Ko, Kang I
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Publication The Dual Roles of NF-kB Activation in Prx1+ Mesenchymal Cells in Health and Disease(2020-11-11) Ko, Kang INuclear factor kappa-B (NF-kB) was discovered in 1986 and has since been studied extensively for its role as a master inflammatory transcription factor. As inflammation is critical for normal immune response but its chronic presence can be detrimental under pathological conditions, I sought to investigate the role of NF-kB in mesenchymal tissues under diabetic and homeostatic conditions. Aberrant activation of NF-kB and chronic inflammation have been documented in diabetic complications of kidney, eyes and cardiovascular system. Here I found that experimental type 1 diabetes caused hyperactivation of NF-kB in skeletal stem cells (SSCs) in the long bones of mice. Deletion of Ikkb, an activator of canonical NF-kB pathway, in Prx1+ (Paired Related Homeobox 1) SSCs prevented NF-kB activity and reversed the effect of diabetes on SSC apoptosis and anti-proliferation. In addition, it rescued the immuno-regulatory property of SSCs by transforming growth factor beta-1 (TGFb1), which in turn promoted macrophage polarization towards pro-resolving phenotype. These findings point to a detrimental role of NF-kB under pathologic condition such as type 1 diabetes. Surprisingly, I observed that NF-kB inactivation in Prx1+ cells caused hyper-inflammation and skin lesion that progressed with aging. The location of lesion was specific to ventral skin, consistent with the pattern of Prx1+ expression in mesenchyme derived from embryonic lateral plate mesoderm. Ikkb deletion in Col1a2Cre+ skin fibroblasts, but not Adipoq-Cre+ mature adipocytes, was sufficient to cause local inflammation but not in spleen or bone marrow. Single cell RNA sequencing analysis revealed an immune response that was characterized by an exaggerated inflammatory macrophage and type 2 T cell responses in the experimental animals. Furthermore, Prx1+ fibroblasts that had Ikkb deletion overexpressed CCL11 (also known as eotaxin-1), a potent chemoattractant for eosinophils. These results indicate Ikkb-NFkB activity in fibroblasts as an important contributor of immune homeostasis against an inflammatory response that mirrors the signs of atopic dermatitis. Thus, Ikkb-NFkB exhibits dual and opposing roles in Prx1+ mesenchymal cells where it is critical for homeostasis in dermal immunity, but it is detrimental in diabetic bone healing. These differential responses may be explained by the healthy or diseased status and/or by the niche-specific role of Prx1+ cells.Publication Molecular and functional heterogeneity and identification of fibroblasts(2024-06-28) Ko, Annette; Sahingur, Sinem Esra; Chang, Yu-Cheng; Ko, Kang I; Korostoff, Johnathan M; Chang, Yu-ChengIntroduction: Oral wounds heal with exceptional regenerative capacity, which contrasts skin wound repair. Paired related homeobox 1 (Prrx1) is a marker for mesenchymal progenitors in bone, and recent studies have demonstrated presence and functional significance of Prrx1+ fibroblasts in dermis. Our previous findings suggest pro-healing role of Prrx1+ oral fibroblasts in mouse model, thus we sought to examine equivalent Prrx1+ cells using human gingival tissue biopsies. Here, we hypothesize that human Prrx1+ fibroblasts reside in different oral gingival tissues and that they exhibit enhanced regenerative potential for wound healing. Methods: Human gingival samples were collected from the anterior rugae, healed sites (distal wedge, edentulous crest), and tooth-associated sites (marginal gingiva from crown lengthening procedure or osseous surgery) in accordance to approved IRB protocol. The tissues were processed in paraffin-embedded block and sectioned at 5um. Immunofluorescence staining was performed with antibodies against Prrx1 and vimentin to detect Prrx1+ oral fibroblasts in various oral anatomic sites. Image analysis was carried out by counting spindle-shaped vimentin+ and Prrx1+ cells in lamina propria, normalized by area (mm2). To examine the regenerative potential of Prrx1+ cells in oral tissues, human anterior rugae samples were collected and processed for single-cell RNA sequencing (scRNA-seq). Transcriptomic analysis was performed after combining with the public scRNA-seq data (GEO: GSE164241, GSE152042). Results: Prrx1+ fibroblasts were present throughout all types of oral soft tissues. Anterior palate tissue had 72% fibroblasts expressing Prrx1, which was significantly more than those found in distal wedge, crestal tissue and marginal gingivae (39%, 30%, 26%, respectively; P<0.05) in the reticular layer of lamina propria and submucosa. ScRNA-seq analysis of the combined data demonstrated upregulation of several WNT-associated genes in Prx1+ fibroblasts, such as SFRP1 and SLPI, which had previously been reported to be involved in stem cell function and regeneration. The transcriptomic analysis further revealed that Prx1+ fibroblasts exhibit progenitor phenotype with projected differentiation trajectory toward chemotactic fibroblasts and expedited wound healing potential via immunomodulation in innate immune response. Further characterization of these inflammatory fibroblasts showed high expression of intercellular adhesion molecule-1 (ICAM-1), suggesting its potential usage as a surface marker for identification. Conclusion: Our results demonstrate that human Prrx1+ oral fibroblasts reside in the deep layer of the lamina propria, particularly in the anterior palate at higher frequency compared to other anatomic sites. These fibroblasts may exhibit improved regenerative potential via modulating WNT-associated pathway and rapid resolution of inflammation. The findings provide new insight into the enhanced healing potential of oral fibroblast subpopulations that may contribute to developing surgical techniques targeted to improve unpredictable soft tissue augmentation.