Intraperitoneal administration of adipose tissue‐derived stem cells for the rescue of retinal degeneration in a mouse model via indigenous CNTF up‐regulation by IL‐6

Heo, Jeong Hoon; Yoon, Jung Ae; Ahn, Eun Kyung; Kim, Hyun; Urm, Sang Hwa; Oak, Chul Oh; Yu, Byeng Chul; Lee, Sang Joon

doi:10.1002/term.2522

Cited by 9 publications

(9 citation statements)

References 78 publications

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“…Both TNFα and IL-1ß are considered to be neuro-toxic, especially in damaged tissue [52]. IL-6, on the other hand, can have neuro-protective and neuro-regenerative effects in the retina [53][54][55]. This is in line with our previous studies regarding the efforts of the RPE to regulate the inflammatory response in communication with microglia or macrophages, where the RPE induced a differentiated pro-inflammatory response in microglia [13] or a dampening effect on macrophages [45].…”

Section: Discussionmentioning

confidence: 99%

Basolateral activation with TLR agonists induces polarized cytokine release and reduces barrier function in RPE in vitro

Terheyden

Roider

Klettner

2020

Graefes Arch Clin Exp Ophthalmol

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Purpose Systemic inflammation may be of importance in the development of AMD. RPE cells can recognize danger signals with toll-like receptors (TLR) and may react in a pro-inflammatory manner. In this study, we evaluated the basal and apical secretions of TNFα, IL-6, and IL-1β in primary RPE cells and RPE/choroid explant cells under basolateral stimulation of TLR2, 3, and 4; the effects on barrier function; and their influence on neuronal cell viability. Methods RPE/choroid tissue explants were prepared from porcine eyes and cultivated in modified Ussing chambers; primary porcine RPE cells on transwell plates. Cells were basally stimulated with agonists Pam2CSK4 (Pam; TLR2), polyinosinic/polycytidylic acid (Poly I:C; TLR3), and lipopolysaccharide (LPS; TLR4) for 24 h. Supernatants were evaluated with ELISA for cytokines TNFα, IL-6, and IL-1β. Apical supernatants were applied to SHSY-5Y cells, and cell viability was evaluated in MTT assay. Barrier function was tested by measuring transepithelial electrical resistance (TER) and occludin immunostaining. Results None of the tested TLR agonists was toxic on RPE cells after 24 h of exposure. Unstimulated RPE cells secreted hardly any cytokines. Pam induced IL-6, IL-1ß, and TNFα on the basal and apical sides at all concentrations tested. Poly I:C induced IL-6 and TNFα primarily at the basal side at lower but on both sides at higher concentrations. LPS induced IL-6, IL-1ß, and TNFα apically and basally at all concentrations tested. In the RPE/choroid, a strong difference between apical and basal secretions could be found. IL-6 was constitutively secreted basally, but not apically, but was induced by all agonists on both sides. IL-1ß and TNFα alpha were strongly induced on the basal side by all agonists. TER was reduced by all agonists, with Pam and LPS being effective in all concentrations tested. Occludin expression was unaltered, but the distribution was influenced by the agonists, with a less distinct localization at the cell borders after treatment. None of the agonists or supernatants of treated RPE and RPE/choroid organ cultures exerted any effect on viability of SHSY-5Y cells. Conclusions Danger signals activating TLRs can induce polarized cytokine expression and contribute to the loss of barrier function in the RPE.

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Section: Discussionmentioning

confidence: 99%

Basolateral activation with TLR agonists induces polarized cytokine release and reduces barrier function in RPE in vitro

Terheyden

Roider

Klettner

2020

Graefes Arch Clin Exp Ophthalmol

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“…Previous studies have reported the neuroprotective effect of aMSC on different types of retinal cells [ 23 , 24 , 70 – 72 ]. In the current study, NR general morphology was better preserved in cultures with PhC 2 with NIC+VIP, including photoreceptor outer and inner segments and ONL.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cell Secretome Enhancement by Nicotinamide and Vasoactive Intestinal Peptide: A New Therapeutic Approach for Retinal Degenerative Diseases

