Petah Tikva, Israel
Petah Tikva, Israel

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Goldenberg-Cohen N.,Krieger Eye Research Laboratory | Sadikov T.,Krieger Eye Research Laboratory | Stein J.,Bone Marrow Transplant Unit
Cell Transplantation | Year: 2015

We have recently reported that small-sized bone marrow cells (BMCs) isolated by counterflow centrifugal elutri-ation and depleted of lineage markers (Fr25lin-) have the capacity to differentiate and contribute to regeneration of injured islets. In this study, we assess some of the characteristics of these cells compared to elutriated hema-topoietic progenitors (R/O) and whole BMCs in a murine model of streptozotocin-induced chemical diabetes. The GFPbrightCD45+ progeny of whole BMCs and R/O progenitors progressively infiltrate the pancreas with evolution of donor chimerism; are found at islet perimeter, vascular, and ductal walls; and have a modest impact on islet recovery from injury. In contrast, Fr25lin- cells incorporate in the islets, convert to GFPdimCD45-PDX-1+ phenotypes, produce proinsulin, and secrete insulin with significant contribution to stabilization of glucose homeostasis. The elutriated Fr25lin- cells express low levels of CD45 and are negative for SCA-1 and c-kit, as removal of cells expressing these markers did not impair conversion to produce insulin. BMCs mediate two syn-ergistic mechanisms that contribute to islet recovery from injury: support of islet remodeling by hematopoietic cells and neogenesis of insulin-producing cells from stem cells. © 2015 Cognizant Comm. Corp.


Rappoport D.,Hebrew University of Jerusalem | Goldenberg-Cohen N.,Krieger Eye Research Laboratory | Goldenberg-Cohen N.,Pediatric Ophthalmology Unit | Goldenberg-Cohen N.,Tel Aviv University | And 2 more authors.
Journal of Neuro-Ophthalmology | Year: 2014

Parainfectious optic neuritis may appear at any age. The aim of our report was to compare the clinical manifestations and outcomes of this form of optic neuritis between children and adults. METHODS:: The study sample consisted of all patients diagnosed with parainfectious optic neuritis evaluated by 2 neuro-ophthalmology services between 2005 and 2012. Data were collected retrospectively from the medical files. Findings were compared between patients aged 0-18 years and 19 years or older. RESULTS:: Ten children (50% female) and 8 adults (50% female) met the study criteria. Mean duration of follow-up was 29.4 months (range, 2-72 months) in the pediatric group and 14.2 months (range, 5-80 months) in the adult group. Respective rates of bilateral disease were 50% and 38%, and all patients had optic disc swelling. The associated pathogen was identified in 60% of the pediatric group, mainly Mycoplasma pneumoniae, and 75% of the adult group, in which no microorganism predominated. The interval from the febrile illness to symptom onset was 6 days (range, 1-14 days) in the pediatric group and 19.5 days (range, 14-30 days) in the adult group. Acute disseminated encephalomyelitis (ADEM) was diagnosed in 40% (4/10) of the children and none of the adults. Final visual outcome was 20/30 or better in all patients. There was a higher frequency of bilateral disease in prepubescent vs postpubescent children. CONCLUSIONS:: Parainfectious optic neuritis is associated with a favorable visual prognosis regardless of age. Children tend to manifest visual symptoms sooner after the antecedent infectious illness and more often bilaterally and in conjunction with ADEM. The causative agent is isolated less frequently in children compared with adults. © 2014 by North American Neuro-Ophthalmology Society.


Goldenberg-Cohen N.,Krieger Eye Research Laboratory | Goldenberg-Cohen N.,Tel Aviv University | Banin E.,Hebrew University of Jerusalem | Zalzstein Y.,Beilinson Hospital | And 8 more authors.
Molecular Vision | Year: 2013

