Human umbilical tissue-derived cells rescue retinal pigment epithelium dysfunction in retinal degeneration

Cao, Jing; Murat, Christopher; An, Weijun; Yao, Xiang; Lee, John; Santulli-Marotto, Sandra; Harris, Ian R.; Inana, George

doi:10.1002/stem.2239

Cited by 37 publications

(33 citation statements)

References 89 publications

(146 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The most important finding of the current study is to unravel NDRG2 as the molecular hallmark of photoreceptor-specific cell viability, which was confirmed not only in vitro but also in vivo in retinal degeneration and treatment. In fact, there is a multitude of treatment strategies and compounds that at least partially prevent retinal degeneration in animal models, including the calcium channel blocker D-diltiazem 56 , 57 , various antioxidants 24 , 58 , caspase inhibitors 59 , 60 , multiple neuroprotective agents including NAM 35 , 36 and other neurotrophic cytokines 61 , apoptotic gene therapies 62 , 63 , and the recent stem cell transplantation 64 , 65 . Nevertheless, while retinal degeneration in preclinical studies could be effectively prevented, there does not seem to be a single treatment available at present that rescues photoreceptor cell damages in human 66 , 67 .…”

Section: Discussionmentioning

confidence: 99%

NDRG2 suppression as a molecular hallmark of photoreceptor-specific cell death in the mouse retina

Sui

Wang

et al. 2018

Cell Death Discov.

View full text Add to dashboard Cite

Photoreceptor cell death is recognized as the key pathogenesis of retinal degeneration, but the molecular basis underlying photoreceptor-specific cell loss in retinal damaging conditions is virtually unknown. The N-myc downstream regulated gene (NDRG) family has recently been reported to regulate cell viability, in particular NDRG1 has been uncovered expression in photoreceptor cells. Accordingly, we herein examined the potential roles of NDRGs in mediating photoreceptor-specific cell loss in retinal damages. By using mouse models of retinal degeneration and the 661 W photoreceptor cell line, we showed that photoreceptor cells are indeed highly sensitive to light exposure and the related oxidative stress, and that photoreceptor cells are even selectively diminished by phototoxins of the alkylating agent N-Methyl-N-nitrosourea (MNU). Unexpectedly, we discovered that of all the NDRG family members, NDRG2, but not the originally hypothesized NDRG1 or other NDRG subtypes, was selectively expressed and specifically responded to retinal damaging conditions in photoreceptor cells. Furthermore, functional experiments proved that NDRG2 was essential for photoreceptor cell viability, which could be attributed to NDRG2 control of the photo-oxidative stress, and that it was the suppression of NDRG2 which led to photoreceptor cell loss in damaging conditions. More importantly, NDRG2 preservation contributed to photoreceptor-specific cell maintenance and retinal protection both in vitro and in vivo. Our findings revealed a previously unrecognized role of NDRG2 in mediating photoreceptor cell homeostasis and established for the first time the molecular hallmark of photoreceptor-specific cell death as NDRG2 suppression, shedding light on improved understanding and therapy of retinal degeneration.

show abstract

Section: Discussionmentioning

confidence: 99%

NDRG2 suppression as a molecular hallmark of photoreceptor-specific cell death in the mouse retina

Sui

Wang

et al. 2018

Cell Death Discov.

View full text Add to dashboard Cite

show abstract

“…MSC‐secreted factors activate prolife signal transduction pathways in preapoptotic cells that are jeopardized by metabolic dysregulation from oxygen, glucose, or nutrient deprivation . Ex vivo assays showed that MSC‐CdM supports photoreceptor survival ex vivo and enhances RPE internalization of POSs , with an increase in RPE metabolic viability (Fig. 6C, 6D).…”

Section: Discussionmentioning

confidence: 93%

“…6C, 6D). Rat MSCs have been shown to secrete BDNF , the transcriptional silencing of which , or antibody neutralization in MSC‐CdM (Fig. 6M), reduced RPE phagocytosis ability.…”

Section: Discussionmentioning

confidence: 99%

“…6M), reduced RPE phagocytosis ability. Although not yet clear, a putative mechanism by which RPE phagocytosis might circumvent MERTK function was recently described to occur through opsonizing bridge molecules secreted by human umbilical tissue‐derived cells (hUTCs) . Transcript silencing of opsonizing peptides yielded hUTC‐CdM with reduced ability to promote POS uptake by cultured RPE cells derived from RCS rats.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Multimodal Delivery of Isogenic Mesenchymal Stem Cells Yields Synergistic Protection from Retinal Degeneration and Vision Loss

