TGF-ß1 enhances phagocytic removal of neuron debris and neuronal survival by olfactory ensheathing cells via integrin/MFG-E8 signaling pathway.

Olfactory ensheathing cells (OECs) have been shown to be a leading candidate in cell therapies for central nervous system (CNS) injuries and neurodegenerative diseases. Rapid clearance of neuron debris can promote neuronal survival and axonal regeneration in CNS injuries and neurodegenerative diseases. The phagocytic removal of neuron debris by OECs has been shown to contribute to neuronal outgrowth. However, the precise molecular and cellular mechanisms of phagocytic removal of neuron debris by OECs have not been explored. In this study, we found that OECs secreted anti-inflammatory cytokine transforming growth factor ß1 (TGF-ß1) during the phagocytic removal of neuron debris. TGF-ß1 enhanced phagocytic activity of OECs through regulating integrin/MFG-E8 signaling pathway. In addition, TGF-ß1 shifted OECs towards a flattened shape with increased cellular area, which might also be involved in the enhancement of phagocytic activity of OECs. Furthermore, the removal of neuron debris by OECs affected neuronal survival and outgrowth. TGF-ß1 enhanced the clearance of neuron debris by OECs and increased neuronal survival. These results reveal the role and mechanism of TGF-ß1 in enhancing the phagocytic activity of OECs, which will update the understanding of phagocytosis of OECs and improve the therapeutic use of OECs in CNS injuries and neurodegenerative diseases.

Pupillary capture following sutureless scleral-fixated intraocular lens in children with Marfan syndrome.

AIM: To compare the clinical outcomes between two approaches for sutureless scleral-fixated intraocular lens (SFIOL) in children with Marfan syndrome (MFS). METHODS: The study included 15 children (26 eyes) with lens subluxation due to MFS. These children underwent lensectomy, anterior vitrectomy, and sutureless SFIOL. According to the position of placement of intraocular lens (IOL) haptics, two study groups were reviewed for best corrected visual acuity (BCVA) and postoperative complications: group A, 14 eyes with haptics fixated at 2.0 mm from the limbus; group B, 12 eyes with the haptics fixated at 2.5 mm from the limbus. RESULTS: The mean axial length for all patients was 25.66±2.35 mm. Postoperative BCVA in logMAR were significant improved in both groups (0.77±0.32 to 0.17±0.12 in group A, 0.66±0.25 to 0.24±0.12 in group B, both P<0.001) while no significant difference between two groups (P>0.05). Pupillary capture was main postoperative complication, occurring between 3d and 18mo. It occurred in 7 eyes in group A and one eye in group B (P=0.02). CONCLUSION: Sutureless SFIOL is an effective treatment approach for lens subluxation in children with MFS. Pupillary capture is the main postoperative complication. Fixated IOL haptics at 2.5 mm from the limbus can reduce the occurrence of pupillary capture.

Human Umbilical Cord Blood-Derived CD133+CD34+ Cells Protect Retinal Endothelial Cells and Ganglion Cells in X-Irradiated Rats through Angioprotective and Neurotrophic Factors.

Radiation retinopathy (RR) is a common complication following radiation therapy of globe, head, and neck malignancies, and is characterized by microangiopathy, neuroretinopathy, and the irreversible loss of visual function. To date, there is no effective treatment for RR. Stem cells have been clinically used to treat retinal degeneration. CD133+CD34+ cells from human umbilical cord blood (hUCB-CD133+CD34+ cells), a subpopulation of hematopoietic stem cells, were applied to determine their protective efficacy on irradiated rat retinas. After X-ray irradiation on the retinas, rats were intravitreally injected with hUCB-CD133+CD34+ cells. Transplantation of hUCB-CD133+CD34+ cells prevented retinal dysfunction 2 weeks post-operation and lasted at least 8 weeks. CD133+CD34+ cells were distributed along the retinal vessel and migrated to the ganglion cell layer. Moreover, grafted CD133+CD34+ cells reduced the apoptosis of endothelial and ganglion cells in irradiated rats and increased the number of survived CD31+ retinal endothelial cells and Brn3a+ ganglion cells at 2 and 4 weeks, respectively, post-operation. Co-culturing of CD133+CD34+ cells or supernatants with irradiated human retinal microvascular endothelial cells (hRECs) in vitro, confirmed that CD133+CD34+ cells ameliorated hREC apoptosis caused by irradiation. Mechanistically, we found that angioprotective mediators and neurotrophic factors were secreted by CD133+CD34+ cells, which might attenuate irradiation-induced injury of retinal endothelial cells and ganglion cells. hUCB-CD133+CD34+ cell transplantation, as a novel treatment, protects retinal endothelial and ganglion cells of X-irradiated rat retinas, possibly through angioprotective and neurotrophic factors.