Purpose: Retinitis pigmentosa (RP), the most genetically heterogeneous disorder in humans, actually represents a group of pigmentary retinopathies characterized by night blindness followed by visual-field loss. RP can appear as either syndromic or nonsyndromic. One of the most common forms of syndromic RP is Usher syndrome, characterized by the combination of RP, hearing loss, and vestibular dysfunction. Methods: The underlying cause of the appearance of syndromic and nonsyndromic RP in three siblings from a consanguineous Israeli Muslim Arab family was studied with whole-genome homozygosity mapping followed by whole exome sequencing. Results: The family was found to segregate novel mutations of two different genes: myosin VIIA (MYO7A), which causes type 1 Usher syndrome, and phosphodiesterase 6B, cyclic guanosine monophosphate-specific, rod, beta (PDE6B), which causes nonsyndromic RP. One affected child was homozygous for both mutations. Since the retinal phenotype seen in this patient results from overlapping pathologies, one might expect to find severe retinal degeneration. Indeed, he was diagnosed with RP based on an abnormal electroretinogram (ERG) at a young age (9 months). However, this early diagnosis may be biased, as two of his older siblings had already been diagnosed, leading to increased awareness. At the age of 32 months, he had relatively good vision with normal visual fields. Further testing of visual function and structure at different ages in the three siblings is needed to determine whether the two RP-causing genes mutated in this youngest sibling confer increased disease severity. Conclusions: This report further supports the genetic heterogeneity of RP, and demonstrates how consanguinity could increase intrafamilial clustering of multiple hereditary diseases. Moreover, this report provides a unique opportunity to study the clinical implications of the coexistence of pathogenic mutations in two RP-causative genes in a human patient. © 2013 Molecular Vision.


Goldenberg-Cohen N.,Pediatric Unit | Goldenberg-Cohen N.,Krieger Eye Research Laboratory | Goldenberg-Cohen N.,Tel Aviv University | Dratviman-Storobinsky O.,Krieger Eye Research Laboratory | And 4 more authors.
Journal of Neuro-Ophthalmology | Year: 2011

Background: Bax expression is a prerequisite for retinal ganglion cell (RGC) apoptosis. Experimental studies have reported Bax protein upregulation following optic nerve transection. The stimuli that trigger apoptosis share a common executioner proteolysis cascade, including caspase-3 and poly-(adenosine diphosphate ribose) polymerase cleavage. This study sought to elucidate the role of the mitochondrial apoptotic pathway in RGCs using a Bax transgenic knockout mouse model. Methods: The right optic nerves of 26 C57BL mice, 7 Bax, 7 Bax, and 12 Bax, were subjected to crush injury and analyzed for apoptosis and neuronal cell loss on days 1, 3, and 21. Levels of Bax, Bcl-2, and caspase-3 messenger RNA expression were determined with real-time polymerase chain reaction. Results: Multiple apoptotic cells were detected in the retinas of the Bax and Bax mice at days 1 and 3, but not in the Bax mice. The Bax/Bcl-2 ratio was higher in the Bax than in the Bax mice on day 1 (1.33 and 0.83, respectively), with a trend toward an increase on day 3 (1.47 and 1.66, respectively); Bax/Bcl-X showed the same elevation on day 1 in the wild-type mice (1.34) but decreased on day 3 (0.8). Bax gene expression was undetectable in the Bax mice. Caspase-3 gene expression was higher in the Bax than in the Bax mice on day 1 and dropped toward baseline on day 3. The opposite trend was noted in the Bax mice. Conclusion: The lack of apoptosis combined with the reduction in proapoptotic genes in the Bax mice after injury compared to the Bax and Bax mice suggests that Bax plays a crucial role in the induction of apoptosis. Suppression of Bax expression may reduce retinal cell loss. © 2011 Lippincott Williams & Wilkins, Inc.


Goldenberg-Cohen N.,Krieger Eye Research Laboratory | Goldenberg-Cohen N.,Pediatric Unit | Goldenberg-Cohen N.,Tel Aviv University | Avraham-Lubin B.-C.R.,Krieger Eye Research Laboratory | And 5 more authors.
Stem Cells and Development | Year: 2012

Ischemic or mechanical injury to the optic nerve is an irreversible cause of vision loss, associated with limited regeneration and poor response to neuroprotective agents. The aim of this study was to assess the capacity of adult bone marrow cells to participate in retinal regeneration following the induction of anterior ischemic optic neuropathy (AION) and optic nerve crush (ONC) in a rodent model. The small-sized subset of cells isolated by elutriation and lineage depletion (Fr25lin -) was found to be negative for the neuroglial markers nestin and glial fibrillary acidic protein (GFAP). Syngeneic donor cells, identified by genomic marker in sex-mismatched transplants and green fluorescent protein, incorporated into the injured retina (AION and ONC) at a frequency of 0.35%-0.45% after intravenous infusion and 1.8%-2% after intravitreous implantation. Perivascular cells with astrocytic morphology expressing GFAP and vimentin were of the predominant lineage that engrafted after AION injury; 10%-18% of the donor cells incorporated in the retinal ganglion cell layer and expressed NeuN, Thy-1, neurofilament, and beta-tubulin III. The Fr25lin - cells displayed an excellent capacity to migrate to sites of tissue disruption and developed coordinated site-specific morphological and phenotypic neural and glial markers. In addition to cellular reconstitution of the injured retinal layers, these cells contributed to endothelial revascularization and apparently supported remodeling by secretion of insulin-like growth factor-1. These results suggest that elutriated autologous adult bone marrow-derived stem cells may serve as an accessible source for cellular reconstitution of the retina following injury. © Copyright 2012, Mary Ann Liebert, Inc.