Bakondi

Girman

Lü

et al. 2016

Stem Cells Translational Medicine

View full text Add to dashboard Cite

We previously demonstrated that subretinal injection (SRI) of isogenic mesenchymal stem cells (MSCs) reduced the severity of retinal degeneration in Royal College of Surgeons rats in a focal manner. In contrast, intravenous MSC infusion (MSCIV) produced panoptic retinal rescue. By combining these treatments, we now show that MSCIV supplementation potentiates the MSCSRI‐mediated rescue of photoreceptors and visual function. Electrophysiological recording from superior colliculi revealed 3.9‐fold lower luminance threshold responses (LTRs) and 22% larger functional rescue area from combined treatment compared with MSCSRI alone. MSCIV supplementation of sham (saline) injection also improved LTRs 3.4‐fold and enlarged rescue areas by 27% compared with saline alone. We confirmed the involvement of MSC chemotaxis for vision rescue by modulating C‐X‐C chemokine receptor 4 activity before MSCIV but without increased retinal homing. Rather, circulating platelets and lymphocytes were reduced 3 and 7 days after MSCIV, respectively. We demonstrated MSCSRI‐mediated paracrine support of vision rescue by SRI of concentrated MSC‐conditioned medium and assessed function by electroretinography and optokinetic response. MSC‐secreted peptides increased retinal pigment epithelium (RPE) metabolic activity and clearance of photoreceptor outer segments ex vivo, which was partially abrogated by antibody blockade of trophic factors in concentrated MSC‐conditioned medium, or their cognate receptors on RPE. These data support multimodal mechanisms for MSC‐mediated retinal protection that differ by administration route and synergize when combined. Thus, using MSCIV as adjuvant therapy might improve cell therapies for retinal dystrophy and warrants further translational evaluation. Stem Cells Translational Medicine 2017;6:444–457

show abstract

“…17 Subsequent in vitro studies showed that palucorcel was capable of rescuing RPE phagocytic dysfunction, promoting excitatory synaptic connectivity, enhancing neuronal survival, and enhancing neurite outgrowth via paracrine signaling pathways. 19,20 A recent phase 1/2a study evaluated the administration of palucorcel in 35 adults, 50 years of age and older, with bilateral GA secondary to AMD. A microcatheter delivery system (iTrack 275; iScience, Inc., Menlo Park, CA, USA) was used in conjunction with an ab externo surgical approach to access the subretinal space.…”

mentioning

confidence: 99%

A Subretinal Cell Delivery Method via Suprachoroidal Access in Minipigs: Safety and Surgical Outcomes

Smet¹,

Lynch

Dejneka

et al. 2018

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

PURPOSE. This study evaluated a new subretinal method for delivery of human or pig umbilical tissue-derived cells (hUTC or pUTC, respectively) using a novel subretinal injection cannula and suprachoroidal approach in Göttingen minipig eyes. hUTC (palucorcel) are currently under development for treating geographic atrophy in humans.METHODS. Twenty-four Göttingen minipigs (divided into eight groups) were subretinally administered palucorcel, pUTC, or vehicle. In some cases, fluorescently labeled cells and vehicle were administered. Conjunctival cutdown and sclerotomy were performed, then a flexible cannula containing a microneedle was inserted and advanced into the suprachoroidal space. The microneedle was deployed and visualized; 50 lL cells (target concentration, 11.2 3 10 6 cells/mL [560,000 cells/eye]) or vehicle was injected subretinally. Safety outcomes were evaluated.RESULTS. For all animals, cells and vehicle were successfully administered. Labeled cells or fluorescent vehicle were contained in the subretinal bleb, without leakage into the vitreous. No retinal detachment or vitreous traction band was identified by ophthalmologic examination. At all time points, observed microscopic changes were attributable to experimental procedures. On histopathology immediately after injection, localized retinal detachments were seen, along with focal retinal, choroidal, and/or scleral discontinuities. A moderate inflammatory response was seen in a limited number of animals. In the allogeneic setting, no antibody responses were detectable. Anti-human UTC antibodies were detected in the xenogeneic setting.CONCLUSIONS. Palucorcel, pUTC, and vehicle were successfully administered to Göttingen minipigs using a novel subretinal injection cannula via a suprachoroidal surgical approach, with no significant adverse events; therefore, this technique appears to be feasible for further clinical development.

show abstract

Human umbilical tissue-derived cells rescue retinal pigment epithelium dysfunction in retinal degeneration

Cited by 37 publications

References 89 publications

NDRG2 suppression as a molecular hallmark of photoreceptor-specific cell death in the mouse retina

NDRG2 suppression as a molecular hallmark of photoreceptor-specific cell death in the mouse retina

Multimodal Delivery of Isogenic Mesenchymal Stem Cells Yields Synergistic Protection from Retinal Degeneration and Vision Loss

A Subretinal Cell Delivery Method via Suprachoroidal Access in Minipigs: Safety and Surgical Outcomes

Contact Info

Product

Resources

About