Coordinating Tissue Regeneration through TGF-beta Activated Kinase 1 (TAK1) In-activation and Re-activation. Stem cells (Dayton, Ohio) Sung Hsieh, H. H., Agarwal, S., Cholok, D. J., Loder, S. J., Kaneko, K., Huber, A., Chung, M. T., Ranganathan, K., Habbouche, J., Li, J., Butts, J., Reimer, J., Kaura, A., Drake, J., Breuler, C., Priest, C. R., Nguyen, J., Brownley, C., Peterson, J., Ozgurel, S. U., Niknafs, Y. S., Li, S., Inagaki, M., Scott, G., Krebsbach, P., Longaker, M. T., Westover, K., Gray, N., Ninomiya-Tsuji, J., Mishina, Y., Levi, B. 2019


Aberrant wound healing presents as inappropriate or insufficient tissue formation. Using a model of musculoskeletal injury, we demonstrate that loss of TGF-beta 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 re-activation to elicit differentiation and extracellular matrix (ECM) production. While 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 are 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 re-activate 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 re-activation) states during regenerative therapy using a mouse model with broad utility to study targeted therapies for disease. SIGNIFICANCE STATEMENT: We target the TAK1 pathway to reduce heterotopic ossification, a pathologic condition in which bone develops within muscle or soft tissues. We show that Tak1 knockout leads to cellular proliferation; this can be harnessed to increase the number of cells present at the injury site. Using a mouse model, we inactivate and reactivate the Tak1 gene. We show that inactivation and reactivation of Tak1 can improve bony healing through the coordination of increased proliferation (inactivation) followed by differentiation (reactivation). This approach elucidates a new paradigm in regenerative medicine in which coordination between treatment and withdrawal of treatment can augment healing. © AlphaMed Press 2019.

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