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

Autor: Shawn Loder, Joe Nguyen, Paul H. Krebsbach, Michael T. Chung, Caitlin Priest, Kenneth D. Westover, Benjamin Levi, Shuli Li, Yashar S. Niknafs, Greg Scott, David Cholok, Kavitha Ranganathan, Arminder Kaura, John Li, Maiko Inagaki, Cameron Brownley, Jonathan Butts, Joe Habbouche, Jonathan Reimer, Jonathan R. Peterson, James Drake, Shailesh Agarwal, Jun Ninomiya-Tsuji, Nathanael S. Gray, Serra Ucer Ozgurel, Yuji Mishina, Hsiao Hsin Sung Hsieh, Christopher Breuler, Michael T. Longaker, Kieko Kaneko, Amanda K. Huber
Rok vydání: 2018
Předmět:
0301 basic medicine
Male
Technology
Bone Regeneration
Cellular differentiation
Proliferation
Inbred C57BL
Regenerative Medicine
Regenerative medicine
Progenitor cells
Medical and Health Sciences
Transgenic
Extracellular matrix
Fractures
Bone
Mice
0302 clinical medicine
Stem/progenitor cell
media_common
Cell Differentiation
Biological Sciences
MAP Kinase Kinase Kinases
Founder Effect
Differentiation
DNA Nucleotidyltransferases
Cellular proliferation
Molecular Medicine
Female
Stem cell
Signal Transduction
Drug
progenitor cell
media_common.quotation_subject
Immunology
Primary Cell Culture
Mice
Transgenic
Biology
Stem
Article
03 medical and health sciences
Animals
Progenitor cell
Bone
Protein Kinase Inhibitors
Cell Proliferation
Wound Healing
Osteoblasts
Integrases
Skull
Mesenchymal Stem Cells
Cell Biology
Stem Cell Research
Mice
Inbred C57BL
030104 developmental biology
Good Health and Well Being
Gene Expression Regulation
Musculoskeletal
Cancer research
Tissue regeneration
Wound healing
Fractures
030217 neurology & neurosurgery
Developmental Biology
Transforming growth factor
Zdroj: Stem Cells
Stem cells (Dayton, Ohio), vol 37, iss 6
ISSN: 1549-4918
Popis: 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
Databáze: OpenAIRE
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