tretinoin and Demyelinating-Diseases

Demyelinating disorders, with a particular focus on multiple sclerosis (MS), have a multitude of detrimental cognitive and physical effects on the patients. Current treatment options that involve substances promoting remyelination fail in the clinics due to difficulties in reaching the central nervous system (CNS). Here, the dual encapsulation of retinoic acid (RA) into lipid nanocapsules with a nominal size of 70 nm, and a low PdI of 0.1, coupled with super paramagnetic iron oxide nanoparticles (SPIONs) was accomplished, and joined by an external functionalization process with a transferrin-receptor binding peptide. This nanosystem showed a 3-fold improved internalization by endothelial cells compared to the free drug, ability to interact with oligodendrocyte progenitor cells and microglia, and improvements in the permeability through the blood-brain barrier by 5-fold. The lipid nanocapsules also induced the differentiation of oligodendrocyte progenitor cells into more mature, myelin producing oligodendrocytes, as evaluated by high-throughput image screening, by 3-5-fold. Furthermore, the ability to tame the inflammatory response was verified in lipopolysaccharide-stimulated microglia, suppressing the production of pro-inflammatory cytokines by 50-70%. Overall, the results show that this nanosystem can act in both the inflammatory microenvironment present at the CNS of affected patients, but also stimulate the differentiation of new oligodendrocytes, paving the way for a promising platform in the therapy of MS.

Topics: Animals; Cell Differentiation; Demyelinating Diseases; Endothelial Cells; Inflammation; Lipids; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Myelin Sheath; Nanocapsules; Neurodegenerative Diseases; Oligodendroglia; Tretinoin

The molecular basis of CNS myelin regeneration (remyelination) is poorly understood. We generated a comprehensive transcriptional profile of the separate stages of spontaneous remyelination that follow focal demyelination in the rat CNS and found that transcripts that encode the retinoid acid receptor RXR-γ were differentially expressed during remyelination. Cells of the oligodendrocyte lineage expressed RXR-γ in rat tissues that were undergoing remyelination and in active and remyelinated multiple sclerosis lesions. Knockdown of RXR-γ by RNA interference or RXR-specific antagonists severely inhibited oligodendrocyte differentiation in culture. In mice that lacked RXR-γ, adult oligodendrocyte precursor cells efficiently repopulated lesions after demyelination, but showed delayed differentiation into mature oligodendrocytes. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats after demyelination caused an increase in remyelinated axons. Our results indicate that RXR-γ is a positive regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination and might be a pharmacological target for regenerative therapy in the CNS.

Topics: Aged; Alitretinoin; Animals; Benzoates; Biphenyl Compounds; Cell Differentiation; Cell Lineage; Cells, Cultured; Central Nervous System; Cerebellum; Demyelinating Diseases; Female; Gene Expression Profiling; Humans; Male; Mice; Mice, Knockout; Middle Aged; Multiple Sclerosis; Myelin Sheath; Nerve Regeneration; Neurotoxins; Oligodendroglia; Rats; Rats, Sprague-Dawley; Receptors, Retinoic Acid; Retinoic Acid Receptor gamma; RNA Interference; Stem Cells; Tretinoin

Topics: Alitretinoin; Animals; Brain; Demyelinating Diseases; Drug Delivery Systems; Humans; Morphogenesis; Myelin Sheath; Nerve Fibers, Myelinated; Neuroprotective Agents; Oligodendroglia; Retinoid X Receptor gamma; Stem Cells; Tretinoin

In attempts to produce mature oligodendrocytes from human embryonic stem (huES) cells, we searched conditions inducing transcription factors Olig1/2, as well as Nkx2.2 and Sox10, which are needed for maturation. This was obtained by retinoic acid treatment followed by noggin, an antagonist of bone morphogenetic proteins (BMPs). We found that retinoic acid induces BMPs in huES cells. Addition of noggin at a specific step was essential to form numerous mature oligodendrocytes with ramified branches and producing myelin basic protein (MBP). We describe a procedure converting huES cells into enriched populations of oligodendrocyte precursors that can be expanded and passaged repeatedly and subsequently differentiated into mature cells. Transplantation of such precursors showed that pretreatment by noggin markedly stimulates their capacity to myelinate in the brain of MBP-deficient shiverer mice in organotypic cultures and in living animals. Arrays of numerous long MBP+ fibers were generated over extended areas in the brain, with evidence of cell migration after transplantation and with formation of compact myelin sheaths.

Topics: Animals; Animals, Newborn; Carrier Proteins; Cell Differentiation; Cell Line; Demyelinating Diseases; Drug Interactions; Embryonic Stem Cells; Fetus; Gene Expression Profiling; Gene Expression Regulation; Homeobox Protein Nkx-2.2; Homeodomain Proteins; Humans; Intercellular Signaling Peptides and Proteins; Mice, Neurologic Mutants; Microscopy, Electron, Transmission; Myelin Basic Protein; Nerve Tissue Proteins; Nuclear Proteins; Oligodendroglia; Organogenesis; Stem Cell Transplantation; Transcription Factors; Tretinoin