2019 journal article
Coordinating Tissue Regeneration Through Transforming Growth Factor-beta Activated Kinase 1 Inactivation and Reactivation
STEM CELLS, 37(6), 766–778.
author keywords: Cellular proliferation; Differentiation; Progenitor cells; Proliferation; Stem; progenitor cell; Tissue regeneration
MeSH headings : Animals; Bone Regeneration / drug effects; Bone Regeneration / genetics; Cell Differentiation / drug effects; Cell Proliferation / drug effects; DNA Nucleotidyltransferases / genetics; DNA Nucleotidyltransferases / metabolism; Female; Founder Effect; Fractures, Bone / drug therapy; Fractures, Bone / enzymology; Fractures, Bone / genetics; Fractures, Bone / pathology; Gene Expression Regulation; Integrases / genetics; Integrases / metabolism; MAP Kinase Kinase Kinases / antagonists & inhibitors; MAP Kinase Kinase Kinases / deficiency; MAP Kinase Kinase Kinases / genetics; Male; Mesenchymal Stem Cells / cytology; Mesenchymal Stem Cells / drug effects; Mesenchymal Stem Cells / enzymology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Osteoblasts / cytology; Osteoblasts / drug effects; Osteoblasts / enzymology; Primary Cell Culture; Protein Kinase Inhibitors / pharmacology; Signal Transduction; Skull / drug effects; Skull / injuries; Skull / metabolism; Wound Healing / drug effects; Wound Healing / genetics
TL;DR:
It is demonstrated that loss of transforming growth factor‐β activated kinase 1 (TAK1) signaling reduces inappropriate tissue formation (heterotopic ossification) through reduced cellular differentiation, and the importance of both the “drug on” and "drug off" states during regenerative therapy is revealed.
(via Semantic Scholar)
UN Sustainable Development Goal Categories
3. Good Health and Well-being
(Web of Science; OpenAlex)
Source: Web Of Science
Added: July 22, 2019
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-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