Chemical induction of neurogenic properties in mammalian Müller glia.

Müller glia (MG), cells that maintain homeostasis in the retina, are dormant stem cells that can regenerate neurons upon injury. However, the regenerative property of MG, which is reproducibly displayed in the lower vertebrates, is not readily observed in the mammals even upon forced expression of regulatory genes or exposure to growth factors. Here, we demonstrate a reproducible unmasking of the neurogenic properties of enriched rodent MG by serial exposure to different combinations of small molecules.

Mapping developmental trajectories and subtype diversity of normal and glaucomatous human retinal ganglion cells by single-cell transcriptome analysis.

Glaucoma is characterized by a progressive degeneration of retinal ganglion cells (RGCs), leading to irreversible vision loss. Currently, there is no effective treatment for RGC degeneration. We used a disease-in-a-dish stem cell model to examine the developmental susceptibility of RGCs to glaucomatous degeneration, which may inform on the formulation of therapeutic approaches.

Recapitulating developmental mechanisms for retinal regeneration.

Degeneration of specific retinal neurons in diseases like glaucoma, age-related macular degeneration, and retinitis pigmentosa is the leading cause of irreversible blindness. Currently, there is no therapy to modify the disease-associated degenerative changes. With the advancement in our knowledge about the mechanisms that regulate the development of the vertebrate retina, the approach to treat blinding diseases through regenerative medicine appears a near possibility.

Human retinal ganglion cell axon regeneration by recapitulating developmental mechanisms: effects of recruitment of the mTOR pathway.

The poor axon regeneration in the central nervous system (CNS) often leads to permanent functional deficit following disease or injury. For example, degeneration of retinal ganglion cell (RGC) axons in glaucoma leads to irreversible loss of vision. Here, we have tested the hypothesis that the mTOR pathway regulates the development of human RGCs and that its recruitment after injury facilitates axon regeneration.

miR-29c regulates neurogliogenesis in the mammalian retina through REST.

In the developing central nervous system, including its simple and accessible model retina, neurogenesis is followed by gliogenesis. However, the mechanism underlying the neurogliogenic switch remains poorly understood despite the identification of several regulatory genes, associated with the lineage identity and transition. The mechanism may involve cross talks between regulatory genes, facilitated through microRNAs.

Lin28a regulates neurogliogenesis in mammalian retina through the Igf signaling.

In the developing central nervous system (CNS) the majority of neurons are born before the generation of glia. Emerging evidence implicates heterochronic gene, Lin28 in the temporal switch between two distinct lineages. However, the respective contributions of Lin28a and Lin28b in neurogliogenesis remain poorly understood.

Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities.

Glaucoma represents a group of multifactorial diseases with a unifying pathology of progressive retinal ganglion cell (RGC) degeneration, causing irreversible vision loss. To test the hypothesis that RGCs are intrinsically vulnerable in glaucoma, we have developed an in vitro model using the SIX6 risk allele carrying glaucoma patient-specific induced pluripotent stem cells (iPSCs) for generating functional RGCs. Here, we demonstrate that the efficiency of RGC generation by SIX6 risk allele iPSCs is significantly lower than iPSCs-derived from healthy, age- and sex-matched controls.

A Co-culture Model for Determining the Target Specificity of the Generated Retinal Ganglion Cells.

In glaucoma, the output neurons of the retina, the retinal ganglion cells (RGCs), progressively degenerate, leading to irreversible blindness (Ahram , 2015). The stem cell method to replace degenerated RGCs remains a potentially viable approach (Levin , 2004). However, the success of the approach depends upon the ability of the generated RGCs to connect over the long distance with specific targets in the central visual pathway.

Feeder & basic fibroblast growth factor-free culture of human embryonic stem cells: Role of conditioned medium from immortalized human feeders.

Background & Objectives: Human embryonic stem cell (hESC) lines are commonly maintained on inactivated feeder cells, in the medium supplemented with basic fibroblast growth factor (bFGF). However, limited availability of feeder cells in culture, and the high cost of growth factors limit their use in scalable expansion of hESC cultures for clinical application. Here, we describe an efficient and cost-effective feeder and bFGF-free culture of hESCs using conditioned medium (CM) from immortalized feeder cells.

Generation of Functional Human Retinal Ganglion Cells with Target Specificity from Pluripotent Stem Cells by Chemically Defined Recapitulation of Developmental Mechanism.

Glaucoma is a complex group of diseases wherein a selective degeneration of retinal ganglion cells (RGCs) lead to irreversible loss of vision. A comprehensive approach to glaucomatous RGC degeneration may include stem cells to functionally replace dead neurons through transplantation and understand RGCs vulnerability using a disease in a dish stem cell model. Both approaches require the directed generation of stable, functional, and target-specific RGCs from renewable sources of cells, that is, the embryonic stem cells and induced pluripotent stem cells.

Enhanced Reprogramming Efficiency and Kinetics of Induced Pluripotent Stem Cells Derived from Human Duchenne Muscular Dystrophy.

Unlabelled: The generation of disease-specific induced pluripotent stem cells (iPSCs) holds a great promise for understanding disease mechanisms and for drug screening. Recently, patient-derived iPSCs, containing identical genetic anomalies of the patient, have offered a breakthrough approach to studying Duchenne muscular dystrophy (DMD), a fatal disease caused by the mutation in the dystrophin gene. However, development of scalable and high fidelity DMD-iPSCs is hampered by low reprogramming efficiency, the addition of expensive growth factors and slow kinetics of disease-specific fibroblasts.

Continuous non-cell autonomous reprogramming to generate retinal ganglion cells for glaucomatous neuropathy.

Glaucoma, where the retinal ganglion cells (RGCs) carrying the visual signals from the retina to the visual centers in the brain are progressively lost, is the most common cause of irreversible blindness. The management approaches, whether surgical, pharmacological, or neuroprotective do not reverse the degenerative changes. The stem cell approach to replace dead RGCs is a viable option but currently faces several barriers, such as the lack of a renewable, safe, and ethical source of RGCs that are functional and could establish contacts with bona fide targets.

Cornelia de Lange syndrome: a case study.

Cornelia de Lange syndrome (CDLS) is a relatively common multiple congenital anomaly/mental retardation disorder with an unknown genetic and molecular pathogenesis. The essential features of this developmental malformation syndrome are retardation in growth, developmental delay, various structural limb abnormalities, and distinctive facial features. Most cases are sporadic and are thought to result from a new dominant mutation.