Induction of retinal pigment epithelium properties in ciliary margin progenitor cells

Vossmerbaeumer, Urs; Kuehl, Sandra; Kern, Susanne; Klüter, Harald; Jonas, Jost B.

doi:10.1111/j.1442-9071.2008.01770.x

Cited by 17 publications

(14 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The simple fact that RPE regeneration occurs robustly in MRL/MpJ mice may help efforts to identify the cell sources that effect RPE repair in a mammalian system. Studies from our own and other laboratories have shown that HSC derived donor cells can form cells within the RPE layer that are morphologically indistinguishable from native RPE (Carr et al, 2009; Harris et al, 2006; Harris et al, 2009; Idelson et al, 2009; Uygun et al, 2009; Vossmerbaeumer et al, 2008). However, only low levels of donor cell incorporation were observed and it was challenging to confirm that these cells were fully functional.…”

Section: Discussionmentioning

confidence: 92%

“…A second strategy is to inject bone marrow-derived stem cells into the vitreous or the systemic circulation. We and others have provided evidence in rodent models that injected bone marrow-derived cells reach the choroidal-retinal interface and transdifferentiate into RPE cells, but the efficiency is currently too low to be considered as a robust therapeutic approach (Carr et al, 2009; Harris et al, 2006; Harris et al, 2009; Idelson et al, 2009; Uygun et al, 2009; Vossmerbaeumer et al, 2008). A third, untested, strategy is to induce regeneration chemically by local introduction of factors that reprogram resident stem cells or undamaged RPE cells to repopulate the damaged tissue, as proposed for other organs (Xu et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Enhanced retinal pigment epithelium regeneration after injury in MRL/MpJ mice

Xia

Krebs

Kaushal

et al. 2011

Experimental Eye Research

View full text Add to dashboard Cite

Regenerative medicine holds the promise of restoring cells and tissues that are destroyed in human disease, including degenerative eye disorders. However, development of this approach in the eye has been limited by a lack of animal models that show robust regeneration of ocular tissue. Here, we test whether MRL/MpJ mice, which exhibit enhanced wound healing, can efficiently regenerate the retinal pigment epithelium (RPE) after an injury that mimics the loss of this tissue in age-related macular degeneration. The RPE of MRL/MpJ and control AKR/J mice was injured by retro-orbital injection of sodium iodate at 20 mg/kg body weight, which titration studies indicated was optimal for highlighting strain differences in the response to injury. Five days after sodium iodate injection at this dose, electroretinography of both strains revealed equivalent retinal responses that were significantly reduced compared to untreated mice. At one and two months post-injection, retinal responses were restored in MRL/MpJ but not AKR/J mice. Brightfield and fluorescence microscopy of eyecup cryosections indicated an initial central loss of RPE cells and RPE65 immunostaining in MRL/MpJ and AKR/J mice, with preservation of peripheral RPE. Phalloidin staining of posterior eye wholemounts confirmed this pattern of RPE loss, and revealed a transition region characterized by RPE cell shedding and restructuring in both strains, suggesting a similar initial response to injury. At one month post-injection, central RPE cells, RPE65 immunostaining and phalloidin staining were restored in MRL/MpJ but not AKR/J mice. BrdU incorporation was observed throughout the RPE of MRL/MpJ but not AKR/J mice after one month of administration following sodium iodate treatment, consistent with RPE proliferation. These findings provide evidence for a dramatic regeneration of the RPE after injury in MRL/MpJ mice that supports full recovery of retinal function, which has not been observed previously in mammalian eyes. This model should prove useful for understanding molecular mechanisms that underlie regeneration, and for identifying factors that promote RPE regeneration in age-related macular degeneration and related diseases.

show abstract

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Enhanced retinal pigment epithelium regeneration after injury in MRL/MpJ mice

Xia

Krebs

Kaushal

et al. 2011

Experimental Eye Research

View full text Add to dashboard Cite

show abstract

“…on May 12, 2018 by guest http://jvi.asm.org/ and hematopoietic cells also express functional VIP receptors (6,7,35,82). While there are no published reports linking VIP to HCMV reactivation in vivo, this association is plausible based on the following considerations.…”

