| First Author | Ko KI | Year | 2019 |
| Journal | Diabetes | Volume | 68 |
| Issue | 11 | Pages | 2095-2106 |
| PubMed ID | 31439641 | Mgi Jnum | J:280473 |
| Mgi Id | MGI:6368478 | Doi | 10.2337/db19-0496 |
| Citation | Ko KI, et al. (2019) Diabetes-Induced NF-kappaB Dysregulation in Skeletal Stem Cells Prevents Resolution of Inflammation. Diabetes 68(11):2095-2106 |
| abstractText | 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-kappaB (NF-kappaB) activation in SSCs and substantially enhanced inflammation in vivo. Constitutive or tamoxifen-induced inhibition of NF-kappaB in SSCs rescued the impact of diabetes on inflammation, SSC expansion, and tissue formation. In contrast, NF-kappaB inhibition in chondrocytes failed to reverse the effect of T1D. Mechanistically, diabetes caused defective proresolving macrophage (M2) polarization by reducing TGF-beta1 expression by SSCs, which was recovered by NF-kappaB inhibition or exogenous TGF-beta1 treatment. These data identify an underlying mechanism for altered healing in T1D and demonstrate that diabetes induces NF-kappaB hyperactivation in SSCs to disrupt their ability to modulate M2 polarization and resolve inflammation. |
