitha Ranganathan, Joe Habbouche, John Li, Jonathan Butts, Jonathan Reimer, Arminder Kaura, James Drake, Christopher Breuler, Caitlin R. Priest, Joe Nguyen, Cameron Brownley, Jonathan Peterson, Serra Ucer OzgurelYashar S. Niknafs, Shuli Li, Maiko Inagaki, Greg Scott, Paul H. Krebsbach, Michael T. Longaker, Kenneth Westover, Nathanael Gray, Jun Ninomiya-Tsuji, Yuji Mishina*, Benjamin Levi

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Aberrant wound healing presents as inappropriate or insufficient tissue formation. Using a model of musculoskeletal injury, we demonstrate that loss of transforming growth factor-β activated kinase 1 (TAK1) signaling reduces inappropriate tissue formation (heterotopic ossification) through reduced cellular differentiation. Upon identifying increased proliferation with loss of TAK1 signaling, we considered a regenerative approach to address insufficient tissue production through coordinated inactivation of TAK1 to promote cellular proliferation, followed by reactivation to elicit differentiation and extracellular matrix production. Although the current regenerative medicine paradigm is centered on the effects of drug treatment (“drug on”), the impact of drug withdrawal (“drug off”) implicit in these regimens is unknown. Because current TAK1 inhibitors are unable to phenocopy genetic Tak1 loss, we introduce the dual-inducible COmbinational Sequential Inversion ENgineering (COSIEN) mouse model. The COSIEN mouse model, which allows us to study the response to targeted drug treatment (“drug on”) and subsequent withdrawal (“drug off”) through genetic modification, was used here to inactivate and reactivate Tak1 with the purpose of augmenting tissue regeneration in a calvarial defect model. Our study reveals the importance of both the “drug on” (Cre-mediated inactivation) and “drug off” (Flp-mediated reactivation) states during regenerative therapy using a mouse model with broad utility to study targeted therapies for disease. Stem Cells 2019;37:766–778.

Original languageEnglish
Pages (from-to)766-778
Number of pages13
JournalStem Cells
Issue number6
StatePublished - Jun 2019
Externally publishedYes


  • Cellular proliferation
  • Differentiation
  • Progenitor cells
  • Proliferation
  • Stem/progenitor cell
  • Tissue regeneration


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