Endogenous Retinal Progenitor Cell Regeneration and Reported Retinitis Pigmentosa Therapeutics Promoting Stem Cell Neurogenesis, or Photoreceptor Differentiation


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Endogenous Retinal Progenitor Cell Regeneration and Reported Retinitis Pigmentosa Therapeutics Promoting Stem Cell Neurogenesis, or Photoreceptor Differentiation
John J. McMurtrey, M.S. Copyright 2014, revised. 4/21/2016

Introduction



Retina Progenitor Cell Populations -- A population of very small embryonic-like stem cells (0.06% @ postnatal day 28) is in the ganglion cell layer of adult mice that is quiescent, but can differentiate into ectodermal retinal cells (including photoreceptors), and mesoderm, or endoderm under stimulation by appropriate cell culture protocols. 1 Another reported adult mouse stem cell population consists of relatively rare pigmented cells in the cilliary margin that have a multipotent ability to become photoreceptors, bipolar neurons, and Muller glia cells under appropriate in vitro conditions. 2 Muller cells can have self renewal, and multipotent development along basic retinal cell lines characteristic of stem cells. 3 Muller glia have an ability to regenerate retina in teleost fish that is remarkable, while a lesser degree of retinal repair occurs chicks, but there is limited Muller cell proliferation in response to injury for mammals, 4 and any regeneration is ordinarily meager. 5 However, reports of conditions under which retinal regenerative processes can be promoted are numerous.

Injury by explant culture induces dedifferentiated Muller cells that exhibit some proliferation, which can be increased by >20 fold with the addition of 100 ng/ml Wnt3a. 6 Photoreceptor differentiation can then be induced by subsequent application of retinoic (0.3 μM), or valproic (1mM) acids. Error: Reference source not found

Retinitis Pigmentosa Progenitor Capacity -- Visual field enlargement was reported for 3 (37.5%) of 8 Retinitis Pigmentosa (RP) patients administered Nerve Growth Factor (NGF) eye drops over 10 days. 7 Nerve growth factor signaling with Muller cell trans differentiation has been reported for the transient neurogenesis following sodium iodate injury to the retina that included some photoreceptor regeneration, 8 and for retinas having transplanted rat bone marrow stem cells. 9

Injury can produce dedifferentiation of Muller cells towards progenitor cells, and Muller stem cell qualities are regulated by Wnt, and Notch signaling that governs the dominant pathway network of the developing retina. Error: Reference source not found Retinal explants from 12 postnatal day rd-1Pde RP model mice treated with 100 ng/ml Wnt3a increase cellular proliferation (indicated by BrdU labeling) that on Wnt3a withdrawal, and application of either retinoic, or valproic acids each increased the number of rhodopsin labeled cells (Valproic acid induces the NeuroD transcription factor that participates in photoreceptor differentiation by inhibiting histone deacetylases). Error: Reference source not found Muller cell dedifferentiation gene expression study in RP rd10Pde model mice included Notch signaling along with neurotrophic factors. 10 The faster degenerating RP model of the same gene but different amino acid mutation (also engineered with a reporter transgene) is the rd-1Pde Tcf-LacZ mouse, which exhibited increased Wnt signaling mainly localized to retinal Muller cells (glycogen synthetase+) of the retinal inner nuclear layer (though a few microglia cells in the outer nuclear layer had Wnt signaling) [Differential Wnt ligand activity implicated in degeneration are Wnt5a & b, Wnt10a, and Wnt13]. 11

Though Muller cells in 12 day old rd-1Pde RP model mouse retinal explants can proliferate, these explants from 21 day old rd-1Pde mice are reported to lack proliferating cells (by BrdU labelling), Error: Reference source not found even though rd-1Pde Muller cells in vivo are reported to express the nestin neural stem cell antigen, and the rhodopsin rod phototransduction protein for up to 6 months of age. 12 This is long after complete photoreceptor degeneration at two months after birth). Error: Reference source not found The transcription factor cyclic AMP Response Element Binnding protein 1 (CREB-1) is associated with nestin expression, neural progenitor cell proliferation, and relevant differentiation antigens in hippocampal neurogenesis. 13 However, active phosphorylated CREB-1 transcription factor in the rd-1Pde RP model mouse is 30% of levels in the wild type mouse, 14 while the rd10Pde mouse (another mutation of the same gene yet having slower degeneration) had decreased phosphorylated CREB that was identified to be in Muller cells, which had increased toward wild type by postnatal day 34 (when degeneration was nearly complete). 15 Adult mouse Muller cells without the degenerative mutation do not proliferate, or express either progenitor, or differentiation proteins. Error: Reference source not found Intact retinal tissue may be required for stem cell proliferation, as in the Retinal Pigment Epithelium (RPE) regenerative proliferation was only observed on undamaged epithelium. Error: Reference source not found

