Inflammation and Toll-like receptor ligation differentially affect the osteogenic potential of human mesenchymal stromal cells depending on their tissue origin

Mesenchymal stromal cells (MSCs) can be isolated not only from bone marrow (BM) but also from other tissues, including adipose tissue (AT) and umbilical cord Wharton's Jelly (WJ). Thanks to their ability to differentiate into various cell types, MSC are considered attractive candidates for cell-based regenerative therapy. In degenerative clinical settings, inflammation or infection is often involved. In the present work, we hypothesized that an inflammatory environment and/or Toll-like receptor (TLR) ligation could affect the MSC differentiation potential. MSC were isolated from BM, AT, and WJ. Inflammation was mimicked by a cytokine cocktail, and TLR activation was induced through TLR3 and TLR4 ligation. Osteogenesis was chosen as a model for differentiation. Osteogenic parameters were evaluated by measuring Ca2+ deposits and alkaline phosphatase (ALP) activity at day 7, 14, and 21 of the culture in an osteogenic medium. Our results show that WJ-MSC exhibit a much lower osteogenic potential than the other two MSC types. However, inflammation was able to strongly increase the osteogenic differentiation of WJ-MSC as calcification, and ALP activity appeared as early as day 7. However, this latter enzymatic activity remained much lower than that disclosed by BM-MSC. TLR3 or TLR4 triggering increased the osteogenesis in AT- and, to lesser extent, in BM-MSC. In conclusion, WJ-MSC constitutively disclose a lower osteogenic potential as compared with BM and AT-MSC, which is not affected by TLR triggering but is strongly increased by inflammation, then reaching the level of BM-MSC. These observations suggest that WJ-MSC could constitute an alternative of BM-MSC for bone regenerative applications, as WJ is an easy access source of large amounts of MSC that can effectively differentiate into osteoblasts in an inflammatory setting.     

Rational design of 4-aryl-1,2,3-triazoles for indoleamine 2,3-dioxygenase 1 inhibition

Indoleamine 2,3-dioxygenase 1 (IDO1) is an important therapeutic target for the treatment of diseases such as cancer that involve pathological immune escape. Starting from the scaffold of our previously discovered IDO1 inhibitor 4-phenyl-1,2,3-triazole, we used computational structure-based methods to design more potent ligands. This approach yielded highly efficient low molecular weight inhibitors, the most active being of nanomolar potency both in an enzymatic and in a cellular assay, while showing no cellular toxicity and a high selectivity for IDO1 over tryptophan 2,3-dioxygenase (TDO). A quantitative structure-activity relationship based on the electrostatic ligand-protein interactions in the docked binding modes and on the quantum chemically derived charges of the triazole ring demonstrated a good explanatory power for the observed activities.     

Three cases of post-cataract surgery endophthalmitis due to Rhizobium (Agrobacterium) radiobacter

We present three unrelated post-cataract surgery endophthalmitis cases caused by Rhizobium radiobacter, hospitalized in three different hospitals. Early diagnosis was obtained in two cases by bacterial DNA detection in vitreous samples. All patients recovered from infection, but pars plana vitrectomy was needed in two patients due to rapid clinical deterioration.     

Long-term anatomical and functional outcomes of idiopathic macular hole surgery. The yield of spectral-domain OCT combined with microperimetry

Background

To evaluate the correlations between anatomical and functional changes studied with microperimetry (MPM) and spectral-domain OCT (SD-OCT) in patients after successful repair of idiopathic macular hole (MH).

Methods

Monocentric, retrospective, interventional study in 23 eyes of 23 patients who underwent successful surgery for MH defined as closure of the hole, at least 1 year before. Reported data were pre- and postoperative best-corrected visual acuity (BCVA), retinal sensitivity values on MPM, macular and foveal thicknesses, and retinal anatomic lesions on SD-OCT.

Results

Macular sensitivity (MS) and foveal sensitivity (FS) were lower and the number of lesions of the outer retinal layers was higher in patients with a poorer postoperative VA (P?=?0.029, P?=?0.011 and P?=?0.003 respectively). Preoperative MH size was lower and MS and FS were better in patients with a preserved junction line between the inner and outer segments of photoreceptors (IS/OS) (P?=?0.045, P?=?0.001, and P?=?0.001 respectively). Better postoperative VA was correlated with better preoperative VA (P?=?0.012, r?=?0.513). Postoperative VA was correlated with MS and FS (P?=?0.032, r?=?0.449, and P?=?0.019, r?=?0.483 respectively). Greater foveal thickness was associated with better postoperative VA (P?=?0.020, r?=?0.482).

Conclusion

Postoperative outer retinal layer integrity is associated with better final retinal sensitivity. Further studies are warranted to assess the role of SD-OCT and microperimetry in the pre- and postoperative evaluation of idiopathic macular holes.     

Efficacy of a 2-month dietary supplementation with polyunsaturated fatty acids in dry eye induced by scopolamine in a rat model

Background  This study was conducted to evaluate the efficacy of dietary n-6 and n-3 polyunsaturated fatty acids (PUFAs) in dry eye in a rat model. Methods  Female Lewis rats were fed with diets containing (1) γ-linolenic acid (GLA), (2) eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), or (3) GLA + EPA + DHA, for 2 months before the induction of dry eye using a continuous delivery of scopolamine and during scopolamine treatment. Two, 10 and 28 days after dry-eye induction, clinical signs of corneal dryness were evaluated in vivo using fluorescein staining. MHC II expression and mucin rMuc5AC production in the conjunctival epithelium were evaluated by immunostaining. Lipids and prostaglandins (PGs) E₁ and E₂ were analysed from the exorbital lacrimal gland (LG). Results  Dietary PUFAs minimised the occurrence of corneal keratitis 28 days after induction of dry eye. The decrease in mucin production observed on the conjunctival epithelium was partially prevented by EPA + DHA supplementation after 2 days of scopolamine treatment, as well as by GLA and GLA + EPA + DHA diets after 10 days of treatment. The overexpression of MHC II in the conjunctival epithelium caused by dry eye induction was significantly reduced only with the GLA + EPA + DHA diet after 28 days of treatment. Dietary PUFAs were incorporated into phospholipids of the exorbital LG. Induction of dry eye was associated with a significant increase in PGE₁ and PGE₂ levels in the exorbital LG, which was inhibited by dietary EPA + DHA at 10 days (for PGE₂) and 28 days (for PGE₁). Conclusions  Dietary GLA, EPA and DHA significantly interfered with lipid homeostasis in the exorbital LG and partially prevented the course of dry eye. In particular, our results demonstrate the efficacy of the combination of n-6 and n-3 PUFAs. Support: Regional Council of Burgundy (Dijon, France) for S. Viau (PhD fellowship) and C. Joffre (Grant no 29000026) The Nutrition, Chemical Food Safety and Consumer Behaviour Division from INRA (Dijon, France) for S. Viau (BTH01698) Horus Pharma (Saint Laurent du Var, France) for C. Joffre (research contract no 29000144)