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- Title
Diabetes-Induced NF-κB Dysregulation in Skeletal Stem Cells Prevents Resolution of Inflammation.
- Authors
Ko, Kang I.; Syverson, Abby L.; Kralik, Richard M.; Choi, Jerry; DerGarabedian, Brett P.; Chen, Chider; Graves, Dana T.
- Abstract
Type 1 diabetes (T1D) imposes a significant health burden by negatively affecting tissue regeneration during wound healing. The adverse effect of diabetes is attributed to high levels of inflammation, but the cellular mechanisms responsible remain elusive. In this study, we show that intrinsic skeletal stem cells (SSCs), a subset of mesenchymal stem cells, are essential for resolution of inflammation to occur during osseous healing by using genetic approaches to selectively ablate SSCs. T1D caused aberrant nuclear factor-κB (NF-κB) activation in SSCs and substantially enhanced inflammation in vivo. Constitutive or tamoxifen-induced inhibition of NF-κB in SSCs rescued the impact of diabetes on inflammation, SSC expansion, and tissue formation. In contrast, NF-κB inhibition in chondrocytes failed to reverse the effect of T1D. Mechanistically, diabetes caused defective proresolving macrophage (M2) polarization by reducing TGF-β1 expression by SSCs, which was recovered by NF-κB inhibition or exogenous TGF-β1 treatment. These data identify an underlying mechanism for altered healing in T1D and demonstrate that diabetes induces NF-κB hyperactivation in SSCs to disrupt their ability to modulate M2 polarization and resolve inflammation.
- Subjects
STEM cells; TYPE 1 diabetes; MESENCHYMAL stem cells; INFLAMMATION; WOUND healing
- Publication
Diabetes, 2019, Vol 68, Issue 11, p2095
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db19-0496