Open AccessCoordinating Tissue Regeneration Through Transforming Growth Factor‐β Activated Kinase 1 Inactivation and Reactivation
Author(s) -
Hsieh Hsiao Hsin Sung,
Agarwal Shailesh,
Cholok David J.,
Loder Shawn J.,
Kaneko Kieko,
Huber Amanda,
Chung Michael T.,
Ranganathan Kavitha,
Habbouche Joe,
Li John,
Butts Jonathan,
Reimer Jonathan,
Kaura Arminder,
Drake James,
Breuler Christopher,
Priest Caitlin R.,
Nguyen Joe,
Brownley Cameron,
Peterson Jonathan,
Ozgurel Serra Ucer,
Niknafs Yashar S.,
Li Shuli,
Inagaki Maiko,
Scott Greg,
Krebsbach Paul H.,
Longaker Michael T.,
Westover Kenneth,
Gray Nathanael,
NinomiyaTsuji Jun,
Mishina Yuji,
Levi Benjamin
Publication year - 2019
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.2991
Subject(s) - biology , phenocopy , regenerative medicine , regeneration (biology) , microbiology and biotechnology , drug , extracellular matrix , cancer research , drug development , growth factor , stem cell , pharmacology , receptor , genetics , phenotype , gene
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