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Coordinating Tissue Regeneration Through Transforming Growth Factor-ß 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.
Afiliação
  • Hsieh HHS; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Agarwal S; School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA.
  • Cholok DJ; Experimental Rheumatology Department, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Loder SJ; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Kaneko K; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Huber A; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Chung MT; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Ranganathan K; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Habbouche J; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Li J; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Butts J; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Reimer J; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Kaura A; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Drake J; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Breuler C; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Priest CR; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Nguyen J; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Brownley C; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Peterson J; School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA.
  • Ozgurel SU; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Niknafs YS; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Li S; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Inagaki M; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Scott G; Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
  • Krebsbach PH; Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina, USA.
  • Longaker MT; Knock Out Core, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
  • Westover K; Section of Periodontics, UCLA School of Dentistry, Los Angeles, California, USA.
  • Gray N; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
  • Ninomiya-Tsuji J; Department of Biochemistry, University of Texas Southwestern, Dallas, Texas, USA.
  • Mishina Y; Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Levi B; Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina, USA.
Stem Cells ; 37(6): 766-778, 2019 06.
Article em En | MEDLINE | ID: mdl-30786091
ABSTRACT
Aberrant wound healing presents as inappropriate or insufficient tissue formation. Using a model of musculoskeletal injury, we demonstrate that loss of transforming growth factor-ß 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;37766-778.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Osteoblastos / Cicatrização / Regeneração Óssea / MAP Quinase Quinase Quinases / Fraturas Ósseas / Células-Tronco Mesenquimais Idioma: En Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Osteoblastos / Cicatrização / Regeneração Óssea / MAP Quinase Quinase Quinases / Fraturas Ósseas / Células-Tronco Mesenquimais Idioma: En Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos