Salma A. Abdou

Microenvironmental cues enhance mesenchymal stem cell-mediated immunomodulation and regulatory T-cell expansion

Mesenchymal stem cells (MSCs) are known to both have powerful immunosuppressive properties and promote allograft tolerance. Determining the environmental oxygen tension and inflammatory conditions under which MSCs are optimally primed for this immunosuppressive function is essential to their utilization in promoting graft tolerance. Of particular interest is the mechanisms governing the interaction between MSCs and regulatory T cells (Tregs), which is relatively unknown. We performed our experiments utilizing rat bone marrow derived MSCs. We observed that priming MSCs in hypoxia promotes maintenance of stem-like characteristics, with greater expression of typical MSC cell-surface markers, increased proliferation, and maintenance of differentiation potential. Addition of autologous MSCs to CD4+/allogeneic endothelial cell (EC) co-culture increases regulatory T cell (Treg) proliferation, which is further enhanced when MSCs are primed in hypoxia. Furthermore, MSC-mediated Treg expansion does not require direct cell-cell contact. The expression of indolamine 2,3-dioxygenase, a mediator of MSC immunomodulation, increases when MSCs are primed in hypoxia, and inhibition of IDO significantly decreases the expansion of Tregs. Priming with inflammatory cytokines IFNγ and TNFα increases also expression of markers associated with MSC immunomodulatory function, but decreases MSC proliferation. The expression of IDO also increases when MSCs are primed with inflammatory cytokines. However, there is no increase in Treg expansion when MSCs are primed with IFNγ, suggesting an alternate mechanism for inflammatory-stimulated MSC immunomodulation. Overall, these results suggest that MSCs primed in hypoxia or inflammatory conditions are optimally primed for immunosuppressive function. These results provide a clearer picture of how to enhance MSC immunomodulation for clinical use.

Targeted Nrf2 activation therapy with RTA 408 enhances regenerative capacity of diabetic wounds

AIMSnThough unmitigated oxidative stress in diabetic chronic non-healing wounds poses a major therapeutic challenge, currently, there are no effective pharmacological agents. We targeted the cytoprotective Nrf2/Keap1 pathway, which is dysfunctional in diabetic skin and the regenerative environment in the diabetic wound. We assessed the efficacy of a potent Nrf2-activator, RTA 408, a semi-synthetic oleanane triterpenoid, on accelerating diabetic wound healing.nnnMETHODSnUsing Leprdb/dbmice, we made 10u202fmm-diameter excisional humanized wounds in dorsal skin. We administered RTA 408 formulations daily, and used ANOVA for comparison of time to closure, in vivo real-time ROS, histology, molecular changes.nnnRESULTSnWe found that RTA 408, specifically a 0.1% formulation, significantly reduced wound healing time and increased wound closure rate. While either systemic or topical administration of RTA 408 is effective, wound closure time with the latter was far superior. RTA 408-treated diabetic wounds upregulated Nrf2 and downstream antioxidant genes, and exhibited well-vascularized granulation tissue that aided in re-epithelialization. Reintroduction of redox mechanisms via RTA 408-induced Nrf2 resulted in reduction of the oxidative status of wounds, to coordinate successful wound closure.nnnCONCLUSIONSnThis preclinical study shows that promoting Nrf2-mediated antioxidant activity in the localized regenerative milieu of a diabetic wound markedly improves the molecular and cellular composition of diabetic wound beds. RTA 408 treats and corrects the irregularity in redox balance mechanisms involving Nrf2, in an avenue not explored previously for treatment of diabetic wounds and tissue regeneration. Our study supports development of RTA 408 as a therapeutic modality for chronic diabetic wounds.

Lower Eyelid Blepharoplasty: Does the Literature Support the Longevity of This Procedure?

BackgroundnLower eyelid blepharoplasty has continued to evolve with ongoing debate regarding optimal techniques. Despite large case series publishing excellent results and minimal complications, the true longevity of these procedures remains unclear.nnnObjectivesnThe aim of this study was to determine how thoroughly the aesthetic surgery literature assesses the longevity of lower blepharoplasty.nnnMethodsnA 20-year comprehensive literature review from 1997 to 2017 was conducted. The titles and abstracts of 180 articles were reviewed, yielding 86 potential publications; 49 studies met inclusion criteria and were analyzed.nnnResultsnA total of 10,698 patients were included for analysis. Reported follow-up ranged between 1 week and 192 months. Mean follow-up was 14.8 months for the 29 studies (59.2%) that reported these data. Pooled analysis of complication rates demonstrated 0.77% (n = 82) reoperation, 0.37% (n = 39) scleral show, 0.25% (n = 27) lid malposition, and 0.24% (n = 25) ectropion rates, among others. Forty-four studies (89.8%) published postoperative photographs with a total of 141 unique postoperative time points that were supported with photographic evidence (mean: 15.3 months; range: 1 week-192 months). In this series, for only 10 patients (0.094%) were postoperative photographs available at time points beyond 24 months.nnnConclusionsnLower eyelid blepharoplasty is a powerful procedure with seemingly minimal morbidity despite its technical demands. The longevity of this procedure is poorly supported with photographic evidence in the literature. Studies do not adequately report or represent their follow-up to capture long-lasting results. Standardized reporting of results is needed to ensure that anyone seeking this treatment can be adequately counseled.nnnLevel of Evidence 4