Sutured Intrascleral Posterior Chamber Intraocular Lens Fixation with Ciliary Sulcus Location Guided by Ultrasonic Biological Microscopy: A Retrospective Analysis of Anatomical and Refractive Outcome.

PURPOSE: To report the outcome of sutured intrascleral posterior chamber intraocular lens (PC IOL) fixation with ciliary sulcus location guided by ultrasonic biological microscopy (UBM). METHODS: Patients who underwent a sutured intrascleral PC IOL fixation were reviewed and divided into four groups. In group 1, the traditional sulcus fixation (2 mm from limbus) of IOL was performed. In groups 2, 3, and 4, UBM was performed before surgery to locate the position of the ciliary sulcus as the haptics insertion position. IOL power was selected by decreasing the calculated value of the IOL power by 1.0 D, 1.0 D, 0.5 D, and 0.0 D, respectively. RESULTS: Sixty-one patients (63 eyes) were included in the four groups. After 4.1 ± 3.0 months' follow-up, the postsurgery spherical equivalent (SE) was 0.73 ± 1.86, 0.71 ± 0.84, 1.14 ± 0.45, and 0.07 ± 0.89 diopters (D), respectively. Statistical significance was reached for the postsurgery SE with target refraction between group 1 (p = 0.027, <0.05), group 2 (p = 0.003, <0.01), and group 3 (p = 0.017, <0.05). No significant difference existed for the postsurgery SE with target refraction in group 4 (p = 0.779, >0.05), and the postsurgery SE in group 4 was the nearest to target refraction. CONCLUSION: Intrascleral PC IOL fixation guided by UBM is helpful for locating the ciliary sulcus and satisfactory visual outcomes with a predictable IOL power calculation.

Transplantation of cultured olfactory mucosal cells rescues optic nerve axons in a rat glaucoma model.

PURPOSE: To determine whether transplantation of olfactory mucosal cells (OMCs) is able to rescue the loss of optic nerve axons after the intraocular pressure (IOP) is elevated in rats. METHODS: The IOP was raised by injection of magnetic microspheres into the anterior chamber of the eye. OMCs cultured from the adult olfactory mucosa were transplanted into the region of the optic disc. RESULTS: We demonstrated that although the raised IOP returned to its normal level at six weeks, there was an irreversible 58% loss of optic nerve axons in the control group. However, the loss of the axons was reduced to 23% in the group with the transplanted OMCs. The Pattern Electroretinograms (pERG) showed that the decrement of the voltage amplitudes in association with the raised IOP was significantly alleviated in the group with transplantation of OMC. CONCLUSIONS: Transplantation of OMCs is able to rescue loss of optic nerve axons induced by raised IOP in the rats. The pERG recording suggested that the functional activities of the axons are also protected. TRANSLATIONAL RELEVANCE: The results demonstrated the ability of the transplanted OMCs to protect against the loss of the optic nerve axons and the loss of function caused by raised IOPs. The findings provide a basis for future human clinical trials by autografting OMCs from autologous nasal epithelial biopsies to treat or delay glaucoma diseases.

ROCK Inhibitor Y27632 Induced Morphological Shift and Enhanced Neurite Outgrowth-Promoting Property of Olfactory Ensheathing Cells via YAP-Dependent Up-Regulation of L1-CAM.

Olfactory ensheathing cells (OECs) are heterogeneous in morphology, antigenic profiles and functions, and these OEC subpopulations have shown different outcomes following OEC transplantation for central nervous system (CNS) injuries. Morphologically, OECs are divided into two subpopulations, process-bearing (Schwann cells-like) and flattened (astrocytes-like) OECs, which could switch between each other and are affected by extracellular and intracellular factors. However, neither the relationship between the morphology and function of OECs nor their molecular mechanisms have been clarified. In the present study, we first investigated morphological and functional differences of OECs under different cytokine exposure conditions. It demonstrated that OECs mainly displayed a process-bearing shape under pro-inflammatory conditions (lipopolysaccharide, LPS), while they displayed a flattened shape under anti-inflammatory conditions [interleukin-4 (IL-4) and transforming growth factor-ß1 (TGF-ß1)]. The morphological changes were partially reversible and the Rho-associated coiled-coil-containing protein kinase (ROCK)/F-actin pathway was involved. Functionally, process-bearing OECs under pro-inflammatory conditions showed increased cellular metabolic activity and a higher migratory rate when compared with flattened OECs under anti-inflammatory conditions and significantly promoted neurite outgrowth and extension. Remarkably, the morphological shift towards process-bearing OECs induced by ROCK inhibitor Y27632 enhanced the neurite outgrowth-promoting property of OECs. Furthermore, as the downstream of the ROCK pathway, transcriptional co-activator Yes-associated protein (YAP) mediated morphological shift and enhanced the neurite outgrowth-promoting property of OECs through upregulating the expression of the neural adhesion molecule L1-CAM. Our data provided evidence that OECs with specific shapes correspond to specific functional phenotypes and opened new insights into the potential combination of OECs and small-molecule ROCK inhibitors for the regeneration of CNS injuries.