Section: Discussionmentioning

confidence: 99%

“…(4,16,32) in which HCMV also reactivates with greater frequency (26,33,40,43,51,80). VIP receptors are expressed on progenitors of neuronal, hepatic, retinal pigment epithelial, and hematopoietic cells (6,7,35,82). On the basis of this information, VIP was further studied in the HCMV reactivation model.…”

Section: Cells and Virusesmentioning

confidence: 99%

Breaking Human Cytomegalovirus Major Immediate-Early Gene Silence by Vasoactive Intestinal Peptide Stimulation of the Protein Kinase A-CREB-TORC2 Signaling Cascade in Human Pluripotent Embryonal NTera2 Cells

Yuan

Liu

et al. 2009

J Virol

View full text Add to dashboard Cite

. We speculate that neurohormonal stimulation via this signaling cascade is a possible means for reversing HCMV silence in vivo.Persons with impaired cellular immunity risk tissue-invasive disease from reactivation of latent human cytomegalovirus (HCMV). HCMV reactivation in tissues or blood of immunocompetent patients suffering illness from another cause also occurs but usually goes unnoticed and is self-limiting. For instance, nearly one-third of patients who are critically ill or in septic shock have detectable findings of HCMV reactivation in their bloodstream (12,26,43,45,80). HCMV reactivation infection in intestinal tissues with preexisting inflammatory disease (e.g., inflammatory bowel disease) is also well described for immunocompetent patients (28,39,40,51). The precise triggering mechanisms that underlie HCMV reactivation are unknown.So far, only cells of myeloid lineage have been determined to fulfill criteria for cellular sites of HCMV latency in vivo. In healthy HCMV-seropositive persons, precursors of macrophages and dendritic cells, including CD34ϩ hematopoietic progenitor cells, carry latent HCMV genomes at a low frequency (75). The terminal differentiation of these cells into a macrophage-or dendritic cell-like phenotype is a prerequisite for HCMV reactivation ex vivo (67, 76). However, this reactivation appears to be a rare event, suggesting that other, as yet unidentified factors may promote HCMV reactivation. Stimulation with tumor necrosis factor alpha (TNF-␣) or gamma interferon may promote HCMV reactivation from differentiated counterparts of monocytic-dendritic cell precursors that had been infected latently in vitro or in vivo (25,66,67,76).For both HCMV and murine CMV, viral major immediateearly (MIE) gene expression is greatly restricted or shut off during viral latency, and the productive viral life cycle cannot advance without this expression (57,74,75,78). The MIE enhancer/promoter controlling expression is regulated by the coordinated actions of multiple types of cis-acting elements (57). These elements are bound by cellular transcription factors whose functions are modulated by input supplied by the cell, the virus, and the external surrounding (57). Higher-order chromatin structure contributes to this regulation. Heterochromatin components amass on the inactive MIE enhancer/promoter in viral latency, whereas the chromatin signatures of transcriptional activity predominate at the active MIE enhancer/ promoter in acute and reactivation infections (47,67). MIE enhancer/promoter silencing is also favored by innate antiviral mechanisms that partly involve the repressive actions of nuclear ND10 domain components (e.g., hDAXX, PML, ATRX, and histone deacetylase [HDAC]) (52) but does not involve CpG methylation of the MIE enhancer/promoter (29).Quiescent HCMV infection of human NTera2/D1 cells (NT2 cells) is a tractable model system for studying the regulation of HCMV MIE enhancer/promoter reactivation (37, 54). NT2 cells share many phenotypic features with pluripotent

show abstract

“…Another approach has included enhancing the expression of cell-matrix adhesion molecules, i.e., integrins, to improve RPE adhesion and survival. 182,[192][193][194][195] Efforts to induce RPCs to differentiate into RPE continue, 196,197 but there are no pure, fully characterized RPE cells from RPCs yet. Such a scaffold could provide an environment that would allow easy placement of an RPE graft in the right orientation and/or promote RPE survival and differentiation.…”

Section: Transplanted Rpe Survival and Differentiation On Aged Bruch'mentioning

confidence: 99%