Goldenberg-Cohen N.,Krieger Eye Research Laboratory | Iskovich S.,Center for Stem Cell Research | Askenasy N.,Center for Stem Cell Research
Stem Cells and Development | Year: 2015

Small-sized adult bone marrow cells isolated by counterflow centrifugal elutriation and depleted of lineage markers (Fr25lin-) have the capacity to differentiate into insulin-producing cells and stabilize glycemic control. This study assessed competitive migration of syngeneic stem cells to the bone marrow and islets in a murine model of chemical diabetes. VLA-4 is expressed in ∼25% of these cells, whereas CXCR4 is not detected, however, it is transcriptionally upregulated (6-fold). The possibility to enrich stem cells by a bone marrow homing (BM-H) functional assay was assessed in sequential transplants. Fr25lin- cells labeled with PKH26 were grafted into primary myeloablated recipients, and mitotically quiescent Fr25lin-PKHbright cells were sorted from the bone marrow after 2 days. The contribution of bone marrow-homed stem cells was remarkably higher in secondary recipients compared to freshly elutriated cells. The therapeutic efficacy was further increased by omission of irradiation in the secondary recipients, showing a 25-fold enrichment of islet-reconstituting cells by the bone marrow homing assay. Donor cells identified by the green fluorescent protein (GFP) and a genomic marker in sex-mismatched transplants upregulated PDX-1 and produced proinsulin, affirming the capacity of BM-H cells to convert in the injured islets. There was no evidence of transcriptional priming of freshly elutriated subsets to express PDX-1, insulin, and other markers of endocrine progenitors, indicating that the bone marrow harbors stem cells with versatile differentiation capacity. Affinity to the bone marrow can be used to enrich stem cells for pancreatic regeneration, and reciprocally, conditioning reduces the competitive incorporation in the injured islets. © Copyright 2015, Mary Ann Liebert, Inc. 2015.


Dratviman-Storobinsky O.,Krieger Eye Research Laboratory
Investigative ophthalmology & visual science | Year: 2012

RASSF1A inactivation in uveal melanoma (UM) is common and methylation-induced. We investigated the effect of RASSF1A re-expression on the UM phenotype in vivo and in vitro. The phenotypic effect of methylation-induced inactivation of RASSF1A in UM was explored using a stable RASSF1A-expressing UM-15 clone. RASSF1A expression was assessed using QRT-PCR. Proliferation was evaluated in vitro using MTT assays. Additionally, athymic NOD/SCID mice were injected subcutaneously or intraocularly with RASSF1A-expressing and -non-expressing UM-15 clones, and euthanized when tumors reached a volume of 1500 mm(3), or at 56 or 46 days, respectively. Tumor tissues, eyes, and livers were analyzed histologically. In vitro analysis confirmed the lack of RASSF1A expression and full methylation of the RASSF1A promoter region in the UM-15 cell line, which was reversible following treatment with 5-Aza-2-deoxycytidine. Cells expressing exogenous RASSF1A showed slower proliferation than controls and regained sensitivity to cisplatin. Compared to mice injected with control cells, mice treated with UM-15 cells expressing exogenous RASSF1A did not acquire intraocular tumors, and their subcutaneous tumors were relatively delayed and small. Neither group had liver metastases. UM cells reduced tumorigenicity in the presence of activated RASSF1A. RASSF1A apparently has an important role in the development of UM, and its reactivation might be applied in the development of new treatments.