Alonso-Alonso

Srivastava

Usategui-Martín

et al. 2020

Stem Cells International

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Mesenchymal stem cells (MSC) secrete neuroprotective molecules that may be useful as an alternative to cell transplantation itself. Our purpose was to develop different pharmaceutical compositions based on conditioned medium (CM) of adipose MSC (aMSC) stimulated by and/or combined with nicotinamide (NIC), vasoactive intestinal peptide (VIP), or both factors; and to evaluate in vitro their proliferative and neuroprotective potential. Nine pharmaceutical compositions were developed from 3 experimental approaches: (1) unstimulated aMSC-CM collected and combined with NIC, VIP, or both factors (NIC+VIP), referred to as the aMSC-CM combined composition; (2) aMSC-CM collected just after stimulation with the mentioned factors and containing them, referred to as the aMSC-CM stimulated-combined composition; and (3) aMSC-CM previously stimulated with the factors, referred to as the aMSC stimulated composition. The potential of the pharmaceutical compositions to increase cell proliferation under oxidative stress and neuroprotection were evaluated in vitro by using a subacute oxidative stress model of retinal pigment epithelium cells (line ARPE-19) and spontaneous degenerative neuroretina model. Results showed that oxidatively stressed ARPE-19 cells exposed to aMSC-CM stimulated and stimulated-combined with NIC or NIC+VIP tended to have better recovery from the oxidative stress status. Neuroretinal explants cultured with aMSC-CM stimulated-combined with NIC+VIP had better preservation of the neuroretinal morphology, mainly photoreceptors, and a lower degree of glial cell activation. In conclusion, aMSC-CM stimulated-combined with NIC+VIP contributed to improving the proliferative and neuroprotective properties of the aMSC secretome. Further studies are necessary to evaluate higher concentrations of the drugs and to characterize specifically the aMSC-secreted factors related to neuroprotection. However, this study supports the possibility of improving the potential of new effective pharmaceutical compositions based on the secretome of MSC plus exogenous factors or drugs without the need to inject cells into the eye, which can be very useful in retinal pathologies.

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“…Endogenous cells secrete these neurotrophic factors mediated by paracrine effectors of transplanted cells. These trophic factors generally play an active role in neuronal development and survival by promoting proliferation, regeneration, and maturation of neurons 32 . The administration of trophic factors, e.g., CNTF, BDNF, and NT-4 has resulted in prevention of ON-injury-induced RGC death 36 .…”

Section: Discussionmentioning

confidence: 99%

Transplantation Efficacy of Human Ciliary Epithelium Cells from Fetal Eye and Lin-ve Stem Cells from Umbilical Cord Blood in the Murine Retinal Degeneration Model of Laser Injury

et al. 2020

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A number of degenerative conditions affecting the neural retina including age-related macular degeneration have no successful treatment, resulting in partial or complete vision loss. There are a number of stem cell replacement strategies for recovery of retinal damage using cells from variable sources. However, literature is still deficit in the comparison of efficacy of types of stem cells. The purpose of the study was to compare the therapeutic efficacy of undifferentiated cells, i.e., lineage negative stem cells (Lin-ve SC) with differentiated neurosphere derived from ciliary epithelium (CE) cells on retinal markers associated with laser-induced retinal injury. Laser-induced photocoagulation was carried out to disrupt Bruch’s membrane and retinal pigmented epithelium in C57BL/6 mouse model. Lineage negative cells were isolated from human umbilical cord blood, whereas neurospheres were derived from CE of post-aborted human eyeballs. The cells were then transplanted into subretinal space to study their effect on injury. Markers of neurotropic factors, retina, apoptosis, and proliferation were analyzed after injury and transplantation. mRNA expression was also analyzed by real-time polymerase chain reaction at 1 week, and 3-month immunohistochemistry was evaluated at 1-week time point. CE cell transplantation showed enhanced differentiation of rods and retinal glial cells. However, Lin-ve cells exerted paracrine-dependent modulation of neurotrophic factors, which is possibly mediated by antiapoptotic and proliferative effects. In conclusion, CE transplantation showed superior regenerative outcome in comparison to Lin-ve SC for rescue of artificially injured rodent retinal cells. It is imperative that this source for transplantation may be extensively studied in various doses and additional retinal degeneration models for prospective clinical applications.

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Intraperitoneal administration of adipose tissue‐derived stem cells for the rescue of retinal degeneration in a mouse model via indigenous CNTF up‐regulation by IL‐6

Cited by 9 publications

References 78 publications

Basolateral activation with TLR agonists induces polarized cytokine release and reduces barrier function in RPE in vitro

Basolateral activation with TLR agonists induces polarized cytokine release and reduces barrier function in RPE in vitro

Mesenchymal Stem Cell Secretome Enhancement by Nicotinamide and Vasoactive Intestinal Peptide: A New Therapeutic Approach for Retinal Degenerative Diseases

Transplantation Efficacy of Human Ciliary Epithelium Cells from Fetal Eye and Lin-ve Stem Cells from Umbilical Cord Blood in the Murine Retinal Degeneration Model of Laser Injury

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