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Functional myelination of neurons

a technology of functional myelin and neurons, applied in the field of functional myelination of neurons, can solve the problems of neurological problems, particular techniques that can be effective in replacing myelin loss in humans, and reduce the speed of neural transmission or stop it altogether

Inactive Publication Date: 2016-03-03
U S GOVERNMENT REPRESENTED BY THE DEPT OF VETERANS AFFAIRS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a method for isolating melanocyte stem cells from the hair follicle of mammalian skin and converting them into CD34(+) multipotent neural crest progenitor cells that can express myelin basic protein. These cells can be used to produce a dense myelin sheath around an axon or to treat demyelination caused by various factors such as immune-mediated diseases or trauma. The isolated cells can be obtained from mammalian hair follicle bulge or lower permanent portion of the hair follicle and are at least 80% pure. The technical effect of this patent is to provide a reliable and efficient method for obtaining and manipulating melanocyte stem cells for research and potential therapeutic applications.

Problems solved by technology

This reduces the speed of neural transmission or stops it altogether.
While results with oligodendrocyte stem cell transplantation in mice have been encouraging, whether this particular technique can be effective in replacing myelin loss in humans is still unknown.
When the myelin sheath is damaged, nerve impulses slow or even stop, causing neurological problems.
Sufferers of pernicious anemia can also suffer nerve damage if the condition is not diagnosed quickly.
Subacute combined degeneration of spinal cord secondary to pernicious anemia can lead to slight peripheral nerve damage to severe damage to the central nervous system, affecting speech, balance, and cognitive awareness.
When myelin degrades, conduction of signals along the nerve can be impaired or lost, and the nerve eventually withers.

Method used

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  • Functional myelination of neurons
  • Functional myelination of neurons
  • Functional myelination of neurons

Examples

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example 1

Materials and Methods

Generation and Characterization of Dct-H2BGFPKI Bitransgenic Mouse Model.

[0111]A knock-in mouse model expressing the tetracycline-regulated transactivator (tTA) gene under the control of the murine dopachrome tautomerase (Dct) melanocyte specific promoter was used to identify MeSCs. The transgenic mouse was generated to allow a melanocyte specific tTA transactivation in vivo. The transgenic cassette expressing the tTA gene under the control of the Dct promoter was inserted in the Hprt gene. The Hprt gene is localized on the X-chromosome. This transgenic mouse was then crossed with TRE-H2BGFP mice to generate a bitransgenic mouse model. The Dct-tTA knock-in mouse was designed to drive expression of H2BGFP constitutively in bitransgenic Dct-tTA knock-in; TRE-H2BGFP mice in the absence of doxycycline. See FIG. 6A-6E for photographs providing a characterization of the Dct-TtaKIH2b-Gfp bitransgenic mouse model.

Immunofluorescence Assay

[0112]Dorsal skin obtained from t...

example 2

Identification of GFP-Expressing MPCs in Bulge / LPP and SHG of Telogen HF

[0136]To identify melanocyte label-retaining cells with the properties of melanocyte stem cells (MeSCs) in the telogen, or resting stage, murine hair follicle (HF), Dct-H2BGFP mice were developed. Dct-H2BGFP mice are bitransgenic mice with both the Dct-tTA and TRE-H2BGFP transgenes. To overcome problems with the fidelity of expression of randomly inserted Dct-tTA transgenes, instead a version of Dct-tTA mice was generated in which the transgene was inserted into the Hprt gene locus using gene targeting. By manipulating the administration of doxycycline to these mice, quiescent melanocyte label-retaining cells (LRCs) could be generated and visualized in the telogen HF. Similar to cells from the Tet-On iDct-GFP mice, Dct-H2BGFP cells were present in both the CD34-expressing bulge / LPP region of the HF and the CD34-negative, P-cadherin-expressing secondary hair germ (SHG) region at the base of the telogen HF (FIG. 1...

example 3

Isolation and Characterization of CD34(+) Vs. CD34(−)MeSCs in HF at 2nd Telogen

[0137]CD34 expression selectively by bulge / LPP Dct-H2BGFP cells provided a strategy to separate these cells from SHG Dct-H2BGFP cells to evaluate their molecular and functional properties. Single cell suspensions prepared from shaven, dorsal skin of approximately 8-week-old (P56) mice, an age when all HFs are synchronously in the telogen stage, were incubated with anti-CD34 antibody and prepared (FIG. 2A) for fluorescence-activated cell sorting (FACS). Dct-H2BGFP cells could be separated into distinct CD34(+) and CD34(−) populations using FACS.

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Abstract

Hair follicle bulge region / LLP region CD34(+) MeSCs can be isolated from mammalian skin bearing hair follicles. These cells are multipotent and retain the ability to differentiate into cells of neural crest lineage, including glia-like cells that express the glial marker Gfap, and are able to express myelin basic protein, and to remyelinate naked (unmyelinated or demyelinated) neuronal processes with a functional, dense myelin sheath. These cells of neural crest lineage can be used to produce a dense myelin sheath on neurons which lack myelin due to genetic defect, trauma, toxin, infection, or disease process. Therefore, embodiments of the invention provide methods for preparing such cells, the cells themselves and compositions containing the cells, as well as methods for using the cells.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of provisional application 62 / 042,975, entitled “Functional Myelination of Neurons with Melanocyte Stem Cells,” filed Aug. 28, 2014, the entire contents of which are incorporated herein.STATEMENT OF GOVERNMENT INTEREST[0002]This invention was made with government support under Grant Number AR064810 awarded by the National Institutes of Health and under Project Number 1-I01BX002582 awarded by the United States Department of Veteran Affairs. The government has certain rights in the invention.BACKGROUND[0003]Destruction of the myelin sheath is a common theme in a wide range of neurological disorders, but the underlying causes are many fold. Demyelination may be immune-mediated, auto-antibody mediated, or caused by a demyelinating disease, trauma, toxins, bacterial infection, parasitic infection, viral infection, or genetic defect and can cause demyelination of neurites. This reduces the speed of neural tra...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12N5/0797
CPCC12N2506/091C12N5/0623A61K35/36C12N5/0622C12N5/0626C12N2501/115C12N2501/125C12N2501/33C12N2501/365C12N2501/86C12N2502/081
Inventor HORNYAK, THOMASJOSHI, SANDEEP
Owner U S GOVERNMENT REPRESENTED BY THE DEPT OF VETERANS AFFAIRS
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