Goldenberg-Cohen N.,Pediatric Ophthalmology Unit | Goldenberg-Cohen N.,Krieger Eye Research Laboratory | Goldenberg-Cohen N.,Tel Aviv University | Gabbay M.,Kiryat Ono Community Health Center | And 8 more authors.
Retina | Year: 2011

Purpose: There are 2 common alleles for Hp (Hp-1 and Hp-2) and 3 common Hp genotypes: Hp1-1, Hp2-1, and Hp2-2. The haptoglobin genotype may play a dual role in morbidities of diabetes: Hp1-1, protective and Hp2-2, provocative. This study investigated the possible association of haptoglobin genotypes with onset of retinopathy in Type 2 diabetes (DM2). Methods: The sample included 98 consecutive adults with DM2 under routine outpatient follow-up from 2007 to 2009 who met the criteria for either no retinopathy at ≥10 years after diagnosis (Group 1) or proliferative retinopathy at ≤10 years after diagnosis (Group 2). Blood samples were collected for haptoglobin genotyping by polymerase chain reaction. Findings were compared between and within groups. Results: Eighty-four patients had no retinopathy and 14 had early proliferative retinopathy. The distributions of the Hp genotypes were as follows: no-retinopathy group: 28.6% Hp1-1, 35.7% Hp2-1, and 35.7% Hp2-2 and proliferative retinopathy group: 22.6% Hp1-1, 27.4% Hp2-1, and 50% Hp2-2 (NS). On statistical analysis (limited to the larger no-retinopathy group), a predominance of Hp1-1 was noted in older patients; Hp2-2 was associated with an increased rate of stroke. Conclusion: The Hp genotype apparently plays no role in the development or worsening of proliferative retinopathy in DM2. Hp1-1 may be involved in delaying the onset of diabetes. Hp2-2 may pose a microvascular risk. Copyright © by Ophthalmic Communications Society, Inc.


PubMed | Krieger Eye Research Laboratory
Type: Journal Article | Journal: Investigative ophthalmology & visual science | Year: 2012

RASSF1A inactivation in uveal melanoma (UM) is common and methylation-induced. We investigated the effect of RASSF1A re-expression on the UM phenotype in vivo and in vitro.The phenotypic effect of methylation-induced inactivation of RASSF1A in UM was explored using a stable RASSF1A-expressing UM-15 clone. RASSF1A expression was assessed using QRT-PCR. Proliferation was evaluated in vitro using MTT assays. Additionally, athymic NOD/SCID mice were injected subcutaneously or intraocularly with RASSF1A-expressing and -non-expressing UM-15 clones, and euthanized when tumors reached a volume of 1500 mm(3), or at 56 or 46 days, respectively. Tumor tissues, eyes, and livers were analyzed histologically.In vitro analysis confirmed the lack of RASSF1A expression and full methylation of the RASSF1A promoter region in the UM-15 cell line, which was reversible following treatment with 5-Aza-2-deoxycytidine. Cells expressing exogenous RASSF1A showed slower proliferation than controls and regained sensitivity to cisplatin. Compared to mice injected with control cells, mice treated with UM-15 cells expressing exogenous RASSF1A did not acquire intraocular tumors, and their subcutaneous tumors were relatively delayed and small. Neither group had liver metastases.UM cells reduced tumorigenicity in the presence of activated RASSF1A. RASSF1A apparently has an important role in the development of UM, and its reactivation might be applied in the development of new treatments.


PubMed | Krieger Eye Research Laboratory
Type: Journal Article | Journal: Stem cells and development | Year: 2012

Ischemic or mechanical injury to the optic nerve is an irreversible cause of vision loss, associated with limited regeneration and poor response to neuroprotective agents. The aim of this study was to assess the capacity of adult bone marrow cells to participate in retinal regeneration following the induction of anterior ischemic optic neuropathy (AION) and optic nerve crush (ONC) in a rodent model. The small-sized subset of cells isolated by elutriation and lineage depletion (Fr25lin(-)) was found to be negative for the neuroglial markers nestin and glial fibrillary acidic protein (GFAP). Syngeneic donor cells, identified by genomic marker in sex-mismatched transplants and green fluorescent protein, incorporated into the injured retina (AION and ONC) at a frequency of 0.35%-0.45% after intravenous infusion and 1.8%-2% after intravitreous implantation. Perivascular cells with astrocytic morphology expressing GFAP and vimentin were of the predominant lineage that engrafted after AION injury; 10%-18% of the donor cells incorporated in the retinal ganglion cell layer and expressed NeuN, Thy-1, neurofilament, and beta-tubulin III. The Fr25lin(-) cells displayed an excellent capacity to migrate to sites of tissue disruption and developed coordinated site-specific morphological and phenotypic neural and glial markers. In addition to cellular reconstitution of the injured retinal layers, these cells contributed to endothelial revascularization and apparently supported remodeling by secretion of insulin-like growth factor-1. These results suggest that elutriated autologous adult bone marrow-derived stem cells may serve as an accessible source for cellular reconstitution of the retina following injury.

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