Intravitreal injection of RHOS334ter RP model rats with Notch and Wnt stimulators (Jag1 and Wnt3a, respectively) produced a significantly better optokinetic (visual head-neck) response that correlated to a 7.3 fold increase in dividing Muller cells identified by being glutamate synthetase+, but were presumptive photoreceptors with demonstrable opsin by immune histochemistry versus RHOS334ter controls. 16

Sonic hedgehog is a stem cell signalling pathway that promotes proliferation by relieving cell cycling inhibition on binding the membrane receptor called patched, but mutational inactivation of patched also increases cell division such that mice heterozygous for patched (ptc +/-) have a population of dividing progenitor cells (Chx10+, nestin+) at the retinal margin that is reminiscent of the ciliary margin zone of lower vertebrates 17 capable of retinal regeneration. RHOP23H RP model mice with patched (ptc +/-) heterozygosis even had a 50% greater cell division at the retinal margin than ptc +/- heterozygotes without retinal degeneration, and produced progenitor cells evidencing the photoreceptor differentiation marker recoverin. a Error: Reference source not found

Mammalian Retinal Regeneration Inhibition Factors -- Transforming Growth Factor β (TGFβ) maintains quiescence of rat progenitor and Muller cell mitosis, while TGFβ inhibitors restore cell proliferation in vitro, and in vivo. 18 TGFβ inhibits Muller cell proliferation by activation of Protein kinase C, Error: Reference source not found and by expression of P27Kip, a cyclin dependent kinase inhibitor. Error: Reference source not found ZacI is a zinc finger transcription factor that controls ectopic rod photoreceptor, and amacrine cell proliferation by causing cell cycle exit, and TGFβ2 regulated apoptosis involving activated Smad 2/3 signaling (report quantitates mainly amacrine cells). 19 TGF-α, and epidermal growth factor also inhibit rod photoreceptor differentiation, but TGFβ3 does not inhibit rods. 20 TGFβ1, TGFβ2, and TGFβ3 expression are all reported increased in the rd10Pde RP model mouse. Error: Reference source not found

RCSMerTK rat retina with transplanted human Muller stem cells had Muller cell migration inhibited by chondroitin sulfate proteoglycans secreted in part by CD68 activated microglia, but Muller stem cell migration, and integration could be increased by transplantation with chondroitinase ABC, and maximized to almost 80% migration by adding 4 immunosuppressants. 21

Circulating Mesenchymal Stem Cells Contribute to Repair/Regeneration -- Peripheral injection of 106 culture expanded bone marrow-derived mesenchymal stem cells into RCSMerTK RP model rats preserved photoreceptors, and increased optokinetic visual function with evident stem cell migration into the retina versus control rats. 22 Similar stem cell injections benefit other neurological deficit experimental models. Intravenous 3 X 106 bone marrow stromal/mesenchymal cells administered to rats one day after middle cerebral artery occlusion improved neurological recovery with the stem cells having the greatest accumulation in the brain damaged area. 23

Stromal cell-Derived Factor 1 (SDF-1/CXCL12) had observation in the rd10Pde mouse RP model, 24 and is a cytokine of the CXC chemokine family that attracts stem, as well as several types of immune cells. On massive sodium iodate retinal pigment epithelial injury in mice, bone marrow derived Green Fluorescent Protein labeled lin stem/progenitor cells began to appear in the retina when histological damage was evident and retinal SDF-1/CXCL12 chemokine was expressed, but was not detectable in the blood. 25 Cell migration towards SDF-1/CXCL12 is indicated (in mouse embryonic fibroblasts & macrophage studies) to require activation of NF-κB isoforms simultaneously by both the canonical Inhibitor of κB Kinase (IKK) β pathway (which maintains CXCR4 receptor expression), and the more inflammation resolving non-canonical IKKα pathway that is required to maintain polarity, and velocity of migration) towards a SDF-1 gradient. 26 SDF-1/CXCL12 activates IKKα, but the only other known activators of IKKα are CD40L, lymphotoxin β, and B cell activating factor (BAFF). Error: Reference source not found

Intravenous infusion of mesenchymal stem cells distributes the cells all over the body with a low rate of engraftment, so in humans at least 1 to 2 X 106 MSCs per kilogram patient body weight, or 150 to 300 million cells administered twice per week over two weeks have been used, though optimum dosage is unclear. 27 Such numbers of MSCs require in vitro culture expansion, but culture conditions alter MSC phenotype, and migratory pattern, which can degrade regenerative capacity. Error: Reference source not found Two natural products that increase CXCR4 are tanshinone IIA, and astragaloside IV, while transient hypoxia preconditioning increases CXCR4, and migratory ability through induction of hypoxia inducible factor 1α. Error: Reference source not found
rBMSC cultures produced NGF, BDNF, GDNF, CTNF, and bFGF. Error: Reference source not found

