Coordinating Tissue Regeneration Through Transforming Growth Factorâ β Activated Kinase 1 Inactivation and Reactivation
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; Ninomiya‐tsuji, Jun; Mishina, Yuji; Levi, Benjamin
2019-06
Citation
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; Ninomiya‐tsuji, Jun ; Mishina, Yuji; Levi, Benjamin (2019). "Coordinating Tissue Regeneration Through Transforming Growth Factorâ β Activated Kinase 1 Inactivation and Reactivation." STEM CELLS 37(6): 766-778.
Abstract
Aberrant wound healing presents as inappropriate or insufficient tissue formation. Using a model of musculoskeletal injury, we demonstrate that loss of transforming growth factorâ 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 (â drug onâ ), the impact of drug withdrawal (â drug offâ ) implicit in these regimens is unknown. Because current TAK1 inhibitors are unable to phenocopy genetic Tak1 loss, we introduce the dualâ inducible COmbinational Sequential Inversion ENgineering (COSIEN) mouse model. The COSIEN mouse model, which allows us to study the response to targeted drug treatment (â drug onâ ) and subsequent withdrawal (â drug offâ ) 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 â drug onâ (Creâ mediated inactivation) and â drug offâ (Flpâ mediated reactivation) states during regenerative therapy using a mouse model with broad utility to study targeted therapies for disease. Stem Cells 2019;37:766â 778Manipulating transforming growth factor βâ activated kinase 1 for cell and scaffold free tissue regeneration using a dualâ inducible Combinational Sequential Inversion Engineering mouse model.Publisher
John Wiley & Sons, Inc.
ISSN
1066-5099 1549-4918
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