Olfactory Ensheathing Cells Inhibit Gliosis in Retinal Degeneration by Downregulation of the Müller Cell Notch Signaling Pathway.

Retinal regeneration and self-repair, whether in response to injury or degenerative disease, are severely impeded by glial scar formation by Müller cells (specialized retinal macroglia). We have previously demonstrated that the activation of Müller cells and gliosis in the degenerative retina are significantly suppressed by the subretinal transplantation of a mixture of olfactory ensheathing cells (OECs) and olfactory nerve fibroblasts. However, the underlying molecular mechanism has remained elusive. Here we transplanted purified rat OECs into the subretinal space of pigmented Royal College of Surgeons (RCS) rats, a classic rodent model of retinal degeneration. Using behavioral testing and electroretinography, we confirmed that the grafted OECs preserved the visual function of rats for 8 weeks, relative to vehicle controls (phosphate-buffered saline). Histological evaluation of outer nuclear layer thickness and composition demonstrated that more photoreceptors and ON-bipolar cells were preserved in the retinas of OEC-treated RCS rats than in controls. The grafted OECs migrated into the outer plexiform layer, inner nuclear layer, and inner plexiform layer. They interacted directly with Müller cells in the retina of RCS rats, in three distinct patterns, and secreted matrix metalloproteinases 2 and 3. Previous studies have demonstrated that rat OECs express delta-like ligand (DLL), while Müller cells express Notch3, the receptor for DLL. Here we found that the grafted OECs significantly decreased the expression, by retinal cells, of Notch signaling pathway components (including Notch3, Notch4, DLL1, DLL4, Jagged1, Hes1, and Hes5) 2 weeks after the cell transplantation and that this effect persisted for a further 2 weeks. Based on these findings, we suggest that transplanted OECs inhibit the activation of Müller cells and the associated gliosis, at least partly through suppression of the Notch pathway.

Spectral-domain optical coherence tomography in patients with congenital nystagmus.

AIM: To study macular features in patients with congenital nystagmus and to assess the utility of spectral-domain optical coherence tomography (SD-OCT) in nystagmus. METHODS: The macular areas of 51 outpatients with congenital nystagmus were examined using SD-OCT. Morphological changes in the retinal layers of the macular area were analysed. RESULTS: Macular images were successfully obtained with SD-OCT from 50 (98%) patients. Patients with ocular albinism mainly have macular hypoplasia, abnormal foveal depression, and increased foveal thickness with persistence of an inner nuclear layer, an inner plexiform layer, a ganglion cell layer and a nerve fiber layer. Macular morphology similar to albinism was observed in three patients with idiopathic macular hypoplasia. The OCT findings of cone dystrophy included unclear, disrupted or invisible photoreceptor outer segment/inner segment in the fovea; fusion, thickening and uneven reflection of the outer segment/inner segment with external limiting membrane. Some patients with congenital idiopathic nystagmus showed normal macular morphology and structure, and others showed indistinct macular external limiting membrane reflection. CONCLUSION: SD-OCT is an effective and reliable method to detect the macular morphology of congenital nystagmus patients. This technique has diagnostic value in particular for patients with macular hypoplasia and cone cell dystrophy with no distinct abnormality on fundoscopy.

Investigating Müller glia reprogramming in mice: a retrospective of the last decade, and a look to the future.

Müller glia, as prominent glial cells within the retina, plays a significant role in maintaining retinal homeostasis in both healthy and diseased states. In lower vertebrates like zebrafish, these cells assume responsibility for spontaneous retinal regeneration, wherein endogenous Müller glia undergo proliferation, transform into Müller glia-derived progenitor cells, and subsequently regenerate the entire retina with restored functionality. Conversely, Müller glia in the mouse and human retina exhibit limited neural reprogramming. Müller glia reprogramming is thus a promising strategy for treating neurodegenerative ocular disorders. Müller glia reprogramming in mice has been accomplished with remarkable success, through various technologies. Advancements in molecular, genetic, epigenetic, morphological, and physiological evaluations have made it easier to document and investigate the Müller glia programming process in mice. Nevertheless, there remain issues that hinder improving reprogramming efficiency and maturity. Thus, understanding the reprogramming mechanism is crucial toward exploring factors that will improve Müller glia reprogramming efficiency, and for developing novel Müller glia reprogramming strategies. This review describes recent progress in relatively successful Müller glia reprogramming strategies. It also provides a basis for developing new Müller glia reprogramming strategies in mice, including epigenetic remodeling, metabolic modulation, immune regulation, chemical small-molecules regulation, extracellular matrix remodeling, and cell-cell fusion, to achieve Müller glia reprogramming in mice.