Wnt activators protect dissociated primary retinal cultures from H2O2 induced oxidative stress. Error: Reference source not found

Regeneration of the Retinal Pigment Epithelium, and Other Ocular Tissues

[The RPE participates in some lower vertebrate retinal regeneration, and provides essential functions as well as factors for photoreceptors.] Mouse ocular organ culture ablation by the diptheria toxin transgene produced by the promoter for a unique, essential Retinal Pigment Epitherium (RPE) protein (tyrosinase related protein 1) indicates that the RPE is required for neural retina development, and maintenance. 28 In culture, a population of human RPE cells can be induced to form self renewing multipotent stem cells that can differentiate along mesenchymal, osteogenic, adipogenic, chrondrogenic, and neurogenic lines. 29 Regeneration in low dose sodium iodate (15 mg/kg) mouse Retinal Pigment Epithelium (RPE) injury had report of scotopic ERG b-wave improvement at 3 months post-injury with demonstration of pigment epithelia proliferation (double staining of proliferating cell nuclear antigen with RPE65), and observation of cell proliferation only on uninjured RPE tissue. 30 Although no RPE neurotrophin expression was observed, the RPE can express all the receptors for response (TrkA, TrkB, TrkC, and p75). Error: Reference source not found

Several; three-dimensional (suspension) culture studies report the generation of optic cup-like structures reminiscent of embryology having multiple retinal tissue layers, of which the fastest most enhancing of eye cup-like structures from human ES included 5 or, 10 ng/ml of Insulin-like Growth Factor-1, and there was expression of proteins for accessory tissues such as lens, and cornea as well. 31

Progenitor Cell Signaling Pathways in Retinitis Pigmentosa Animal Models

IL-6 Family Cytokines -- Leukemia Inhibitory Factor (LIF) delays RHOVPP RP model mouse photoreceptor degeneration by upregulation of Endothelin 2 (Edn2), STAT3, FGF2, and GFAP, whereof LIF is implicated to induce Edn2 from damaged photoreceptors, which stimulates a subset of Muller cells that have low glutamine synthetase activity. 32 LIF endothelin-2 (Edn-2), and Fibroblast Growth Factor-2 (FGF2) are an upregulated pathway in the rd10Pde RP model that also had activation of Glial Fibrilliary Acidic Protein (GFAP), and JAK-STAT3 signaling with increased p-JAK2, and p-STAT3 (and elevated CCAAT/enhancer binding protein). 33 Oncostatin M protects rods and promotes the regeneration of cone outer segments with phosphorylation of STAT3 in Muller cells (but not photoreceptors), which indicates Muller cells mediate oncostatin M effects. 34 CNTF, LIF, and oncostatin M are of the IL-6 family of cytokines. Error: Reference source not found

Wnt Signaling -- Postnatal day 35 rd-1Pde retina expressed 3 fold more Dickkopf-3, 35 which is produced by Muller glia.

Dickkopf-3 potentiates Wnt 3a signaling under conditions of staurosporine promoted apoptosis through antagonizing Dickkopf-1-Kremen dependent inhibition of Wnt signalling, where Dickkopf 3 can bind both Kremen 1, or 2 in membrane vesicles that apparently eventually become peri-nuclear. 36 The Wnt signaling antagonists, Secreted Frizzled-Related Proteins (SFRP) of SFRP1 and SFRP5 are restricted to surviving photoreceptors in human RP, while SFRP1, SFRP2, SFRP3, and SFRP5 are localized to the inner limiting membrane. 37

Intercellular/Paracrine Mechanisms -- Mammalian rod photoreceptors require a critical density of other cells for differentiation. Error: Reference source not found [ . . . ] [Besides the importance of developmental signaliung pathways, and other critical influence of the extracellular matrix] Culturing retinal progenitor cells on lamin β2/S-laminin increases the number differentiating as rod photoreceptors, but soluble factors have a considerable role in photoreceptor development. Error: Reference source not found
Inflammation and Regeneration
Inflammation increases CXCR7, which influences SDF-1/CXCL12 induced chemotaxis because CXCR7 has a 10-fold greater affinity for SDF-1/CXCL12 than CXCR4, and CXCR7 has anti-apoptotosis effects without being linked to the usual chemokine G-protein mechanism of CXCR4. 38
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