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Title: Dissecting the role of apolipoprotein CIII in diabetic wound healing
Authors: Cho Mar Myint Wai
Keywords: DRNTU::Science::Medicine
Issue Date: 2019
Source: Cho Mar Myint Wai. (2019). Dissecting the role of apolipoprotein CIII in diabetic wound healing. Doctoral thesis, Nanyang Technological University, Singapore.
Abstract: The overarching aim of this thesis is to determine whether ApoCIII plays any role in diabetic wounds. We first determined ApoCIII levels in Asian diabetic serum and compared to our values to Caucasian counterparts. We next studied the role of ApoCIII in the skin and finally our mechanistic pursuit led us to study its putative binding partner (i.e. Toll-Like Receptors) in the pancreatic islet, the latter being an mini-organ that functionally responds to exogenously added ApoCIII. For our first aim, we determined APOCIII levels in a Singapore-based cohort of healthy, type-1 and type-2 diabetics (obtained through courtesy of local biobanks) and found no significant difference in serum APOCIII levels. Our ApoCIII serum values for healthy individuals were different from published values leading us to speculate that for APOCIII determination fresh serum samples are perhaps required. Nonetheless, as elevated APOCIII levels were reported in diabetics, and as the role of lipoproteins in the skin remains relatively unknown, we decided to determine the role of ApoCIII on wound healing. We sought to determine the role of ApoCIII during wound healing in healthy and diabetic states. We hypothesized that elevated levels of ApoCIII at the wound site delays wound healing and that this delay is exacerbated in diabetic wounds. In this study, we provided evidence that ApoCIII delays keratinocyte (HaCaT cells) migration in vitro through a yet undefined process that may involve changes in gene expression of pro-inflammatory cytokines and ECM depositing genes. ApoCIII was found to be expressed in the skin of healthy and diabetic mice In addition, ApoCIII expression was observed to be elevated in the wounds and its expression was highest around the wound edges. Given the increased levels of ApoCIII in wounds compared to intact skin and our in vitro observations that APOCIII hinders keratinocyte migration, we proceeded to knockdown ApoCIII at the wound site by topical application of ApoCIII-antisense oligonucleotide (ASO) at wound site. ApoCIII-ASO treatment significantly improved percent wound closure by 87.44% (± 2.1%) compared to control wounds (74.13% ± 4.8%) in healthy mice at day 9 post-wounding. The observed higher rate of wound closure was corroborated with histology showing improved epithelialization and dermal collagen formation compared to control-treated wounds. The benefit of ApoCIII-ASO was also seen in the excisional wounds of type-2 diabetic mice (db/db). In diabetic mice, topical application of ApoCIII-ASO at the same dose and time as in healthy mice, significantly improved wound closure by 90.78 (± 3.2%) at day 16 post wounding compared to adjacent control-treated wounds (70.54 ± 4.8%). Similar to healthy mice, histological examination also showed improved epithelialization and dermal collagen maturation in ApoCIII-ASO treated wounds. Taken together, the results here suggest that ApoCIII is expressed in the skin and that treatment with ApoCIII-ASO alters the wound healing process in vivo. This opens the possibility of targeting ApoCIII at the wound site to improve healing, with particular consideration for diabetic non-healing wounds.
DOI: 10.32657/10220/48515
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:IGS Theses

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